Introduction

Prostate cancer (PCa) is the most common malignancy and the second most common cause of cancer-related deaths affecting men in developed countries.1 PCa incidence has risen over the recent decades. Factors responsible for this rise include aging population, obesity due to western dietary habits, and increasing use of prostate-specific antigen (PSA) testing.2 Prostate cells, normal or cancerous, are dependent upon androgens for survival and growth. Consequently, androgen deprivation therapy (ADT) (also called hormone therapy by some clinicians) is still the mainstay of PCa treatment. Surgical (bilateral orchiectomy) or chemical (pharmaceutical) interventions resulting in the reduction of serum testosterone or blockade of the androgen receptor, are referred to as ADT. Antiandrogens alone like flutamide, enzalutamide, and apalutamide (the modern derivatives) are not considered ADT but are used in combination with surgical or chemical castration. ADT was initially achieved by orchiectomy as the testes are the principal source of circulating androgens (producing nearly 95% of total); the remaining 5% are produced by the adrenal glands. Luteinizing hormone-releasing hormone (LHRH) agonists are the most widely used contemporary ADT modality usually offered when patients are diagnosed either with recurrent cancer after first-line treatment (such as radical prostatectomy or radiation treatment) for local disease or with advanced (incurable) disease at presentation.3 This review provides for the practicing clinician and medical provider not only a systemic overview on the evolution and the oncologic dynamics in patients undergoing traditional ADT, but also the clinical aspects and indications for the emerging new pharmaceutical ADT modalities.

The HypothalamicPituitaryGonadal axis functions as a single system or entity due to direct interaction and feedback (Figure 1). Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is secreted from the hypothalamus by GnRH-expressing neurons and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the anterior portion of the pituitary gland which then stimulates the gonads for producing estrogen and testosterone. The therapeutic principle of Androgen Deprivation Therapy (ADT) in prostate cancer (PCa) has been established and not changed much over the last 80 years since Charles B. Huggins demonstrated the testosterone dependency of PCa.4 Huggins and Hodges first reported the dramatic clinical effects of suppressing serum testosterone levels (Figure 2) in men with advanced prostate cancer in 1941.5 Following bilateral orchiectomy of eight subjects with prostate cancer, serum acid phosphate levels decreased indicating decreased activity of the cancer. Five subjects with prostate cancer injected with stilbestrol also showed decreased serum levels of acid phosphatase while three subjects injected with testosterone propionate had an increase in serum acid phosphatase levels. For this pioneering work in treatment of advanced and metastatic prostate cancer Huggins was awarded the Nobel Prize for Medicine in 1966.

Figure 1 The hypothalamus-pituitary-testicular axis.

Figure 2 Molecule structure of testosterone.

In 1938 diethylstilbestrol (DES, Figure 3) also known as stilbestrol or stilboestrol, was discovered and then introduced for medical use in 1939.6 DES is an estrogen and it suppresses luteinizing hormone-releasing hormone (LHRH) (Figure 4) production at the level of the hypothalamus. In the past, it was widely used for a variety of indications, including treatment of metastatic prostate cancer (chemical castration) and hormonal support during pregnancy for women with recurrent miscarriage. DES has excellent bioavailability and is well tolerated when taken by mouth.7

Figure 3 Molecule structure of diethylstilbestrol (DES).

Figure 4 Molecule structure of luteinizing hormone-releasing hormone (LHRH).

In 1959 the Veterans Administrative Cooperative Urological Research Group (VACURG) was established which further evolved ADT in the treatment of advanced prostate cancer. The VACURG used prospective randomized clinical trials for investigating the role of monotherapy of estrogen versus combined therapy of orchiectomy plus estrogen in advanced prostate cancer patients.8 The major conclusions were: 1.) A daily dose of 3 mg DES was considered the optimal dose and became the accepted regimen for pharmacologic castration. 2.) A lower DES dose (1 mg) was associated with reduced cardiovascular toxicity but did not reliably achieve castrate levels of testosterone. 3.) No survival advantage of early versus delayed initiation of hormonal therapy in advanced disease. Up to the 1970s DES as hormonal therapy was widely accepted as the treatment for advanced and metastatic prostate cancer. However, its main adverse effects were increased risks of blood clots and cardiovascular events.9

Furthermore, reports in the 1970s revealed that DES caused clear-cell carcinoma of the vagina, a rare tumor in girls and women who had been exposed to this medication in utero. Due to these discoveries and the significant cardiovascular side effects DES essentially disappeared from the pharmaceutical market.10

Both surgical and pharmacologic castration resulted in dramatic palliation of painful bony metastatic lesions, and improved quality of life in prostate cancer patients. In 1971 Schally and associates purified the decapeptide gonadotropin-releasing hormone (LHRH).9 Studies showed that constant exposure to LHRH ultimately suppressed testosterone serum levels by desensitizing pituitary cells through downregulation of the LHRH receptors.11 Modification of the sixth amino acid position of the LHRH molecule was significantly more potent.12 The monthly depot of leuprolide (Figure 5) was the first LHRH agonist granted FDA approval for advanced prostate cancer. In a randomized clinical trial, leuprolide was equivalent to 3 mg of DES in reducing serum testosterone to castrate levels, but with much lower cardiovascular toxicity.13 Ultimately in the 1980s Leuprolide replaced DES and orchiectomy as the preferred approach to androgen deprivation.

Figure 5 Molecule structure of leuprolide.

Over the following decades substitutions at the sixth amino acid position yielded a variety of more LHRH agonists (goserelin, triptorelin, and histrelin), which then also became commercially available in the United States. These LHRH agonists are differentiated by their route of administration (intramuscular injection vs subcutaneous injection vs subcutaneous implant) and frequency of administration (112 months). All these LHRH agonists have similar therapeutic effectiveness in lowering serum testosterone to castrate levels, but also have a similar profile of adverse effects. One study directly compared different LHRH agonists.14 Overall improved survival with triptorelin compared with leuprolide, 97% vs 90.5% at 9 months (P = 0.033). Although not statistically significant, triptorelin seemed to better maintain castrate levels of testosterone over a 9-month interval.

The luteinizing hormone-releasing hormone (LHRH) agonists offered true medical castration but showed clinical issues due to testosterone surge and tumor flare when first administered. The flare phenomenon is attributed to the surge of serum testosterone levels caused by the initial stimulation of LHRH receptors. The introduction of antiandrogens was considered to ease this clinical issue by inhibiting the stimulation effect at the level of the androgen receptor.15 Despite initial expectations, the combined medical therapy of antiandrogens and LHRH agonists did not improve cancer-specific survival. The costs, inconvenience of therapy, added toxicity, and the introduction of the saturation model were considered the main reasons why the combined treatment never became standard of care. A 2017 literature review concluded that there is no evidence of testosterone flare following initiation of an LHRH agonist.16 It was proposed that this is due to the limited ability of androgens to stimulate prostate growthalso known as the saturation model.16 The saturation model, introduced in 2009, showed tumor growth increased when exposed to low levels of androgen, however after reaching a certain threshold, androgens no longer affected tumor growth. In the current literature there is still an ongoing and controversial debate on the validity of this saturation model.17

The introduction of Gonadotropin-releasing hormone (GnRH) antagonists offered a solution for the above mentioned flare phenomenon. This new drug class proved a rapid reduction of serum testosterone to castrate level without the initial testosterone surge and tumor flare. However, the long-term clinical benefits are still debated. A recent meta-analysis study comparing GnRH agonists and antagonists in patients with metastatic prostate cancer, showed that GnRH antagonist use was associated with a lower risk for all-cause mortality and cardiovascular events, respectively. However, this study did not find any significant differences between groups in PSA progression, musculoskeletal events, fractures or serious adverse events such as hepatic failure.18

In summary, ADT has come a long way since its introducing by Huggins for treatment of advanced and metastatic prostate cancer 80 years ago. Whereas surgical ADT via orchiectomy has become obsolete, medical ADT plays still a main role in the repertoire of treatment options for patients with recurrent, progressive and advanced prostate cancer.

LHRH/GnRH agonists, such as leuprorelin/leuprolide, goserelin, and triptorelin, are by far the most commonly utilized forms of ADT in clinical practice in the treatment of PCa, targeting the LHRH/GnRH receptor in the anterior pituitary gland and administered as an intramuscular or subcutaneous injection. They stimulate the receptor, creating a temporary surge in LH and testosterone levels followed by downregulation of the receptor over the next 23 weeks with a subsequent reduction in LH and suppression of testosterone production by the testes.19 They achieve serum testosterone levels below castration (<50 ng/dL) within 46 weeks with a subsequent reduction in the PSA level.20 The most common adverse effects (AE) associated with treatment are hot flashes, fatigue, sexual/erectile dysfunction, testicular atrophy, cognitive decline, increased risk of diabetes and cardiovascular events, and decreased bone mineral density associated with joint disorders and/or osteoporosis that needs to be monitored periodically with bone density scanning.21

LHRH/GnRH antagonists, such as degarelix, abarelix, and relugolix, are newer agents that competitively bind to the LHRH/GnRH receptor, inhibiting downstream LH signaling and suppressing testosterone secretion from the testes. LHRH/GnRH antagonists are not associated with an initial surge of serum testosterone, and castration levels are achieved within 23 days, so they are a good therapeutic option for the initiation of ADT in a newly diagnosed PCa patient.22 While degarelix is only available as a 1-month subcutaneous dose with a higher risk of adverse skin reactions, relugolix is a daily oral agent, although a food effect can reduce exposure by 50%.23 The side effect profile of LHRH/GnRH antagonists is similar to that of LHRH/GnRH agonists although since degarelix reduces FSH more than the LHRH/GnRH agonists (90 vs 50%), these lower levels of FSH may be cardioprotective, especially in men with preexisting cardiovascular disease, and may produce less muscle mass loss.24

Antiandrogens, such as bicalutamide, flutamide, and nilutamide, are some of the oldest drugs that inhibit binding of dihydrotestosterone (DHT) to the androgen receptor (AR).25 Since they do not reduce serum levels of testosterone, they can be considered as monotherapy in nonmetastatic patients who want to preserve libido and avoid the metabolic and sexual side effects of traditional ADT.26 They are, however, less effective than surgical castration or LHRH agonists/antagonists in metastatic prostate cancer (PCa) and are typically utilized concurrently with these agents for dual androgen blockade, especially during initiation of treatment with LHRH agonists to prevent clinical manifestations of testosterone surge within the first month.27 Table 1 summarizes single use versus combined use of ADT drugs and antiandrogens.

Table 1 List of ADT Drugs and Antiandrogens That Can Be Used in Combination

After long-term testosterone suppression, reactivation of AR pathways in some cell populations occur from multiple mechanisms including production of androgens by the adrenal glands and PCa cells themselves, androgen-independent activation of the AR, and AR gene amplification or overexpression.28 In this state, elimination of testosterone production from the testes is no longer sufficient to fully suppress PCa tumor cell growth, and another generation of antiandrogens is available for further testosterone suppression typically below 20 ng/dL.29

Abiraterone (in combination with traditional ADT) reduces androgen production from all sources including the testes, adrenal glands, and PCa cells through selective and irreversible inhibition of the enzyme 17-hydroxylase/C17,20-lyase (CYP17), which can suppress testosterone levels even lower than with traditional LHRH/GnRH agonists alone. In the LATITUDE and STAMPEDE study, the addition of abiraterone acetate and prednisone to standard ADT significantly increased overall survival (OS) and radiographic progression-free survival (PFS) in men with newly diagnosed, metastatic, castration-sensitive PCa.30,31 In the LATITUDE study, OS was significantly longer in the abiraterone acetate plus prednisone group compared to the placebo group (median OS: 53.3 vs 36.5 months) when administered in combination with standard ADT.32 In a meta-analysis of both studies, abiraterone plus prednisone with standard ADT resulted in a 38% risk reduction of death compared to placebo with standard ADT for metastatic hormone-sensitive PCa.33 In addition to the expected AEs associated with testosterone suppression, abiraterone may also produce side effects associated with mineralocorticoid toxicity (ie, hypertension, hypokalemia, and fluid retention) and liver function abnormalities.34 Those patients with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia need to be monitored more closely while on treatment.

Enzalutamide, another third-generation antiandrogen, competitively binds to the AR at the androgen-binding site, inhibiting nuclear translocation and interaction of the AR with chromosomal DNA, which prevents further transcription of tumor-associated Androgen genes. This prevention of AR-dependent transcription causes decreased cell proliferation and induces cell death. Enzalutamide blocks the action of testosterone at the cellular level regardless of where it is derived from and, in conjunction with traditional ADT, can be utilized for newly diagnosed, metastatic, castration-sensitive PCa.35 In the ENZAMET trial, enzalutamide with traditional ADT was associated with significantly longer PFS and OS compared to traditional ADT alone in men with metastatic, hormone-sensitive PCa (3-year OS: 80 vs 72%).36 In addition to the commonly expected AEs for an AR inhibitor, seizures and posterior reversible encephalopathy syndrome have also been seen on rare occasions, likely due to the drug crossing the bloodbrain barrier.37 Seizure occurred in 0.4% of patients receiving treatment, but in patients with predisposing factors, seizures were reported in 2.2% of patients.

Apalutamide, another oral, nonsteroidal third-generation antiandrogen that blocks the action of testosterone by blocking the ligand-binding domain of the AR, was also designed to supersede the current androgen pathway inhibitors by overcoming AR-related resistance mechanisms. Like enzalutamide, it blocks androgen-receptor nuclear translocation, inhibits DNA binding, and obstructs AR-mediated transcription. In patients with non-metastatic, castrate-resistant PCa, according to the SPARTAN trial, metastasis-free survival (MFS) and time to symptomatic progression were significantly longer with apalutamide compared with placebo in combination with standard ADT (median MFS was 40.5 months in the apalutamide group versus 16.2 months in the placebo group).38 At median 52-month follow-up, median OS was markedly longer with apalutamide than placebo (73.9 vs 59.9 months).39 In the TITAN trial of patients with metastatic, castration-sensitive PCa, OS and PFS were significantly longer with the addition of apalutamide to standard ADT compared with placebo (OS at 24 months was 82.4% in the apalutamide group versus 73.5% in the placebo group).40 The most common adverse reactions with apalutamide were fatigue, hypertension, rash, and diarrhea.

The second and third generation antiandrogen drugs typically cost more than first-generation ADT drugs such as leuprolide or antiandrogens (bicalutamide) because they are not generic and usually patent-protected.

Surgical removal of both testicles (bilateral orchiectomy) remains a viable option as an alternative to chemical castration to eliminate testicular production of testosterone. Surgical castration may be associated with significantly lower risks of peripheral arterial disease and cardiac-related complications compared to chemical castration.41 Chemical castration, however, has largely replaced bilateral orchiectomy in clinical practice in the treatment of PCa because of the ease of administration, reversibility, and the avoidance of disfiguring surgery with its associated aesthetic and psychological consequences for patients.

ADT is a mainstay second-line treatment of prostate cancer once primary curative treatment, such as radiotherapy or radical prostatectomy, has failed. ADT blocks the HPG axis (for details see chapter 1), upon which testosterone production depends this in turn starves androgen-dependent elements of a tumor. However, patients response to ADT is not uniform. Klotz et al 2015 performed a secondary analysis on data from the PR-7 trial, which had examined intermittent vs continuous ADT. They first excluded all patients who underwent intermittent ADT, then stratified the remaining men into three groups based on their nadir testosterone levels: a) <20ng/dL, b) 2050ng/dL, and c) >50ng/dL. They found that men who reached a nadir level of 2050ng/dL and >50ng/dL were at hazard ratios of 1.62 (95% CI 1.202.18) and 1.90 (95% CI 0.984.70) of developing castrate resistant prostate cancer compared to men who had reached a nadir below 20ng/dL (P<0.015). The same group of researchers also found that the median time to development of CRPC for the three subgroups (<20ng/dL, 2050ng/dL, and >50ng/dL) were 10.0, 7.21, and 3.62 years respectively.42 Morote et al 2007 studied patients with non-metastatic disease who were on ADT either as a primary treatment, or as an adjuvant treatment after radical prostatectomy. They showed that men who had testosterone levels above 50ng/dL after reaching their nadir were at higher risk for androgen-independent progression (defined as 3 consecutive rising PSA levels) (HR 2.8, 95% CI 1.35.9, P<0.008).43

It is a common clinical experience that patients on ADT will develop CRPC at some point in the future, even with low, castrate serum levels of testosterone. Montgomery et al 2008 demonstrated that testosterone levels within the tumor tissue of anorchid men had elevated intra-tumoral testosterone levels (0.74 ng/gm, 95% CI 0.590.89) when compared to tumor tissue samples from untreated eugonadal men (0.23ng/gm, 95% CI 0.030.44, P<0.0001). In addition, tumor tissue from anorchid men also had significantly increased levels of steroidogenic enzymes. The authors concluded that prostate tumors are capable of sustaining themselves through autocrine/paracrine signaling and endogenous androgen production, even when blocking the HPG axis with ADT.44

Adrenal androgens are another source of androgens missed by the central blockade of LHRH. Brendler 1973 reviewed cases of adrenalectomy and hypophysectomy in reactivated prostate cancer after failing castration therapy (nowadays we would call this CRPC). Symptomatic improvement in the adrenalectomy group was 65%, with a similar rate for hypophysectomy patients.45 However, these improvements were short lived, as the prostate cancer in these patients would apparently adapt to a more androgen poor environment. In 1983, Labrie et al revisited the clinical idea of total androgen blockade when studying 87 men with metastatic prostate cancer, some of whom had received previous hormonal therapy and some not. All patients were treated with LHRH and RU-23908, an AR blocker. The results showed that serum prostatic acid phosphatase (PAP) dropped to normal levels in 97% of patients who had not previously received hormonal treatment and had an elevated PAP prior. They also noted positive objective radiologic responses in 100% of treatment-nave patients, with several patients experiencing a complete disappearance of all bone lesions on imaging. They also noted that patients with previous systemic estrogen therapy showed a 55% response with PAP drop and an 80% response on bone imaging, respectively. The authors also found that men who had previously undergone hormonal therapy had a fast diminishing response to total androgen blockade, and they concluded that this clinical phenomenon was likely due to a selection process of tumor cell clones less dependent on systemic testosterone support.46 In 1991, Labrie et al published results of a prospective study based on a similar regimen as described earlier by substituting flumatide for RU-23908. They found that 93% of patients had a positive objective response, with 30% of patients experiencing objective regression of all bone lesions.47 In 1997, Ansari et al conducted a trial in which 100 men with metastatic castrate sensitive prostate cancer were randomized into either orchiectomy alone or orchiectomy plus flutamide. The results showed no significant difference in overall survival at 3 years, with orchiectomy alone at 45.83% and orchiectomy plus flutamide at 48.07%. This pattern held to the 5 year follow-up, with orchiectomy and orchiectomy plus flutamide at 20.83% and 23.07%, respectively.48

The next step forward came with abiraterone, a CPY17 inhibitor. It was first described in 1994 by Barrie et al as one of several novel compounds found to inhibit 17-hydroxylase/C17,20 lyase. When testing several of these compounds on mice, there were significant reductions in the weight of the prostate (50%), seminal vesicles (75%), and testes (25%) (P<0.01 for all).49 The first human trial was done by ODonnell et al in 2004. They tested different doses of abiraterone in men with advanced CRPC who were either still receiving or had received ADT. They found significant reductions in serum testosterone levels in all patients, with no grade III adverse events.50 In 2008, Attard et al performed a Phase I clinical trial of 21 patients who had known mCRPC. They found that 66% of patients experienced a reduction of PSA by 30% or more. In addition, serum testosterone became undetectable in all patients within 8 days of their first dose, and 8/11 patients who had required analgesics at baseline had reduced analgesic requirements after receiving abiraterone.51 There was a further improved response rate reported by Tran et al in 2009 in a phase I/II trial for enzalutamide: 43% of patients had a sustained reduction in PSA by 50% or more.52

The idea of maximum androgen blockade has been a goal for men with metastatic prostate cancer for decades. As mentioned earlier, Brendler described some positive therapeutic results in both patients who had undergone hypophysectomy to inhibit ACTH and thereby adrenal androgens, and in patients who had undergone adrenalectomy for the same reason. However, this success typically came at a high cost. The next step forward on maximum androgen blockade came with Labrie in 1983, when he described the use of both LHRH and a first-generation AR blocker. His results in CRPC were impressive, with many patients experiencing both objective responses on imaging as well as symptomatic relief. Newer anti-androgen pharmaceuticals like abiraterone and enzalutamide have shown impressive objective response rates in prospective and randomized FDA trials, and have evolved to be part of the updated AUA guidelines in the treatment repertoire for asymptomatic and symptomatic mCRPC.

The timing of androgen deprivation therapy (ADT) in the management of recurrent and advanced prostate cancer has been controversial for many years. This is mainly due to a lack of adequate randomized clinical trials comparing early vs delayed ADT in patients with recurrent PSA following failure of local curative treatment. To date the available studies and current guidelines are stating that early use of ADT to be only beneficial in symptomatic patients with recurrent or metastatic disease. The EAU recommends ADT only in symptomatic patients requiring palliative treatment.53 In the following we summarize the current practice guidelines on timing of ADT in patients with recurrent prostate cancer after failing local curative treatment.

Messing et al performed one of the first landmark studies addressing the timing of androgen deprivation therapy (ADT) and its effect on survival in patients with node positive prostate cancer following radical prostatectomy and pelvic lymphadenectomy. This randomized controlled trial enrolled 100 patients between 1988 and 1993 who had previously undergone surgery and had histologically proven nodal metastasis. The patients were randomly assigned to receive either immediate ADT or active surveillance with ADT intervention only given on proven symptomatic recurrences or detection of distant metastasis. This study revealed superiority of immediate ADT compared to delayed ADT: Significantly improved overall survival (hazard ratio 1.84 [95% CI 1.013.35], p=0.04), disease specific survival (4.09 [1.769.49], p=0.0004) and progression free survival (3.42 [1.965.98], p<0.0001). The main points of criticism for this study were the low number of recruited patients and that this study did not involve patients with high-risk local disease without node involvement leading to uncertainty of optimal ADT timing for this category of patients.54 Additionally, this debate emphasized the need for further clinical research on optimal ADT timing in patients with PSA recurrence following local curative treatment.

The EAU/ESTRO/SIOG guidelines for localized prostate cancer state that routine use of ADT should be avoided in nonmetastatic patients with the exception for symptom control. This clinical recommendation is based on the EORTC Trial 30,891 which compared immediate versus deferred ADT in T0-4 N0-2 M0 prostate cancer patients unsuitable for local curative treatment. While this trial did not address PSA recurrence following local curative intervention (i.e RP vs RT), it did, however, provide evidence for the benefit of immediate ADT in patients at increased risk of cancer-specific mortality. This study included patients with high baseline PSA (>50ng/mL) and/or a PSA Doubling Time <12 months. The authors stated that patients not meeting these high-risk inclusion criteria were indeed more likely to die of other causes unrelated to prostate cancer.55

Similar to the European guidelines, the AUA/ASTRO/SUO guidelines do also not recommend early initiation of ADT without proven metastatic disease in patients who have failed maximal local therapy.56 This recommendation is mainly based on the observational study by Garcia-Albeniz et al in 2006 where eligible patients had previously been recruited for the Cancer of the Prostate Strategic Urologic Research Endeavour (CaPSURE). These patients had failed prior local curative treatment and had been treated either with immediate or deferred ADT. The study revealed no survival benefits for immediate ADT vs deferred ADT initiation in patients with recurrent PSA. The adjusted mortality hazard ratio for immediate versus deferred ADT was 0.91 (95% confidence interval (CI), 0.521.60), which would be translated into a similar 5-year survival (difference between groups: 2.0% (95% CI: 10.0 to 5.9%). This suggests that in the absence of randomized control studies early ADT initiation does not provide a major survival benefit compared to deferred ADT therapy.57

Van den Bergh and colleagues performed a systematic literature review to assess the effectiveness of ADT in patients with PSA recurrence following local curative treatment. This meta-analysis found that the benefit of early/immediate ADT for nonmetastatic prostate cancer recurrence remains unproven. The conclusion was that early ADT should be reserved for patients with the highest risk of progression based on PSADT or Gleason Score, but having a long life expectancy. This falls in line with the current standard of care recommendations of the EAU/ESTRO/SIOG and AUA/ASTRO/SUO.58

Overall, currently there is a lack of randomized controlled trials (RCT) assessing the impact of early compared to delayed ADT in the management of recurrent prostate cancer following local curative therapy, which has led to the continued controversial debate on this subject. To date no RCT has addressed or shown the benefit of specific ADT timing in patients with recurrent PSA. Bruchovsky and colleagues proposed the idea of Intermittent Androgen Deprivation Therapy as a means to reduce side effects and improve quality of life. However, further research is needed for clarification of the optimal timing of reexposure of prostate cancer cells to androgens and its impact on delaying androgen resistance, which may also be influenced by early or delayed ADT.59 This situation has led to the clinical practice that early ADT is provided only to symptomatic patients in particular when weighing the long-term risks associated with ADT. Unfortunately, due to the lack of adequate RCTs we still are waiting for clear answers regarding the oncological benefits of early vs delayed ADT in asymptomatic patients with recurrent or advanced prostate cancer.53

Since the 1940s, androgen deprivation therapy (ADT) has been the foundational treatment for prostate cancer. Bilateral orchiectomy, the original form of ADT, is still used worldwide, in particular in the developing world. Medical ADT options are the standard of care when available. It is well documented in the literature that ADT is associated with numerous significant adverse effects which include hot flashes, loss of libido, erectile dysfunction, loss of muscle mass and strength, fatigue, anemia, breast enlargement and tenderness, mood swings, osteoporosis and bone fractures, obesity, cardiovascular disease, insulin resistance and diabetes. Some studies also see ADT associated with cognitive decline and dementia (for details see Chapter 9 of this review).

Intermittent androgen deprivation therapy (iADT) is a cyclic therapy with cessation of ADT (also called treatment holidays by some clinicians) allowing serum androgen recovery. The clinical idea is based on animal studies showing that iADT delayed tumor progression.60 Furthermore, the rationale for iADT is based on balancing drug-related toxicity and oncologic benefits. As continuous ADT (cADT) is associated with substantial side effects, which may increase with duration of therapy, many clinicians consider iADT as an alternative providing reduced morbidity, and thus improved quality of life, with the possible oncological benefit of delaying castration-resistant PCa.

The PR-7 trial, a landmark study, randomized patients for iADT and cADT with biochemical recurrence after either failing primary local treatment or salvage external radiotherapy.61 Eligible patients had PSA levels 3 ng/mL and no evidence for metastatic disease. The overall survival in patients that underwent iADT was 8.8 years compared to 9.1 years in patients that underwent cADT (HR=1.02, 95% CI= 0.861.21) indicating no significant difference. Furthermore, this study showed a non-inferiority P-value of 0.009 for iADT in overall survival. The study also revealed that other causes of death unrelated to PCa were more common in those receiving cADT, leading to the conclusion that intermittent therapy may not only reduce drug-related morbidity, but even mortality associated with cADT toxicity. Furthermore, patients with high-grade disease showed no improved overall cancer-specific survival when receiving cADT.

The ICELAND study published in 2016 is considered one of the main studies on iADT vs cADT in patients with relapsing prostate cancer.62 This prospective study included 102 different locations in 20 European countries and followed more than 700 participants randomized either to iADT or cADT. The authors found no difference in overall survival between the two groups, and they also emphasized the obvious reduced drug cost benefit of iADT over cADT.

The SWOG trial initiated by Dr. Hussain enrolled patients with metastatic, hormone-sensitive disease.63 All patients received an initial 7-month induction course of ADT. Patients with responding PSA levels 4 ng/mL were subsequently randomized to iADT or cADT (770 to iADT and 765 to cADT). The Kaplan-Meier curves were very similar, the hazard ratio was 1.10 with a confidence interval of 0.99 to 1.23. The pre-specified upper boundary of the confidence interval for non-inferiority was 1.20. Therefore, neither superiority nor non-inferiority could be concluded. However, the study data showed improved quality of life outcomes in the iADT arm: Better erectile function, improved bone density, less ischemic and thrombotic events.

A meta-analysis of seven studies with a total of 4810 patients treated with iADT or cADT between the years 2009 and 2015 showed no significant difference regarding cardiovascular events (risk ratio (RR): 0.95; confidence interval (CI) 95%=0.831.08) and thromboembolic events (RR: 1.05; CI 95%=0.851.30). However, iADT was associated with lower cardiovascular-related mortality.64

Another meta-analysis of randomized controlled trials (RCTs) assessed the risks of disease progression, all-cause, and cancer-specific mortality.65 Eight RCTs with 4664 patients were included in this report. It did not find any statistical difference in overall mortality and cancer-specific mortality between iADT and cADT. Again, the authors observed a better quality of life outcome for iADT, and therefore, they concluded that patients should be informed of the potential benefits of iADT.

Dason et al found that iADT was non-inferior to cADT in the primary setting of biochemical recurrence after radiation treatment of non-metastatic local prostate cancer. In the metastatic prostate cancer setting, iADT was also found to be non-inferior to cADT. Additionally, the authors reported that many ADT-related symptoms improved or resolved during the off-cycle with iADT.66

The results of a retrospective Japanese study on PSA recurrence after radical prostatectomy supported the hypothesis that iADT may delay castration-resistance in PCa.67 The iADT group had a significantly higher 5-year non-recurrence rate (92.9% vs 57.9%, p <0.001) and a better 10-year overall survival rate (95.9% vs 84.3%, p = 0.47) than the cADT group.

When summarizing the presented and pooled data, iADT provides better quality of life, whereas cancer-specific mortality shows interchangeable findings for iADT and cADT. Some studies even show improved overall survival for iADT patients likely due to reduced medication-related toxicity. Significantly reduced drug costs are also a strong rationale for iADT. Over more than one decade, iADT has evolved as the first option for patients after failing first-line local treatment in the absence of extensive metastatic disease. Although there are no well-defined recommendations or guidelines, the AUA/ASTRO/SUO website makes the following statement:

if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. (Conditional Recommendation; Evidence Level: Grade B)68

iADT may be considered after at least 912 months of ADT or until PSA nadir has been reached (in an ideal clinical scenario with PSA < 0.1 ng/mL). The off-treatment period varies depending on PSA monitoring and PSA rising, but also on patients and physicians preference. Again, there are no well-defined recommendations or guidelines at what PSA threshold ADT should be resumed. Some clinicians restart ADT when PSA doubling time (PSADT) is less than 6 months or when serum PSA has reached a level of 610 ng/mL. Some clinicians and medical providers set this threshold even far above 10 ng/mL.

Radiation Therapy (RT) and its part in prostate cancer (PCa) management has continued to evolve as this Technology has improved over time, and research has led to a better understanding of the oncologic disease dynamics. Radiation therapy for prostate cancer consists of targeted energy beams such as External Beam Radiation Therapy (EBRT) or implantable radioactive seeds such as Brachytherapy, which destroy and thus eliminate neoplastic cells. While there are diverse subcategories of radiation-based therapies (such as Intensity Modulated Radiation Therapy, Proton Beam Therapy, and Low/High Dose Rate Implants), the risk and benefits of each as well as other factors such as the patients preference ultimately guide the decision of the selected type of therapy. There are varying degrees of early and late mainly gastrointestinal and genitourinary complications caused by RT which underscore the need for shared decision making between treating physicians and PCa patients.56,69

The current AUA/ASTRO/SUO guidelines for management of advanced prostate cancer recommend primary radiotherapy in combination with ADT as a treatment option for selected patients with hormone sensitive prostate cancer and low volume metastatic disease (mHSPC). This is only a conditional recommendation with Grade C (low) level evidence and is mainly based on two preliminary Phase III trials (HORRAD and STAMPEDE Arm H) showing some benefit of combined therapy in these patients.56 These studies are still ongoing and may provide additional information to guide clinical practice in the upcoming years.

However, the AUA/ASTRO/SUO do not recommend combined therapy on localized, low risk prostate cancer except for the management of prostatic size reduction in selected patients undergoing brachytherapy.69 This recommendation stems from the randomized, phase III trial by Jones et al in 1979 which failed to show any overall survival benefit in low risk prostate cancer patients receiving EBRT with ADT vs EBRT alone; the 10-year overall survival was 64% to 67% (hazard ratio, 1.07; 95% CI, 0.83 to 1.39). In this trial the greatest clinical benefit of combined therapy was seen in the intermediate prostate cancer group: overall survival improved from 54% to 61% (hazard ratio, 1.23; 95% CI, 1.02 to 1.49).70

In the HORRAD trial prostate cancer patients with bone metastasis showed no overall survival benefit with the combination of ADT and Radiation Therapy. This study was a multi-Center randomized controlled trial on primary metastatic prostate cancer (20042014), and 432 patients were randomized to ADT with Radiation Therapy vs ADT alone. The median survival was not statistically different: 45 months (95% confidence interval [CI], 40.449.6) in the ADT plus radiation therapy group, and 43 months (95% CI: 32.653.4) in the control group (p=0.4). The overall survival was also not found different (hazard ratio [HR]: 0.90; 95% CI: 0.701.14; p=0.4).71

In the STAMPEDE phase III trial (Arm H) more than 2000 patients with metastatic prostate cancer on lifelong ADT were randomized to receiving additional radiation therapy. Radiation Therapy did improve failure-free survival (HR 0.76, 95% CI 0.680.84; p<0.0001), but not overall survival (0.92, 0.801.06; p=0.266). However, radiation therapy showed a trend to improve overall survival in those patients with low metastatic burden (73% vs 81% at 3 years).72

Shipley et al performed the landmark trial on the benefits of combining ADT and Salvage Radiation Therapy for post prostatectomy patients with persistent/recurrent PSA. These patients had either pT2 disease with positive surgical margins or pT3 disease without nodal involvement. This double blind, placebo-controlled trial recruited 760 eligible patients between 1998 and 2003 who underwent 24 months of ADT (Bicalumatide) in addition to salvage radiation therapy. This study showed in the ADT plus radiation arm significant higher rates in overall survival, but also decreased incidence of metastasis and cancer-related deaths compared to radiation therapy alone.73

The clinical trial done by Warde et al confirmed the unequivocal benefits of combining ADT and Radiation therapy in the management of nonmetastatic, locally advanced high-risk prostate cancer. This randomized, phase III trial included 1205 patients with high-risk pT2 and pT3/T4 prostate cancer over a 10-year period (19952005) who were randomized either to Radiation Therapy + ADT or ADT alone. The results showed an explicit overall survival benefit when receiving the combination therapy (74% vs 66%).74

Based on current guidelines Low and Intermediate Risk local Prostate Cancer may be treated with EBRT alone.69 However, the still ongoing EORTC 22991 trial with over 800 patients randomized to radiation therapy alone vs radiation therapy plus ADT showed at 7.2 years median follow-up that the radiation therapy plus ADT arm had significantly improved biochemical disease-free survival (DFS) (HR, 0.52; 95% CI, 0.41 to 0.66; P = 0.001) as well as clinical progression free survival (PFS) (HR, 0.63; 95% CI, 0.48 to 0.84; P = 0.001). Overall survival data is still pending. These results suggest an overall benefit with combination therapy in improving biochemical and clinical disease-free survival.75

A meta-analysis by Spratt et al revealed that ADT and radiation treatment sequencing may also be an important aspect. Adjuvant ADT post radiation therapy improved Metastasis Free Survival (MFS) and Progression Free Survival (PFS) compared to Neoadjuvant ADT without increasing long-term toxicity. The authors reviewed two randomized Phase II Trials (Ottawa 0101 and RTOG 9413) in the management of localized prostate cancer, and concluded that delaying radiation therapy to perform neoadjuvant ADT did not lead to additional tumor control or reduced toxicity and may actually be inferior to adjuvant ADT.76

Summarizing the present and available data, it appears that the combined therapy (RT + ADT) is of greatest benefit in patients with high-risk local disease. In addition, some patients with hormone sensitive prostate cancer and low volume metastatic disease may also benefit from combination therapy.

Docetaxel, a taxane-based systemic chemotherapy agent, was one of the first additional agents to emerge as a treatment with strong evidence for an overall survival (OS) benefit in patients with metastatic, castrate-sensitive prostate cancer in addition to standard ADT. In the CHAARTED trial, patients with metastatic, hormone-sensitive prostate cancer were randomized to treatment with either traditional ADT alone (which consisted of surgical castration with orchiectomy or medical castration with LHRH agonists such as leuprolide) versus ADT plus docetaxel, which they received as 75 mg/m2 every 21 days for six cycles.77 Median OS was 13.6 months longer (57.6 vs 44.0 months, HR: 0.61) in the ADT plus docetaxel group compared to traditional ADT alone.77 The survival benefit of adding docetaxel to ADT was even more pronounced in high-volume disease (defined as the presence of visceral metastases and/or greater than or equal to four bone lesions with at least one beyond the spine and/or pelvis) with median survival increased by 17.0 months compared to ADT alone (HR: 0.60).77 Additional benefits in the ADT plus docetaxel group included a longer time to the development of castrate-resistant disease, higher rate of decline of the PSA to <0.2 ng/mL at 12 months, and a lower incidence of prostate cancer-related death.77

Another trial called the STAMPEDE trial was published assessing the role of docetaxel in the metastatic hormone-sensitive prostate cancer space.78 When comparing the ADT plus docetaxel group to ADT alone, STAMPEDE again suggested an overall survival benefit with ADT and docetaxel for the subset of patients with metastatic disease (HR: 0.80).78 Patient selection in this trial notably included not only men with metastatic disease (61% of participants), but also patients with node-positive and high-risk localized disease.78

In a meta-analysis performed with the combined data from GETUG-AF15, CHAARTED, and STAMPEDE, men with metastatic castrate-sensitive disease across all three studies had a statistically significant overall survival benefit with the addition of docetaxel to traditional ADT (HR: 0.72).79 The combined data from all three trials yielded an overall 27% risk reduction of death for prostate cancer patients with metastatic disease (HR: 0.73), and a 33% risk reduction of death in high-volume, metastatic, castrate-sensitive prostate cancer patients (HR: 0.67).79

Abiraterone acetate is an androgen biosynthesis inhibitor. Another analysis of the STAMPEDE trial utilized standard ADT alone versus ADT with abiraterone (1000 mg) daily with prednisolone (5 mg daily) to assess its role in men with metastatic, castrate-sensitive prostate cancer, nodal disease, or high-risk localized disease.31 Over a three-year follow-up, overall survival was 83% in the abiraterone plus ADT group vs 76% in the ADT alone group (HR: 0.63).31

In the LATITUDE trial, patients were randomly assigned to ADT alone versus ADT with abiraterone (1000 mg) daily with prednisolone (5 mg daily).30 After a median follow-up of 30.4 months, overall survival was significantly longer in the abiraterone + ADT group than in the ADT alone group (not reached versus 34.7 months, HR: 0.62).30 Progression-free survival was 33.0 months in the abiraterone + ADT group and 14.8 months in the ADT along group (HR: 0.47).30

Enzalutamide is a potent androgen-receptor inhibitor. In the ARCHES trial, 1150 men with metastatic, hormone-sensitive prostate cancer were randomized 1:1 to receive either 160 mg enzalutamide daily plus ADT or ADT plus placebo.80 Sixty-three percent of the study participants had high-volume disease, defined as either visceral metastases or 4 bony metastases with at least one outside the spine/pelvis.80 The risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT compared to placebo plus ADT (HR: 0.39).80 This benefit was similarly seen regardless of disease volume or prior docetaxel chemotherapy. Enzalutamide plus ADT significantly reduced the risk of PSA progression, initiation of new antineoplastic therapy, first symptomatic skeletal-related event, castration resistance, and reduced risk of pain progression compared to ADT with placebo.80

Another contemporary trial evaluating enzalutamide in the metastatic, hormone-sensitive prostate cancer space, ENZAMET, randomized 1125 men with metastatic, castrate-sensitive prostate cancer to treatment with enzalutamide 160 mg daily + ADT versus traditional ADT alone.36 At median follow-up of 34 months, overall survival was improved in the enzalutamide + ADT group compared to the ADT alone group (HR: 0.67).36 Better outcomes with enzalutamide + ADT were also seen in PSA and clinical progression-free survival (HR: 0.39 and 0.40, respectively) compared to ADT alone.36 Enzalutamide was associated with significantly longer progression-free and overall survival than standard care with traditional ADT in men with metastatic, hormone-sensitive prostate cancer.36

Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. In the TITAN trial, over 1000 patients with metastatic, castration-sensitive prostate cancer were randomized to receive apalutamide (240 mg per day) with traditional ADT or placebo with ADT.40 A total of 10.7% had received previous docetaxel therapy, 62.7% had high-volume disease, and 37.3% had low-volume disease.40 Progression-free survival at 24 months was 68.2% in the apalutamide with ADT group versus 47.5% in the placebo with ADT group (HR: 0.48).40 Overall survival at 24 months was also greater with apalutamide + ADT than with placebo + ADT (82.4% versus 73.5%, HR: 0.67).40

All four agents (docetaxel, abiraterone, enzalutamide, and apalutamide) have been FDA-approved for the treatment of metastatic, castration-sensitive prostate cancer and are now listed as category 1 recommendations within the NCCN guidelines.81 Treatment choice between agents for metastatic, hormone-sensitive prostate cancer is a challenge, and there is currently no clear consensus on preferential initial selection or sequencing of these agents. There is, however, a moderate degree of uncertainty in the role of chemotherapy in low-volume disease patients.82 Marchioni et al systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and found that no treatment was superior to docetaxel in terms of overall survival.83 However, abiraterone (HR: 0.89), enzalutamide (HR: 0.90), and apalutamide (HR: 0.90) showed nonstatistically significant lower overall mortality rates when compared to docetaxel.83 Abiraterone (HR: 0.71), enzalutamide (HR: 0.61), and apalutamide (HR: 0.74) also showed statistically significant lower disease progression rates when compared to docetaxel.83

Despite its effectiveness, nearly all patients on ADT will progress to castrate resistant prostate cancer (CRPC).84 CRPC is defined as biochemical or radiologic progression of disease in spite of castrate level testosterone (<50ng/dL). In the past, ADT was stopped after a cancer became castrate resistant however, Taylor showed in 1993 that there was a survival benefit of 26 months with continued ADT.85 Since then, the AUA has recommended continuing ADT in both metastatic and non-metastatic CRPC.86 In 2015, Merseburger reviewed the rationale for continuing ADT as a backbone of treatment after development of CRPC, and found no trials to this point that compared either abiraterone or enzalutamide with ADT versus without. The SPARE trial done in Germany is comparing abiraterone monotherapy with abiraterone plus ADT however, the final results are still pending. Hen comparing clinical studies Merseburger et al noticed that patients with CRPC who were started on abiraterone with prednisolone benefited from continued ADT, as the LH surge after discontinuing ADT overcame the inhibition of abiraterone. Similarly, they found that there was limited data comparing enzalutamide alone versus enzalutamide with ADT all previously published phase III trials on enzalutamide had continuation of ADT as an inclusion criteria.87

In this context the NCCN guidelines state that androgen receptor activation and autocrine/paracrine androgen synthesis are potential mechanisms of recurrence of prostate cancer during ADT (CRPC), and they recommend continuation of traditional ADT.88 Harris et al 2009 studied mechanisms of androgen persistence in prostate cancer despite ADT they found that prostate cancer cells could bypass castration with multiple mechanisms, including upregulation of the androgen receptor and synthesis of DHT in prostate cancer cells.89 Dai et al 2017 discusses changes to the androgen receptor itself as prostate cancer is treated. The androgen receptor is an intracytoplasmic steroid hormone receptor that functions as a nuclear transcription factor after an androgen binds to its ligand binding domain. In men with prostate cancer treated with ADT, mutations in the androgen receptor are seen in 1030%. On of the most common involves the loss of the ligand binding domain (the target of enzalutamide), which uncouples transcription of the targets of the androgen receptor from its activation by androgens.90 As outlined below, these pathways provide targets for newer hormonal therapies.

For a CRPC to be considered non-metastatic, it must meet the criteria of castrate resistance without radiologic evidence of metastasis on CT or technetium-99m bone scan. Once non-metastatic CRPC (nmCRPC for short) has been confirmed, the next important clinical variable is PSA doubling time (PSADT).

In patients with a PSADT greater than 10 months, the AUA and NCCN recommend continued ADT to maintain castrate level. Serial PSAs should be drawn every 36 months for adequate monitoring PSADT. Additionally, imaging should be obtained every 612 months for re-staging and to rule out development of metastatic disease.

In patients with a PSADT less than 10 months, the AUA and NCCN recommend continued ADT with a non-steroidal anti-androgen such as apalutamide, darolutamide, or enzalutamide. Smith et al 2018 showed a difference in median metastasis-free survival of 40.5 months vs 16.2 months in the apalutamide vs placebo group (P<0 0.001), as well as a significant benefit in time to symptomatic progression, with a hazard ratio of 0.45 (95% CI, 0.320.63 - P<0.001).91 Similar benefits for enzalutamide were shown by Hussain et al in 2018, with a difference in median metastasis free survival of 36.6 months for enzalutamide versus 14.7 months for placebo (P<0.001).92 Fizazi et al 2019 showed a similar benefit for darolutamide, with median metastasis free survival at 40.4 months versus 18.4 months for placebo (hazard ratio 0.41, 95% CI 0.340.50, P<0.001).93 Finally, a review by Mori et al 2020 showed that apalutamide and enzalutamide were more effective than darolutamide in regards to metastasis free survival and PSA-progression free survival, while darolutamide had an overall lower rate of adverse events.94

A patient is considered to have progressed from nmCRPC to metastatic CRPC (mCRPC) when metastatic disease is confirmed on imaging. Depending on previous treatments, the patient may have several options for ADT. Importantly, both the AUA and NCCN recommend continuation of traditional ADT with either GnRH/LHRH agonists or antagonists. Further treatment options depend on prior treatment.

In men with mCRPC without any prior novel hormone therapies (including abiraterone, apalutamide, enzalutamide, or darolutamide) several different treatment options are recommended - these include abiraterone with a steroid, docetaxel, and enzalutamide. Abiraterone is an inhibitor of cytochrome P-450c17, which ultimately manifests in inhibition of 17-hydroxylase and 17,20-lyase. Ryan et al 2013 examined abiraterone with steroid versus placebo in patients with mCRPC on ADT, who had not been previously treated with chemotherapy. Median overall survival was not reached in the abiraterone plus steroid group, while it was 27.2 months in the placebo group (HR 0.75, 95% CI 0.610.93, P<0.01). They also benefit in radiographic progression free survival, with 16.5 months versus 8.3 months in the placebo group (Hazard ratio 0.53, 95% CI 0.450.62, P<0.001).95 De Bono et al 2011 examined the role of abiraterone in mCRPC after treatment with chemotherapy and noted an overall survival of 14.8 months for abiraterone plus prednisolone versus 10.9 months for placebo, with a hazard ratio of 0.66 (95% CI 0.560.79, P<0.001). The same study also noted a benefit to progression free survival according to radiographic imaging, with 5.6 months on abiraterone versus 3.6 months with placebo (HR 0.67, 95% CI 0.590.78, P<0.001).96

Similar results were found with the AR blocker enzalutamide in mCRPC. Beer et al 2014 examined enzalutamide in mCRPC before use of chemotherapy. They showed a benefit in in cancer-specific survival, where 72% on enzalutamide and 65% in the placebo group (Hazard ratio 0.71, 95% CI 0.600.84, P<0.001). Additionally, radiographic progression free survival was 65% in the enzalutamide group versus 14% in the placebo group (Hazard ratio 0.19, 95% CI 0.150.23, P<0.001).97 Scher et al showed similar benefits when enzalutamide was used after receiving chemotherapy for mCRPC, with a difference in survival of 18.4 months for enzalutamide versus 13.6 months for placebo (HR 0.63, 95% CI 0.530.75, P<0.001). The same study showed a benefit in radiographic progression free survival, with 8.3 months versus 2.9 months (HR 0.40, 95% CI 0.350.47, P<0.001).98

The conclusion of the above a data is that ADT is still standard of care in nmCRPC and mCRPC alike, even with the introduction of new modalities.

ADT has been associated with undesirable side effects ranging from musculoskeletal decline to autoimmune disorders. The aim of this narrative is to summarize and update the adverse effects of ADT with studies published within the past 6 years.

It is well documented that ADT is associated with decreased bone mineral density (BMD) and an increased risk of developing osteoporosis and bone fractures. In one study, BMD decreased by 2.5%, 4.28%, 5.34%, and 6.16% after 6, 12, 18 and 24 months respectively following initiation of ADT.99 Patients on ADT also had an increased risk for any fracture (HR=1.4, CI=1.281.53), hip fractures (HR= 1.38, CI=1.201.58), and major osteoporotic fractures (HR=1.44, CI 1.281.61).100

Subsequent studies also illustrated the effect of ADT on muscle strength and volume. A 2016 study showed a decrease in self-reported physical functioning in men receiving ADT. Objective measurements of both grip strength and chair rise showed that grip strength was significantly diminished after 12 months of receiving ADT (P=0.01), and chair rise performance was significantly worse at both 6 and 12 months (P=0.02, P=0.003).101 Another study has confirmed differences in muscle volumes, measured by MRI, in patients on ADT. The levator ani muscle volume in men receiving ADT was significantly lower than in men of the control group (P=0.002). These men lost 16% of their initial baseline muscle volume when compared to the control. Patients on ADT had significant muscle loss in the gluteus maximus, iliopsoas, and quadriceps (P=0.017, P=0.013, P=0.031) along with increased intramuscular fat in the gluteus maximus (P=0.003).102

Metabolic syndrome is a set of symptoms that increase the risk of stroke, cardiovascular disease, and type II diabetes mellitus (DM). There is an increased risk of developing DM in prostate cancer patients treated with ADT than patients not treated with ADT (HR=1.49, CI= 1.341.66).103 ADT was also associated with higher risk of complications in patients previously diagnosed with DM. Patients on ADT had a 17% increased risk of developing diabetic retinopathy, 14% higher risk for diabetic neuropathy, and twice as likely to have diabetic amputations.104

In longitudinal cohort study of 190 men undergoing ADT, mean triglycerides (P<0.001), HDL cholesterol (P<0.001), and waist circumference (P<0.001) were significantly increased 6 months and 12 months after initiating ADT.105 Although HDL cholesterol is known to improve cardiovascular Health, an increase in overall cholesterol and triglycerides have negative effects as shown in the next two studies. Patients on ADT were at a higher risk of coronary heart disease and myocardial infarctions (OR=2.07, P<0.01).106 ADT also increased the risk for ischemic stroke (HR= 3.32, CI-1.149.67, P=0.028) when compared to non ADT users.107

The effect of ADT on cognitive function is still controversial. In one study, patients on ADT had more cognitive deficits in language ability, short-term memory, mental flexibility, and inhibitory control (P<0.05) when compared to a control group.108 A literature review and meta-analysis found an increased risk of new dementia onset (of any cause) and Alzheimer disease in patients on ADT (HR=1.21, CI=1.111.33; HR=1.16, CI=1.071.72).109 However, study results are conflicting as another retrospective study using the Taiwan Longitudinal Health Insurance Database in 5340 patients found no significant difference in Alzheimer or Parkinsons disease between patients receiving ADT and patients who did not receive ADT (HR=1.76, CI=0.555.62; HR=1.13, CI=0.582.20).110 When summarizing the reported data, several investigators think that there is a trend of cognitive decline under ADT, but they also agree that further prospective clinical studies are necessary.

A diagnosis of prostate cancer can be devastating patients and their families, and published data has shown that ADT can further increase psychiatric stress, and therefore, its impact must be considered when choosing the best alternative of therapy. The self-reported depression scores were higher in patients on ADT at 12 and 15 months when compared to patients with BPH or post prostatectomy.111 Furthermore, 43.1% of patients on ADT experienced higher incidence of anxiety when compared to control (P<0.001). This study also showed a correlation between longer duration of therapy and higher risk of anxiety (HR= 1.16, CI=2.041.29, P=0.01).112

Androgens can affect hematopoiesis and immunology. Patients on ADT are at increased risk of developing iron deficiency anemia (HR=1.62, CI 1.242.12).113 A retrospective study showed the association between ADT and the risk of developing any hematologic disorder including anemia and hematologic malignancy when compared to patients who underwent radical prostatectomy (HR=1.60, CI=1.291.97; HR 1.98, CI=1.62, 2.42). This associated risk even increased with longer duration of ADT (P<0.001).114

A study in 2016 analyzed the association between ADT and community acquired pneumonia: 62.2% of patients on ADT had respiratory events compared to 54.5% patients who did not receive ADT and 47.8% of patients who underwent one-sided orchiectomy (P<0.001). Patients with more than 11 doses of ADT were at increased risk for developing sinusitis, bronchitis, and pneumonia (HR=1.13; HR=1.26; HR=1.15; all P<0.001).115

The association between ADT and autoimmune diseases apparently depend on the type of disease. Whereas patients on ADT had a 23% increased risk of developing rheumatoid arthritis (HR1.23, CI 1.091.40),116 ADT seems to have a protective role in developing inflammatory bowel diseases: A decreased risk for ulcerative colitis (HR= 0.52, CI= 0.280.99) and Crohns disease (HR=0.38, CI 0.111.37).117

Although ADT is an effective treatment for prostate cancer, it comes with many risks and potentially harmful side effects. Therefore, a detailed risk-benefit discussion should be provided to the patient before initiating this form of treatment.

Bone mineral density (BMD) testing in patients on ADT is underutilized, and many men are unaware how to monitor and maintain good bone health. Clinical investigators have recommended to address patient education on risks of osteoporosis and strategies to improve bone health while on ADT. A 2018 study showed that a bone health pamphlet and support from a bone-health care coordinator resulted in a significantly higher percentage of men undergoing BMD testing when compared to men who underwent usual care (P<0.001). This bone health pamphlet given by the family physician also resulted in a significantly higher percentage of BMD testing (P=0.047).118

Lifestyle modifications including smoking cessation and reduced alcohol intake are recommended for patients on ADT.119 In addition, recent studies have confirmed the benefits of exercise on muscle and bone health for men on ADT. A 2019 study compared BMD in ADT patients who were randomized into immediate exercise and delayed exercise (6 months of usual activity followed by a 6-month exercise program). There was significant preservation of lumbar spine BMD in the immediate exercise group when compared to the delayed exercise group. There were no significant differences in whole body, spine, or hip BMD. Lean mass, appendicular skeletal muscle, and muscle density were preserved in the immediate exercise group after 6 months, while the delayed exercise group recovered after 12 months.120 A 2018 randomized and controlled trial evaluated the effect of home-based exercise intervention on bone-health outcomes. Although there was no difference in bone health, this study showed significantly improved muscle strength in the home-based exercise group when compared to the placebo intervention of stretching exercise.121 Improved muscle strength not only improves vitality in patients on ADT, but may also improve some of the metabolic side effects of ADT. There is some evidence of reduced risks of accidental falls and fractures in patients on ADT when participating in exercising programs, however there is a lack of robust prospective and randomized clinical trials to support this hypothesis.

The National Osteoporosis Foundation recommends a daily calcium intake of 1200 mg and vitamin D supplement of 8001000 IU/d for all men over the age of 50.122 A 2015 study analyzed whether the recommended vitamin D supplementation of 800IU/d increased blood levels of 25-OH vitamin D in patients receiving ADT. Regression analysis showed vitamin D supplementation was associated with increased 25-OH vitamin D serum levels supporting the current recommendation of 800 IU/d for men receiving ADT.123

Two controlled studies have analyzed the effect of zoledronic acid on BMD in patients undergoing ADT. In one study with 32 ADT patients diagnosed with nonmetastatic prostate cancer and osteopenia or osteoporosis received zoledronic acid for 12 months or no treatment. The patients on zoledronic acid treatment were significantly older than the control group and had lower BMD at baseline. BMD of the lumbar spine and hip were significantly increased in the patients on zoledronic acid following 12 months of treatment.124 Similar results were found in a 2-year trial of 76 men showing increased BMD in the lumbar spine and hip when on zoledronic acid versus the control. However, there was no difference in bone microarchitecture measured by high-resolution peripheral quantitative computed tomography indicating that zoledronic acid may slow but does not prevent unbalanced bone modeling.125 These studies have small sample size and inconsistencies in dosing of zoledronic acid, which limit the scientific value, and therefore, larger prospective and randomized clinical trials are needed.

Denosumab, a RANKL inhibitor, has been shown to have similar clinical efficacy when compared to alendronate (Fosamax). One study divided patients into 4 groups: 1) treated with denosumab, 2) treated with alendronate, 3) no treatment, 4) previously treated with alendronate and switched to denosumab. After 1 year, the patients who were treated with denosumab or alendronate had increased bone mass in the lumbar spine and femoral neck when compared to the control. Men treated with denosumab had significantly higher bone mass in the total hip while there was no significant change in men treated with alendronate.126 A subsequent 2017 study on denosumab showed significantly increased bone turnover markers and BMD when compared to alendronate; furthermore, a decreased rate of vertebral fractures were observed.127

Osteonecrosis of the jaw is the most common significant adverse effect of zoledronic acid and denosumab. A retrospective study in 2021 analyzed the incidence of agent-related jaw osteonecrosis in prostate cancer patients: 27.5% developed this feared osteonecrosis of the jaw within 5 years of treatment with a bone-modifying agent.128

Maintaining bone health in prostate cancer patients on ADT is an important clinical aspect as musculoskeletal side effects are common with ADT. The use of vitamin D, calcium, and bone modifying drugs should be properly discussed with patients on ADT in order to protect bone health.

The authors report no conflicts of interest in this work.

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):1029.

2. Ito K. Prostate cancer in Asian men. Nat Rev Urol. 2014;11(4):197212.

3. Connolly RM, Carducci MA, Antonarakis ES. Use of androgen deprivation therapy in prostate cancer: indications and prevalence. Asian J Androl. 2012;14(2):177186.

4. Debruyne F. Hormonal therapy of prostate cancer. Semin Urol Oncol. 2002;20(3 Suppl 1):49.

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Jonathan P. Beauchamp

Human Genetics Department, UCLA David Geffen School of Medicine, Los Angeles, CA, USA

Daniel J. Benjamin&Alexander I. Young

Center for the Advancement of Value in Musculoskeletal Care, Hospital for Special Surgery, New York, NY, USA

Mark Alan Fontana

The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Tune H. Pers,Pascal Timshel,Tarunveer S. Ahluwalia&Thorkild I. A. Srensen

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

Tune H. Pers&Pascal Timshel

Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, the Netherlands

Cornelius A. Rietveld,S. Fleur W. Meddens,Ronald de Vlaming&A. Roy Thurik

Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands

Cornelius A. Rietveld,Ronald de Vlaming&A. Roy Thurik

Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands

Cornelius A. Rietveld,Ronald de Vlaming,Najaf Amin,Frank J. A. van Rooij,Cornelia M. van Duijn,Henning Tiemeier,Andr G. Uitterlinden&Albert Hofman

Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

Guo-Bo Chen,Zhihong Zhu,Andrew Bakshi,Anna A. E. Vinkhuyzen,Jacob Gratten&Jian Yang

Icelandic Heart Association, Kopavogur, Iceland

Valur Emilsson,Albert V. Smith&Vilmundur Gudnason

Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavk, Iceland

Valur Emilsson

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

S. Fleur W. Meddens,Christiaan de Leeuw&Danielle Posthuma

Amsterdam Business School, University of Amsterdam, Amsterdam, the Netherlands

S. Fleur W. Meddens&Mal P. Lebreton

New York Genome Center, New York, NY, USA

Joseph K. Pickrell

Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands

Abdel Abdellaoui,Jouke-Jan Hottenga,Gonneke Willemsen&Dorret I. Boomsma

Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

Tarunveer S. Ahluwalia,Klaus Bnnelykke,Johannes Waage&Hans Bisgaard

Steno Diabetes Center, Gentofte, Denmark

Tarunveer S. Ahluwalia&Johannes Waage

Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden

Jonas Bacelis&Bo Jacobsson

Research Unit of Molecular Epidemiology, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany

Clemens Baumbach&Christian Gieger

Institute of Epidemiology II, Helmholtz Zentrum Mnchen, German Research Center for Environmental Health, Neuherberg, Germany

Clemens Baumbach&Christa Meisinger

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland

Gyda Bjornsdottir,Gudmar Thorleifsson,Bjarni Gunnarsson,Bjarni V. Halldrsson,Kari Stefansson&Unnur Thorsteinsdottir

Department of Cell Biology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands

Johannes H. Brandsma&Raymond A. Poot

Istituto di Ricerca Genetica e Biomedica U.O.S. di Sassari, National Research Council of Italy, Sassari, Italy

Maria Pina Concas,Simona Vaccargiu&Mario Pirastu

Psychology, University of Illinois, Champaign, IL, USA

Jaime Derringer

Institute for Computing and Information Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands

Tessel E. Galesloot&Lambertus A. L. M. Kiemeney

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

Giorgia Girotto,Dragana Vuckovic,Ilaria Gandin,Paolo Gasparini&Nicola Pirastu

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Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals - Nature.com

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A Mercer University professors podcast highlighting women in science, technology, engineering and math has been recognized among the best in its niche.

Dr. Sabrina Walthall, associate professor of science in the College of Professional Advancement, hosts the STEM Lab Podcast, which was ranked No. 13 among the Best 45 Women in STEM Podcasts. The ranking by Feedspot, a web content reader, was based on traffic, social media followers, domain authority and freshness.

Dr. Walthall said she created the STEM Lab Podcast two years ago to highlight women, especially those from marginalized groups, in STEM.

I realized that the news media only seemed to highlight women who, of course, had done something just spectacular and over the top, she said. But I knew a lot of women, who I either went to graduate school with or met at conferences, who were doing great things. These are a lot of women already in the community, doing work in their own community, but no one really knows.

And so, I just felt the podcast was a great way to put the story out there.

Each episode, released monthly, features an interview with a woman who uses science, technology, engineering or math in her work. Episodes have featured two women who hold both M.D. and Ph.D. degrees, a registered nurse, an environmental neuroepidemiologist and a viral immunologist. A recent episode featured an unconventional woman in STEM a celebrity cake artist.

The baker was very unconventional, which I love because I dont think people think of STEM in that way, and then just talking to her I realized, All you do is STEM all day long, Dr. Walthall said.

Her podcast also dives into the challenges women, in particular marginalized women, face in STEM. One of her favorite episodes was an interview with Dr. Ansley Booker, director of diversity and inclusion initiatives at Mercer.

In order for STEM to move forward, we really have to look at diversity, equity and inclusion, Dr. Walthall said.

Representation of women in STEM varies widely, according to a recent Pew Research Center analysis of the STEM workforce.

While women make up half of those employed in STEM careers, they are overrepresented in health-related jobs but underrepresented in other fields, such as the physical sciences, computing and engineering. Meanwhile, Black and Hispanic workers (male and female) are underrepresented in the STEM workforce across the board, the analysis shows.

A lot of times the reason all this is happening, and why I also try to work with girls in STEM, is because of gender stereotypes, Dr. Walthall said. Its just been ingrained in us since we were young that certain careers belong to men and are masculine, and certain careers belong to women.

And you dont always hear of young girls being told that they should grow up to be a scientist or that they can be the engineer or that maybe they can be the mathematician.

She said she hopes a young girl might hear the STEM Lab Podcast and discover she can be like the women being interviewed.

Dr. Walthalls own love for STEM began when she was young. She became fascinated with science after being assigned a report on the heart.

I learned the heart was not the shape of the candy box, but it was the size of our fist, and that fascinated me, she said. And I just remember learning all the information and just going around the house, spouting it to anybody who would listen to it.

She went on to earn a bachelors degree in biology from Emory University and a doctorate in biochemistry and molecular genetics from the University of Alabama at Birmingham. She completed her postdoctoral training with the UAB Community for Outreach Development where she worked on rebuilding science education at the K-12 level in Alabama and discovered her passion for the science of teaching and learning.

Through a National Science Foundation fellowship, she was able to go into an Alabama high school and teach genetics. She realized she really enjoyed it.

I would always make a story out of the science because thats the way Ive always seen science. Its really, literally, a cartoon in my head, she said. I realized I could start a concept in a fun way and then build up to where we understand it truly scientifically, but I had to start them somewhere.

In addition to her work at Mercer, prior to the COVID-19 pandemic, Dr. Walthall volunteered with the Real Impact Center, a Macon-based nonprofit dedicated to exposing girls to STEM careers.

She enjoyed the work so much that she incorporated it into her courses as a service-learning project, which included college students working with youth during events like STEM-tastic Saturdays and a Macon STEM Pop-Up.

The STEM Lab Podcast is available on Apple and Google Podcasts, Anchor, Spotify and YouTube.

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Mercer professor's podcast among the best about women in STEM - Mercer University

Recommendation and review posted by Bethany Smith

There arent enough hours in the day, Marian Andersen says.

Marian Andersen with her dog, Ashley. She reads four newspapers daily and enjoys watching all kinds of sports. Gonzaga is her pick to win the NCAA basketball tournament.

At 93, shes still reading four newspapers daily. Magazines and books also keep her busy.

Im not giving up on newspapers, she said.

She couldnt wait for the NCAA basketball tournament to start she picked Gonzaga to win it all. Baseball is another love, and with a fall trip to Texas, shes seen every major league stadium.

Shes also a huge Nebraska football fan. People are astounded to learn shes been attending games for 90 years. Her father took her to her first one when she was 3 years old.

Marian Andersen at age 5. She went to her first Nebraska football game at the age of 3.

Her social calendar is packed she enjoys playing bridge and attending the movies. Thank goodness for younger friends, she said, since many of her older ones have sadly passed away.

One of the amazing things about Marian is her positive attitude and zest for life and her genuine interest in other people, longtime assistant Jackie Wrieth said. Not only does she want to know everything about you, but also about your kids and grandkids and she remembers it all.

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A mutual friend always said if youre attending a banquet you want to sit at Marian Andersens table. Shes one of a kind.

Marian Andersen and her husband, former Omaha World-Herald publisher Harold W. Andersen, at the Ak-Sar-Ben pre-coronation in October 1994.

Life has always been full for Andersen, who still lives in her home with a cocker spaniel, Ashley. Ashley doesnt cook, Andersen jokes, but shes great company.

Shes got family here, too. Son David, his wife, Leslie, and three grandkids live in the Omaha area as well as San Francisco. Daughter Nancy Andersen and her three sons live in Denver.

Her husband, the late Harold W. Andersen, was publisher of The Omaha World-Herald from 1966 to 1989. Although she didnt have a full-time career, Marian didnt sit home on the sideline. As a longtime community volunteer, she has been a pioneer.

She was the first woman chairman of the University of Nebraska Foundation and the first woman board chair for the Red Cross in Omaha.

Marian Andersen, center, leaves the stage with her daughter Nancy Andersen, left, and son David Andersen after she was honored during the United Way of the Midlands Excellence in Impact event in 2017.

She was on the board and co-chair of the committee that hired the first woman president of the national Public Broadcasting System. The Andersens made significant contributions locally and nationally to PBS.

She was also pleased recently to make the acquaintance of Ava Thomas, The World-Heralds second woman publisher.

Im all for women to break that glass ceiling, she said.

Together, she and Harold supported a long list of organizations.

She was named the United Way of the Midlands Citizen of the Year in 1994. With her husband, she was a co-founder of the Alexis de Tocqueville Society, a group of contributors who donate a minimum of $10,000 to the annual United Way campaign.

She also received the Distinguished Nebraskalander Award from the Nebraskaland Foundation and was named outstanding sustainer by the Junior League of Omaha. She was a past president of Planned Parenthood and co-chairman of the Nebraska Shakespeare Festival.

Marian Andersen in 1974. She was an active volunteer.

Brian Hastings, the president and CEO of the Nebraska Foundation, said Marian Andersen has a long history of supporting the foundation. She is its longest-serving trustee, since 1962, served as the chair of the board of directors in 1984 and 1985 and was the first woman to do so.

She liked to say she broke the glass ceiling for her husband, Harold, who became chair of our board later, in 1991 through 1993, Hastings said. She and Harold were the volunteer chairs of a comprehensive campaign that ran from 1993 through 2000. The goal was to raise $250 million for the University of Nebraska. It raised $727 million due to Marian and Harolds leadership. She is one of the foundations and universitys most ardent and faithful supporters.

Andersen said shes just always been a leader, from when she was student council president at Lincoln High and president of Kappa Kappa Gamma sorority at the University of Nebraska-Lincoln, where she also was a Phi Beta Kappa.

Marian Andersen in 1951. She said she's always been a leader.

I never was intimidated, she said.

After she married at 23, which at that time she said was almost an old maid, she and her husband saw the world. They visited 60 countries and every state.

Another great love of Andersens is tennis, and shes been to the grand slam of tournaments: the Australian Open, the U.S. Open, Wimbledon and the French Open.

During womens history month, Andersen said shes most proud of two things.

I think my family, she said, and the fact that I have maybe made a difference in some of the organizations.

Marian Andersen and her dog, Ashley, at her home in Omaha. She jokes that Ashley cant cook, but shes good company.

2. Standing Bear

c. 1829-1908

Native leader

A renowned Ponca chief, Standing Bear, in 1879, became the first Native to be legally recognized as a person.

In 1877, the federal government forced the Ponca from their northeast Nebraska land to Indian Territory in what is now Oklahoma. A year later, honoring the wish of his 16-year-old son to be buried along the Niobrara River, Standing Bear led a band of tribe members back to Nebraska.

Arrested for leaving the reservation, Standing Bear stood trial at Fort Omaha, his lawyers filing a writ of habeas corpus contesting the detention. The judge ruled in favor of Standing Bear and the U.S. Supreme Court upheld the ruling.

4. George W. Norris

1861-1944

Politician

Called the very perfect, gentle knight of American progressive ideals by President Franklin D. Roosevelt, Norris served five terms in the U.S. House of Representatives (1903-13) and five terms in the U.S. Senate (1913-43), all save the final term as a Republican.

An Ohio native, Norris moved to Beaver City in 1885 to practice law. He established an office in McCook in 1899, practicing law before beginning his political career.

Norris promoted the unicameral Legislature in Nebraska, approved by voters in 1934, and led the creation of the Tennessee Valley Authority, and the Rural Electrification Act, both championing public power.

5. Wm. Jennings Bryan

1860-1925

Politician

A famed orator and leader of the populist wing of the Democratic Party, Bryan was the Democratic presidential nominee three times in 1896, 1900 and 1908. He served two terms in Congress from Nebraska and was Secretary of State under Woodrow Wilson.

Born in Salem, Illinois, The Great Commoner settled in Lincoln in 1887 to practice law. Known for his oratory, Bryan was a champion of free silver and delivered his famous Cross of Gold speech in 1896.

Touring the country as a public speaker, Bryan worked for peace, Prohibition and womens suffrage and opposed the teaching of evolution, joining the prosecution in the famed Scopes Monkey Trial in 1925.

6. John Neihardt

1881-1973

Poet

The writer, poet and historian is best known for "Black Elk Speaks," the biography of the Oglala Lakota holy man Neihardt published in 1932.

Born in Illinois, Neihardt moved to Wayne in 1892 as an 11-year-old. Bancroft became his home in 1901. He became a published author at age 19, started his major work, "The Cycle of the West," at 31 and became Nebraska's Poet Laureate at 40.

At 45, he was literary editor for the St. Louis Post-Dispatch, and at 68 became poet-in-residence and lecturer in English at the University of Missouri. He returned to Nebraska in his 80s, continuing to write until his death at 92.

9. Charles Dawes

1865-1951

Vice president

Dawes (above with pipe) pursued two careers in his lifetime, one in business/finance, the other in public service, with the two coming together in 1925 when he won the Nobel Peace Prize while serving as Calvin Coolidge's vice president.

Dawes moved to Lincoln in 1887, where he practiced law until 1894. Purchases of gas companies in LaCrosse, Wisconsin, and near Chicago started investments that made him rich. The Republican activist took his first government position in 1898.

A self-taught musician, he composed what eventually became the pop standard "It's All in the Game."

10. Ted Sorensen

1928-2010

Presidential adviser

In 1953, the Lincoln native and University of Nebraska College of Law graduate became chief legislative aide for Sen. John F. Kennedy and, after the 1960 election, became President Kennedys chief aide and speechwriter.

Responsible for crafting Kennedys famous inaugural address, Sorensen served as a key adviser during the 1962 Cuban missile crisis and penned the letter to Soviet Premier Nikita Khrushchev that defused the crisis.

After his White House years, Sorensen joined a prominent New York City law firm and built an international law practice.

11. J. Sterling Morton

1832-1902

Politician

Founder of Arbor Day, Morton moved to Nebraska City in 1854 and became editor of the local paper. He served as acting governor in 1858 and again in 1861 and was U.S. Secretary of Agriculture from 1893-1897.

12. Tom Osborne

1937-

Football

The Hastings native played professional football before becoming a Nebraska assistant coach in 1964. Named head coach in 1972, Osborne led the Huskers for 25 years, winning three national championships. He served in Congress from 2001-2007 and as UNL athletic director from 2007-2013.

13. John J. Pershing

1860-1948

Military

In 1891, Army officer Pershing became professor of military science at the University of Nebraska where he earned his law degree in 1893. Black JackPershing served in the Spanish-American War and became the leading American commander in World War I.

14. Harold Edgerton

1903-1990

Engineer

Fremont-born Edgerton grew up in Aurora and received his engineering degree from the University of Nebraska in 1925. In 1927, he began working with stroboscopes and in 1937 began collaborating with a photographer to make his motion capture images.

15. Loren Eiseley

1907-1977

Nature Writer

The Lincoln native began writing while attending the University of Nebraska. In 1947, he began teaching at the University of Pennsylvania. In the 1940s, he began writing his acclaimed nature essays and books combining natural science with literature.

16. Dick Cavett

1936-

Television

Born in Gibbon, Cavett grew up in Lincoln before attending Yale University. Hired as a writer for The Tonight Show in 1960, Cavett also worked in stand-up comedy before landing The Dick Cavett Show, which ran from 1968 to 2007.

17. Bob Kerrey

1943-

Politician

Winning the Congressional Medal of Honor for his service in Vietnam, Lincolns Kerrey was elected governor in 1982, became a U.S senator in 1989 and was a Democratic presidential candidate in 1992. He also served on the 9/11 Commission.

18. Henry Fonda

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'Break that glass ceiling': Omahan Marian Andersen has relished a life filled with firsts - Kearney Hub

Recommendation and review posted by Bethany Smith

If your bad cramps aren't caused by a workout or period pain, there can be another reason: pelvic inflammatory disease (PID). According to the Centers for Disease Control and Prevention (CDC), PID is the infection of the female reproductive organs, and can result from untreated sexually transmitted diseases (STDs) or the use of an improperly placed intrauterine device (IUD).

The only way to avoid PID is to avoid all sexual activity. If you are sexually active, use protection or be smart about your choice of partners, making sure they also test negative for STDs. If you notice abnormal bleeding or severe cramping in the abdomen, it is best to get a diagnosis, as it is always better to treat a disease in its earlier stages because the cause could be PID.

WebMD shared that "PID is an infection of the organs of a women's reproductive system. They include the uterus, ovaries, fallopian tubes, and cervix." This affects about 770,000 women in the U.S. every year, and can ultimately also affect fertility. Consult a doctor if you are sexually active and experience severe pain in your tummy that seems more unusual than period cramps. It can be treated with antibiotics, but serious cases may require hospitalization.

Ultimately, no matter what is causing them, we've got you covered with the best ways to relieve stomach cramps.

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What Does It Mean When When You Have Bad Cramps? - The List

Recommendation and review posted by Bethany Smith

Insects are often seen as pests, but many species can provide new sources of food, materials, and even ways to clean up plastic waste. Here are 10 companies in this space that we think are worth watching.

Many people think of insects simply as pests that eat crops and carry diseases such as malaria. While this is true in some cases, insects have also been an inspiration to scientists for many years. Biotechs and researchers are now applying this knowledge to create new and sustainable food sources for both humans and animals, as well as fertilizers to grow other foods.

The unique biology and chemistry found in insects has inspired the creation of packaging materials, bioplastics, glue, and other biomaterials. Some scientists have even found moth larvae that eat plastic and other, more early-stage research, is looking at ways to repurpose spider venom to treat pain or create insecticides for use on plants.

The number of biotech companies working in the insect or yellow biotechnology space is constantly increasing. Here are 10 firms we think are worth paying attention to.

Founded: 2005

Headquarters: Madrid, Spain

Madrid-based Algenex uses insects and insect cells to produce proteins needed to develop drugs, vaccines, and diagnostics. Jos Escribano founded the company in 2005 and is now CSO.

The company has two main products: CrisBio and TopBac. The former, validated by the EMA last year, uses chrysalises of the cabbage looper moth Trichoplusia ni as living bioreactors to produce medicinal proteins. Living insects can regulate their own temperature and oxygen levels, making them easier than cells to manufacture at scale. The insects are infected with a modified virus, harmless to humans, known as a baculovirus. Prior to infection, the virus is genetically engineered to ensure production of the desired protein. The chrysalises can then produce enough protein to extract in less than a week.

The other product, TopBac, is a DNA sequence that contains instructions necessary to express certain genes in cells. It can be used to improve both the productivity and quality of the proteins produced by the insect cells.

The company has already produced more than 200 types of medicinal proteins used for human and animal diagnostics and therapeutics. Funded by Columbus Venture Partners, Chamber Ventures, and Vita Advisory, the company raised a 8.75M Series B round in 2020 and a 4M Series A financing in 2019.

Founded: 2011

Headquarters: Paris, France

nsect was founded in 2011 in Paris by a group of scientists and environmental activists. The company uses insects to produce high-protein products for animal and fish food, as well as the fertilizer industry, in a sustainable and environmentally friendly way.

The company has created technology that allows vertical production of the yellow mealworm beetle Tenebrio molitor. In 2019, nsect raised 110M in Series C funding the largest-ever amount for agriculture technology outside of the USA to fund the construction of the worlds largest automated insect farm. This was extended to 343M in 2020, bringing its total funding to approximately 391M. Last year, the company acquired Dutch mealworm breeding company Protifarm to expand its reach across Europe.

In January 2021, the European Food Safety Authority concluded that mealworms are safe for human consumption, a positive development for nsects mission to enter the human food market.

Last month, nsect announced the launch of nfabre, an industrial program dedicated to the genetics of these insects. The initiative is designed to bring expertise from different fields together to develop improved phenotyping and genotyping tools, as well as more efficient industrial processes.

Founded: 2002

Headquarters: Abingdon, UK

A spin-off from the University of Oxford founded in 2002, Oxitec genetically engineers mosquitoes with a self-limiting gene to help control diseases such as malaria and dengue. By introducing a gene that kills the female offspring of mosquitoes, the company has claimed massive success in reducing local populations of disease-carrying mosquitoes in locations including Brazil, India, and Panama.

Since its founding, Oxitec has diversified and is applying similar technology to pest insects that attack crops such as the diamondback moth, a massive problem for vegetable farmers, and others such as the soybean looper and the fall armyworm. According to the company, the advantage of this technology is that, unlike chemical insecticides, it does not kill harmless insects like bees and other pollinators.

Oxitec was acquired by US-based Intrexon Corporation in 2015, acting as a separate subsidiary. In 2020, Intrexon sold off Oxitec and other non-healthcare assets to another US company, Third Security.

Founded: 2009

Headquarters: Dongen, The Netherlands

Protix was founded by Kees Aarts and Tarique Arsiwalla in 2009. The company uses a combination of high-tech control systems, artificial intelligence, breeding programs, and robotics to produce lipids, proteins, and pure from larvae of the black soldier fly (Hermetia illucens). It also plans to expand to crickets, locusts, and mealworms in the future.

The company opened its first industrial-scale factory in 2019 in Bergen op Zoom and has a number of different animal food products on the market used to make nutritious food for pets, chickens, and fish. The firm also produces a fertilizer from the byproducts of its industrial process.

Protix started a collaboration with the animal breeding specialist Hendrix Genetics in 2018 and recently announced that they have successfully bred black soldier flies with bigger larvae that will increase yield in their insect farms.

Last month, Protix attracted a 50M investment from BNP Paribas, Monaco Asset Management, and the Luxembourg-based European Circular Bioeconomy Fund. The company has now accrued over 120M in total funding and plans to expand internationally.

Founded: 2014

Headquarters: Salamanca, Spain

Tebrio, previously known as MealFood Europe, was founded by Adriana Casillas and Sabas de Diego in 2014. Similar to nsect, Tebrio focuses on transforming the T. molitor mealworm beetle into different ingredients for a wide variety of uses.

Tebrio has three main product streams: sustainable fish, pet, and animal feed; biofertilizer for plants that also acts as an insect repellant; and chitosan extracted from the insects to make biodegradable plastic that can dissolve in water. Chitosan has many other uses; for example, it can be used for water treatment, as a base for coagulants, or for medical uses as an antibacterial component of dressings and bandages.

In 2020, the company closed a Series A funding round co-led by Caixa Capital Risc and the Spanish Centre for Industrial Technological Development (CDTI). While the total amount of the round was undisclosed, Tebrio announced the cash would allow the firm to develop a 50M insect breeding project.

Founded: 2017

Headquarters: Karmei Yosef, Israel

Smart Resilin is an Israeli biotech, set up in 2017, that is harnessing the power of resilin in its products. Resilin is a rubber-like protein found in the outer skin of most insects that helps them jump large distances and fly by allowing their wings to beat.

The company was spun out of the Hebrew University of Jerusalem by a team including materials scientist and serial entrepreneur Professor Oded Shoseyov, now CSO of the company. The researchers behind the company succeeded in identifying the genetics of resilin production and engineered bacteria to produce the protein.

Experiments have shown that resilin can be very useful in industry. For example, as an addition to glue, resilin improves elasticity and fatigue resistance. The company also plans to use it for other applications such as manufacturing training shoes. Resilin is also biodegradable, sustainable, and compostable, making it attractive for consumers.

Founded: 2016

Headquarters: Meath, Ireland

Hexafly is another company on the list that focuses on the black soldier fly (H. illucens). The company feeds its insects waste materials from breweries so the farm is totally waste-free. Founded by Alvan Hunt and John Lynam, Hexafly is based in Meath, Ireland and runs the countrys only vertical insect farm.

The company makes animal and fish food with their products from proteins and oils extracted from the flies, as well as dried grubs. The team also makes frass, a natural fertilizer for plants that can double up as a pesticide, for example, by reducing the impact of aphids.

The company received 2.2M seed funding in 2018 and has since then set up a pilot plant and received 3M in Series A funding.

Founded: 2020

Headquarters: Jarfalla, Sweden

Norbite, was founded in 2020 by Nathalie Berezina, previously nsect CTO/CSO. The firm was founded based on observations of the greater wax moth (Galleria mellonella) that showed caterpillars of this species are capable of eating plastic.

While the initial observations of the plastic-munching caterpillars occurred accidentally, they have now been confirmed. Greater wax moth larvae can consume around 80% of plastics including polyethylene and polystyrene, which have a similar chemical formulation to the wax they normally consume.

While it is still early days for Norbite, the company hopes to build a plant capable of processing 30,000 tons of plastic within five years. Many industrial biotechs find scaling up a challenge and Norbite will need to overcome major technical and economic obstacles to breed these insects on a wide scale and make its plastic degradation proposal an affordable reality.

Founded: 2016

Headquarters: Kongens Lyngby, Denmark

BioPhero was founded in 2016 by Irina Borodina as a biotechnology spin-out from the Technical University of Denmark. The company uses yeast fermentation technology to produce sustainable and safe insecticide replacements with the same makeup as insect pheromones. Applying pheromones to crops can mask the pheromones that female insects use to attract males, stopping them from mating.

The company currently targets four main pests with its pheromones, the cotton bollworm (Helicoverpa armigera), the diamondback moth (Plutella xylostella), rice stem borers (Chilo suppressalis and Scirpophaga incertulas), and the fall armyworm (Spodoptera frugiperda).

In March last year, BioPhero announced a 15.6M Series A funding round led by DCVC Bio with participation from FMC Ventures, as well as existing investors Syngenta Group Ventures and Novo Holdings.

Founded: 2021

Headquarters: Limburg, The Netherlands

Sib was named after a Costa Rican deity who taught people to work together with nature. It is still at the seed funding stage and was founded last year in the Netherlands by Costa Ricans Daniela Arias and Alejandro Ortega.

Sib is focused on the development and supply of insect-based food ingredients and water-soluble proteins from crickets and yellow mealworms.

The company will carry out technological processing of the insects in the Netherlands at the Brightlands Chemelot Campus in Limburg. The insect farming itself will take place in Costa Rica to ensure a fair deal for farmers in the developing country.

Sibs technology, named Entowise, allows fine separation of nutritional components such as protein, fats, and cytosine from powdered insects. The technology is precise enough that it could be used to extract vitamins such as B12 from insects.

Cover image via Elena Resko

Read this article:
The Top 10 Insect-Powered Biotech Companies - Labiotech.eu

Recommendation and review posted by Bethany Smith

Accusations of unfairness surround trans athletes such as the swimming champion Lia Thomas, far right, in womens sport

RICH VON BIBERSTEIN/GETTY IMAGES

The governments dithering over whether to ban conversion therapy has left policy on this sensitive issue in utter confusion. A double U-turn saw the prime minister at first cast aside a pledge that he would outlaw attempts to change peoples sexual orientation, before reinstating the commitment with measures to ensure it would not affect counselling offered to those suffering from body dysmorphia who want to transition to the opposite sex.

Lobby groups on all sides shrilly condemn discrimination. Mr Johnson had previously described all conversion therapy as abhorrent. However, feminists fear that womens rights are now in jeopardy. And the general public is bemused by arguments that seem as obscure as they are virulent. It is time common sense was brought to the trans debate.

Read more:
The Times view on the trans debate: Back to Basics - The Times

Recommendation and review posted by Bethany Smith

Increasing Application of Stem Cells in Cosmetic Anti-aging Is Expected to Boost the Demand of Anti-aging Products and Therapies Market.

Anti-Aging Products and Therapies Market size is estimated to reach $93.2 billion by 2027, growing at a CAGR of 7.72% during the forecast period 2022-2027. Anti-Aging Products and Therapies are the products and therapeutics which defer, halt or hinder the aging process. Liposuction Surgery is an anti-aging therapy that is a fat elimination process that targets to destroy surplus stubborn fat from the hard-to-shift areas. Liposuction should be thought of as a sculpting process that can alter the curves of the body or face. A Tummy Tuck or Abdominoplasty is an anti-aging therapy that will eliminate surplus fat and skin from around the waist and eliminate surplus skin to leave a flatter, reduced body profile and younger-looking abdomen. Chemical peeling, also termed as chemexfoliation or derma-peeling, is an anti-aging therapy utilized to enhance the countenance of the skin in which a chemical solution is enforced on the skin, which brings about the blister and finally peels off. The novel, enhanced skin is normally smoother and less wrinkled than the old skin. The novel skin also is temporarily more sensitive to the sun. Anti-Pigmentation Therapy may include the application of anti-blemish and anti-pigmentation cream which is a blend of herbal concentrates that enhance the clearness of the skin.

The compelling technological developments in conjunction with emerging R&D activities have led to the launch of anti-aging treatments like liposuction, breast implants, and plastic surgeries are set to drive the Anti-Aging Products and Therapies Market. The increased awareness regarding aging amidst the youth and mature grown-ups is set to propel the growth of the Anti-Aging Products and Therapies Market during the forecast period 2022-2027. This represents the Anti-Aging Products and Therapies Industry Outlook.

Anti-Aging Products and Therapies Market Segment Analysis By Product:

The Anti-Aging Products and Therapies Market based on the product can be further segmented into Anti-Wrinkle Products, Anti-Stretch Mark Products, Hair Color Products, UV Absorption, and Others. The Anti-Wrinkle Products Segment held the largest market share in 2021. This growth is owing to the expanding population of the elderly requiring anti-wrinkle products. Typical anti-aging techniques include liposuction and chemical peeling. The heightened awareness regarding the accessibility of anti-wrinkle products is further propelling the growth of the Anti-Wrinkle Products segment.

Furthermore, the Anti-Stretch Mark Products segment is estimated to grow with the fastest CAGR of 8.41% during the forecast period 2022-2027 owing to the proliferating application of anti-stretch products in cases of stretch marks brought about by obesity and pregnancy in conjunction with more progressive products launched by key players for the treatment of stretch marks apart from the application of typical anti-aging techniques like chemical peeling.

Anti-Aging Products and Therapies Market Segment Analysis By Therapy:

The Anti-Aging Products and Therapies Market based on therapy can be further segmented into Liposuction, BOTOX, Rejuvenation & Dermal Fillers, Hormone Replacement Therapy, Gene Therapy, Sclerotherapy, Hair Restoration Services, Abdominoplasty, Anti-Pigmentation Therapy, Breast Augmentation, and Others. The Liposuction Segment held the largest market share in 2021. This growth is owing to the surging application of liposuction procedures largely attributed to their great recognition attained on social media. The goal of liposuction is esthetic. The proliferating technological progress and heightened awareness regarding liposuction procedures are further propelling the growth of this segment.

Furthermore, the BOTOX segment is estimated to grow with the fastest CAGR of 8.7% during the forecast period 2022-2027 owing to the surging application of botox injections largely ascribed to the health advantages offered like treatment of eye ailments like crossed eyes, smoothening wrinkles thereby minimizing signs of aging and offering alleviation for frequent migraine patients apart from the application of other anti-aging techniques like chemical peeling.

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Anti-Aging Products and Therapies Market Segment Analysis By Geography:

The Anti-Aging Products and Therapies Market based on geography can be further segmented into North America, Europe, Asia-Pacific, South America, and the Rest of the World. North America (Anti-Aging Products and Therapies Market) held the largest share with 36% of the overall market in 2021. The growth of this region is owing to the accessibility of well-developed infrastructure in the region. The soaring application of anti-aging therapies like liposuction and chemical peeling in the U.S. is further driving the growth of the Anti-Aging Products and Therapies Market in this region. The existence of key players like Merck in the U.S. in the region is further propelling the growth of the Anti-Aging Products and Therapies Market in the North American region.

Furthermore, the Asia-Pacific region is estimated to be the region with the fastest CAGR rate over the forecast period 2022-2027. This growth is owing to factors like soaring consumption of skincare products and cosmetics in emerging economies like India in the Asia-Pacific region. The detection of early signs of aging requiring the application of anti-aging techniques like chemical peeling is further fuelling the progress of the Anti-Aging Products and Therapies Market in the Asia-Pacific region

Anti-Aging Products and Therapies Market Drivers

Surging Advantages Of Chemical Peeling Are Projected To Drive The Growth Of Anti-Aging Products and Therapies Market:

Chemical peeling, also termed chemexfoliation or derma peeling, is a clinical process that utilizes plant-based chemical solutions to exfoliate the skin. Relying on the requirement of the client, a dermatologist may suggest a peel from a series of strengths: superficial peels that attain superficial layers of the skin or deeper ones that infiltrate numerous microlayers of skin. A chemical peeling treatment is a skin invigorating process, which utilizes gentle acids extracted from organic sources of changing strengths to exfoliate the upper layers of the skin in a regulated manner, succeeded by conversion of novel healthier layers. Chemical peeling assists in curbing acne breakouts by eliminating surplus sebum, dead skin cells, and dirt. It equalizes the texture of the skin by healthy skin invigoration. It enhances the complexion by minimizing dark spots and discoloration. The surging advantages of chemical peeling are therefore fuelling the growth of the Anti-Aging Products and Therapies Market during the forecast period 2022-2027.

Increasing Application Of Stem Cells In Cosmetic Anti-Aging Is Expected To Boost The Demand Of Anti-Aging Products and Therapies Market:

Typical anti-aging techniques include chemical peeling and liposuction. Stem cells are being utilized with heightening frequency in cosmetic medicine. Stem cells can be injected directly into the skin on the face and other areas. This has been demonstrated to minimize wrinkles, skin discoloration, and advance skin revitalization. It can also minimize the appearance of scars, stretch marks, and advance skin tightening. Investigations demonstrate that including stem cells in additional cosmetic surgeries like Liposuction, Fat Transfer Natural Breast Augmentation, and Awake Tummy Tuck, quicken healing and provide a superior cosmetic outcome. Adding stem cells to resurfacing lasers has been demonstrated to improve the ultimate outcomes as well. This is likely true when augmented with radiofrequency skin tightening as well. The increasing application of stem cells in cosmetic anti-aging is driving the growth of the Anti-Aging Products and Therapies Market during the forecast period 2022-2027.

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Anti-Aging Products and Therapies Market Challenges

Limitations Of Recognized Anti-Aging Treatments Are Hampering The Growth Of The Anti-Aging Products and Therapies Market:

Vitamin E is regarded as one of the most recognized skin anti-aging agents, both as an oral and topical treatment. However, Vitamin E is not regarded safe at the time of pregnancy. Consuming vegetables will not hurt the baby. However, it is presently unclear at what levels Vitamin E supplements become hazardous to unborn babies. Nearly all physicians suggest not to consume more than 400 IU/day. To be entirely efficient as an anti-aging product, vitamin E needs to be consumed orally creams with vitamin E can smoothen and contribute elasticity. However, the actual advantages come from pills and not everyone likes to take pills. Another technique is Botox. Botox is good but not all-inclusive. It is not efficient at combating those wrinkles around the mouth or wrinkles brought about by sun damage. In addition, it will not perform for everyone in an identical manner. These issues are hampering the growth of the Anti-Aging Products and Therapies Market.

Anti-Aging Products and Therapies Market Landscape:

Product launches, mergers and acquisitions, joint ventures, and geographical expansions are key strategies adopted by players in the Anti-Aging Products and Therapies Market. Key companies of this market are:

GaoxinMerckIMEIKBohus BioTechLG Life ScienceGaldermalAllerganIpsenLanzhou InstituteCynosure

Recent Developments

In January 2022, Chanel has introduced a series of skincare and cosmetic products described by Vogue as its most environmentally conscious to date, inclusive of its earliest refillable beauty product. The series of products, termed No. 1 de Chanel, is housed in packaging with no exterior plastic wrapping and no interior paper leaflets. Chanel has also discarded all plastic constituents in the bottles and jars, choosing glass instead and persuading customers to recycle the packaging once it is vacant.

In October 2021, Cynosure declared the Canadian (Health Canada) clearance of its best-in-class Potenza radiofrequency (RF) microneedling system providing clinicians incomparable versatility and customized treatments for patients with its one-of-a-kind Fusion Tip. The novel standard in RF microneedling, the Potenza devices four modes (monopolar or bipolar, conveyed at either 1 MHz or 2 MHz frequency), provides more personalized microneedling treatments for patients than ever before, which permits practitioners to convey both shallow and deep treatments on a single system. The devices monopolar RF mode conveys energy across a big area of tissue for deep heating and skin tightening by way of soft tissue coagulation, not only on the face but also anywhere on the body.

In October 2020, Cynosure declared the U.S. and Canadian introduction of FlexSureTM, the most-recent inclusion to its best-in-class TempSure 300-watt platform and the worlds earliest wrappable radiofrequency (RF) applicator for malleable, hands-free, non-invasive RF treatments. With its rare peel-and-stick single-application applicators, the body-boosting FlexSure treatment conveys deep tissue heating to numerous body parts, inclusive of the abdomen, flanks, back, arms, buttocks, thighs, and above the knees. Accessible in numerous sizes, each equipped with six customizable zones and real-time temperature-sensing capacities, the FlexSure device permits practitioners to carry out constant, quick, and efficient treatments in just 15 minutes per body area.

Key Takeaways

Geographically, North America Anti-Aging Products and Therapies Market accounted for the highest revenue share in 2021 and it is poised to dominate the market over the period 2022-2027 owing to the soaring awareness of aging signs resulting in the application of anti-aging therapies like liposuction and increasing obesity in the North American region.

Anti-Aging Products and Therapies Market growth is being driven by the expanding population of the elderly, surging demand for cosmetic products, and the emerging beauty consciousness amidst youth worldwide resulting in the application of anti-aging therapies like liposuction. However, the binding rules and regulations imposed by the government in endorsing novel products and the fluctuations in the accessibility of raw materials are directly impacting the ultimate price of products which is one of the major factors hampering the growth of the Anti-Aging Products and Therapies Market.

Anti-Aging Products and Therapies Market Detailed Analysis on the Strength, Weakness and Opportunities of the prominent players operating in the market will be provided in the Anti-Aging Products and Therapies Market report.

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Anti Aging Market

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Anti-Aging Products and Therapies Market Size Estimated to Reach $93.2 Billion by 2027 - Digital Journal

Recommendation and review posted by Bethany Smith

image:zebrafish notochord nuclei at 15-somite stage. Grey: nuclear DNA (DAPI). Color: histone H3K9me3 view more

Credit: Phong Nguyen, Franka Rang & Kim de Luca. Copryight Hubrecht Institute.

How is the activity of genes regulated by the packaging of DNA? To answer this question, a technique to measure both gene expression and DNA packaging at the same time was developed by Franka Rang and Kim de Luca, researchers from the group of Jop Kind (group leader at the Hubrecht Institute and Oncode Investigator). This method, EpiDamID, determines the location of modified proteins around which the DNA is wrapped. It is important to gather information about these modifications, because they influence the accessibility of DNA, thereby affecting the gene activity. EpiDamID is therefore valuable for research into the early development of organisms. The results of the study are published in Molecular Cell on April 1st 2022.

In order to fit DNA into the nucleus of a cell, it is tightly packed around nuclear proteins: histones. Depending on the tightness of this winding, the DNA can be (in)accessible to other proteins. This therefore determines whether the process of gene expression, translation of DNA into RNA and eventually into proteins, can take place.

DNA packaging determine gene activity

The tightness of DNA winding around histones is regulated by the addition of molecular groups, so-called post-translational modifications (PTMs), to the histones. For example, if certain molecules are added to the histones, the DNA winding is loosened. This makes the DNA more accessible for certain proteins and causes the genes in this part of the DNA to become active, or expressed. Furthermore, proteins that are crucial for gene expression can directly recognize and bind the PTMs. This enables transcription: the process of DNA copying.

The regulation of gene expression, for instance through PTMs, is also known as epigenetic regulation. Since all cells in a body have the same DNA, regulation of gene expression is needed to (de)activate specific functions in individual cells. For instance, heart muscle cells have different functions than skin cells, thus require different genes to be expressed.

Analysis of single cells using EpiDamID

To understand how PTMs affect gene expression, first authors Franka Rang and Kim de Luca designed a new method to determine the location of the modifications. Using this approach, called EpiDamID, researchers can analyze single cells, whereas previous methods were only able to measure a large group of cells. Analysis on such a small scale results in knowledge on how DNA winding differs per cell, rather than information on the average DNA winding of many cells.

EpiDamID is based on DamID, a technique which is used to determine the binding location of certain DNA-binding proteins. Using EpiDamID, the binding location of specific PTMs on histone proteins can be detected in single cells. Compared to others, a great advantage of this technique is that researchers need very limited material. Furthermore, EpiDamID can be used in combination with other methods, such as microscopy, to study regulation of gene expression on different levels.

Future prospects

Following the development of this technique, the Kind group will focus on the role of PTMs from the point of view of developmental biology. Because single cells are analyzed using EpiDamID, only a limited amount of material is needed to generate enough data. This allows researchers to study the early development of organisms from its first cell divisions, when the embryo consists of only a few cells.

###

Publication

Rang, F. J.*, de Luca, K. L.*, de Vries, S. S., Valdes-Quezada, C., Boele, E., Nguyen, P. D., Guerreiro, I., Sato, Y., Kimura, H., Bakkers, J. & Kind, J. Single-cell profiling of transcriptome and histone modifications with EpiDamID. Molecular Cell, 2022.

*Authors contributed equally

Jop Kind is group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and Oncode Investigator.

About the Hubrecht Institute

The Hubrecht Institute is a research institute focused on developmental and stem cell biology. It encompasses 21 research groups that perform fundamental and multidisciplinary research, both in healthy systems and disease models. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit http://www.hubrecht.eu.

Experimental study

Cells

Single-cell profiling of transcriptome and histone modifications with EpiDamID

1-Apr-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Original post:
Learning from the single cell: A new technique to unravel gene regulation - EurekAlert

Recommendation and review posted by Bethany Smith

Cell and gene therapies are poised to have a major impact on the landscape of modern medicine, carrying the potential to treat an array of different diseases with unmet clinical need.

However, the number of approved, clinically adopted cell and gene therapies is mere compared to the amount that are currently in development. A major barrier for the translation of such therapies is the safe integration of therapeutic genes into the human genome. The insertion of therapeutic genes bears the risk of off target effects, or integration of the gene into an unintended location.

A number of different strategies have been proposed to mitigate this effect. The most recent body of work comes from a collaboration between Harvards Wyss Institute for Biologically Inspired Engineering, Harvard Medical School (HMS) and the ETH Zurich in Switzerland.

Published in Cell Report Methods, the research focused on identifying safe spots in the genome. These locations, known as genomic safe harbors (GSHs), are areas in the genome that meet the following criteria: they can be accessed easily by genome-editing strategies, are within a safe distance from genes that possess functional properties and permit expression of a therapeutic gene, only once it has landed in the harbor. A simple analogy is deciding which harbor to dock a boat there are many considerations, and these depend on the type of boat you are sailing, the weather conditions and ease of access.

The research team adopted computational strategies that enabled the identification of 2,000 predicted GSHs. From this initial identification, they successfully validated two of the sites both in vitro and in vivo using reporter proteins.

Technology Networks interviewed the studys first author, Dr. Erik Aznauryan, research fellow in the laboratory of Professor George Church at Harvard Medical School. Aznauryan dives into further detail on the history of GSH research, the methods adopted to validate the GSH sites and the potential applications of this research.

Molly Campbell (MC): Can you talk about the history of genomic safe harbor research, and how they were discovered?

Erik Aznauryan (EA): Three genomic sites were empirically identified in previous studies to support stable expression of genes of interest in human cells: AAVS1, CCR5 and hRosa26. All these examples were established without any a-priori safety assessment of the genomic loci they reside in.

Attempts have been made to identify human GSH sites that would satisfy various safety criteria, thus avoiding the disadvantages of existing sites. One approach developed by Sadelain and colleagues used lentiviral transduction of beta-globin and green fluorescence protein genes into induced pluripotent stem cells (iPSCs), followed by the assessment of the integration sites in terms of their linear distance from various coding and regulatory elements in the genome, such as cancer genes, miRNAs and ultraconserved regions.

They discovered one lentiviral integration site that satisfied all of the proposed criteria, demonstrating sustainable expression upon erythroid differentiation of iPSCs. However, global transcriptome profile alterations of cells with transgenes integrated into this site were not assessed. A similar approach by Weiss and colleagues used lentiviral integrations in Chinese hamster ovary (CHO) cells to identify sites supporting long-term protein expression for biotechnological applications (e.g., recombinant monoclonal antibody production). Although this study led to the evaluation of multiple sites for durable, high-level transgene expression in CHO cells, no extrapolation to human genomic sites was carried out.

Another study aimed at identifying GSHs through bioinformatic search of mCreI sites regions targeted by monomerized version of I-CreI homing endonuclease found and characterized in green algae as capable to make targeted staggered double-strand DNA breaks residing in loci that satisfy GSH criteria. Like previous work, several stably expressing sites were identified and proposed for synthetic biology applications in humans. However, local and global gene expression profiling following integration events in these sites have not been conducted.

All these potential GSH sites possess a shared limitation of being narrowed by lentiviral- or mCreI-based integration mechanisms. Additionally, safety assessments of some of these identified sites, as well as previously established AAVS1, CCR5 and Rosa26, were carried out by evaluating the differential gene expression of genes located solely in the vicinity of these integration sites, without observing global transcriptomic changes following integration.

A more comprehensive bioinformatic-guided and genome-wide search of GSH sites based on established criteria, followed by experimental assessment of transgene expression durability in various cell types and safety assessment using global transcriptome profiling would, thus, lead to the identification of a more reliable and clinically useful genomic region.

MC: If GSHs do not encode proteins, or RNAs with functions in gene expression, or other cellular processes what is their function in the genome?

EA: In addition to protein coding, functional RNA coding, regulatory and structural regions of the human genome, other less well understood and inactive DNA regions exist.

A large proportion of the human genome seems to have evolved in the presence of a variety of integrating viruses which, as they inserted their DNA into the eukaryotic genome over the course of million years, lead to an establishment of vast non-coding elements that we continue to carry to this day. Furthermore, partial duplications of functional human genes have resulted in the formation of inactive pseudogenes, which occupy space in the genome yet are not known to bear cellular functions.

Finally, functional roles of some non-coding portions of the human genome are not well understood yet. Our search of safe harbors was conducted using existing annotation of the human genome, and as more components of it are deciphered the identification of genomic regions safe for gene insertion will become more informed.

MC: Are you able to discuss why some regions of the genome were previously regarded as GSHs but are now recognized as non-GSHs?

EA: In the absence of other alternatives, AAVS1, CCR5 and hRosa26 sites were historically called GSHs, as they supported the expression of genes of interest in a variety of cell types and were suitable for use in a research setting.

Their caveats (mainly, location within introns of functional genes, closely surrounded by other known protein coding genes as well as oncogenes) however prevent them from being used for clinical applications. Therefore, in our paper we dont call them GSHs, and refer to our newly discovered sites as GSHs.

MC: You thoroughly scanned the genome to identify candidate loci for further study as potential GSHs. Can you discuss some of the technological methods you adopted here, and why?

EA: We used several publicly available databases to identify genomic coordinates of structural, regulatory and coding components of the human genome according to the GSH criteria we outlined in the beginning of our study (outside genes, oncogenes, lncRNAs etc.,). We used these coordinates and bioinformatic tools such as command lines bedtools to exclude these genomic elements as well as areas adjacent to them. This left us with genomic regions putative GSHs from which we could then experimentally validate by inserting reporter and therapeutic genes into them followed by transcriptomic analysis of GSH-integrated vs non-integrated cells.

MC: You narrowed down your search to test five, and then two GSHs. Can you expand on your choice of reporter gene when assessing two GSHs in cell lines?

EA: Oftentimes in research you go with what is available or what is of the most interest to the lab you are currently working in.

Our case was not an exception, and we initially (up until the T cell work) used the mRuby reporter gene as it was widely available and extensively utilized and validated in our lab at ETH Zurich back then.

When I moved to the Wyss Institute at Harvard, I began collaborating with Dr. Denitsa Milanova, who was interested in testing these sites in the context of skin gene therapy particularly the treatment of junctional epidermolysis bullosa caused by mutations in various anchor proteins connecting different layers of skin, among which is the LAMB3 gene. For this reason, we decided to express this gene in human dermal fibroblasts, together with green fluorescent protein to have a visualizable confirmation of expression. We hope we would be able to translate this study into clinics.

MC: Can you describe examples of how GSHs can be utilized in potential therapeutics?

EA: Current cell therapy approaches rely on random insertion of genes of interest into the human genome. This can be associated with potential side effects including cancerous transformation of therapeutic cells as well as eventual silencing of the inserted gene.

We hope that current cell therapies will eventually transition to therapeutic gene insertions precisely into our GSHs, which will alleviate both described concerns. Specific areas of implementation may involve safer engineering of T cells for cancer treatment: insertion of genes encoding receptors targeting tumor cells or cytokines capable of enhancing anti-tumor response.

Additionally, these sites can be used for the engineering of skin cells for therapeutic (as discussed earlier with the LAMB3 example) as well as anti-aging applications, such as expression of genes that result in youthful skin phenotype.

Finally, given the robustness of gene expression from our identified sites, they can be used for industry-scale bio-manufacturing: high-yield production of proteins of interest in human cell lines for subsequent extraction and therapeutic applications (e.g., production of clotting factors for patients with hemophilias).

MC: Are there any limitations to the research at this stage?

EA: A primary limitation to this study is the low frequency of genomic integration events using CRISPR-based knock-in tools. This means that cells in which the gene of interest successfully integrated into the GSH must be pulled out of the vastly larger population of cells without this integration.

These isolated cells would then be expanded to generate homogenous population of gene-bearing cells. Such pipeline is not ideal for a clinical setting and improvements in gene integration efficiencies are needed to help this technology easier translate into clinics.

Our lab is currently working on developing genome engineering tools which would eventually allow to integrate large genes into GSHs with high precision and efficiency.

MC: What impact might this study have on the cell and gene therapy development space?

EA: This study will hopefully lead to many researchers in the field testing our sites, validating them in other therapeutically relevant cell types and eventually using them in research as well as in clinics as more reliable, durable and safe alternatives to current viral based random gene insertion methods.

Additionally, since in our work we shared all putative GSHs identified by our computational pipeline, we hope researchers will attempt to test sites we havent validated yet by implementing the GSH evaluation pipeline that we outlined in the paper. This will lead to identification of more GSHs with perhaps even better properties for clinical translation or bio-manufacturing.

MC: What are your next steps in advancing this work?

We hope to one day translate our successful in vitro skin results and start using these GSHs in an in vivo context.

Additionally, we are looking forward to improving integration efficiencies into our GSHs, which would further support clinical transition of our sites.

Finally, we will evaluate the usability of our GSHs for large-scale production of therapeutically relevant proteins, thus ameliorating the pipeline of manufacturing of biologics.

Dr. Erik Aznauryan was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

View original post here:
Sailing the Genome in Search of Safe Harbors - Technology Networks

Recommendation and review posted by Bethany Smith

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7 Easy Ways to Transition Your Skin Care Routine for Spring - Vancouver Magazine

Recommendation and review posted by Bethany Smith

The following discussion of our financial condition and results of operationsshould be read in conjunction with our audited consolidated financial statementsand related notes and other financial information included elsewhere in thisAnnual Report on Form 10-K. The discussion contains forward-looking statements,such as our plans, expectations and intentions (including those related toclinical trials and business and expense trends), that are based upon currentexpectations and that involve risks and uncertainties. Our actual results maydiffer significantly from management's expectations. The factors that couldaffect these forward-looking statements are in Item 1A of Part I of this report.This discussion should not be construed to imply that the results discussedherein will necessarily continue into the future, or that any expectationsexpressed herein will necessarily be indicative of actual operating results inthe future. Such discussion represents only the best present assessment by ourmanagement.

Business Overview

We have generated aggregate product revenues from our two commercial businessesof $7.2 million and $7.1 million for the years ended December 31, 2021 and 2020,respectively. We currently have no revenue generated from our principaloperations in therapeutic and clinical product development.

Our products are based on multi-decade experience with human cell culture and aproprietary type of pluripotent stem cells, human parthenogenetic stem cells("hpSCs"). Our hpSCs are comparable to human embryonic stem cells ("hESCs") inthat they have the potential to be differentiated into many different cells inthe human body. However, the derivation of hpSCs does not require the use offertilized eggs or the destruction of viable human embryos and also offers thepotential for the creation of immune-matched cells and tissues that are lesslikely to be rejected following transplantation. Our collection of hpSCs, knownas UniStemCell, currently consists of 15 stem cell lines. We have facilitiesand manufacturing protocols that comply with the requirements of GoodManufacturing Practice (GMP) standards as promulgated by the U.S. Code ofFederal Regulations and enforced by the United States Food and DrugAdministration ("FDA").

COVID-19 Pandemic

The impact of the COVID-19 pandemic has been and will likely continue to beextensive in many aspects of society, which has resulted in and will likelycontinue to result in significant disruptions to the global economy, as well asbusinesses and capital markets around the world. Impacts to our business haveincluded a reduction in sales volume primarily from media sales in ourbiomedical market segment and professional channel sales in our anti-agingmarket segment, temporary or reduced occupancy of portions of our manufacturingfacilities, and disruptions or restrictions on our employee's ability to travelto such manufacturing facilities which caused minor delays in manufacturing. Ourmanufacturing facilities continue to operate as they are deemed essentialsuppliers in accordance with laws applicable to California and Maryland. We havetaken precautionary measures to better ensure the health and safety of ourworkers, including staggering employees' shifts and isolating at-risk employees.

The scope and duration of these delays and disruptions, and the ultimate impactsof COVID-19 on our operations, are currently unknown. We are continuing toactively monitor the situation and may take further precautionary and preemptiveactions as may be required by federal, state or local authorities or that wedetermine are in the best interests of public health and safety. We cannotpredict the effects that such actions, or the impact of COVID-19 on globalbusiness operations and economic conditions, may continue to have on ourbusiness, strategy, collaborations, or financial and operating results.

Market Opportunity and Growth Strategy

Therapeutic Market - Clinical Applications of hpSCs for Disease Treatments

With respect to therapeutic research and product candidates, we focus onapplications where cell and tissue therapy is already proven but where there isan insufficient supply of safe and functional cells or tissue. We believe thatthe most promising potential clinical applications of our technology are: 1)Parkinson's disease ("PD"); and 2) traumatic brain injury ("TBI"). Using ourproprietary technologies and know-how, we are creating neural stem cells fromhpSCs as a potential treatment of PD, TBI and stroke.

Our most advanced project is the neural stem cell program for the treatment ofParkinson's disease. In 2013 we published in Nature Scientific Reports the basisfor our patent on a new method of manufacturing neural stem cells which is usedto produce the clinical-grade cells necessary for future clinical studies andcommercialization. In 2014 we completed the majority of the preclinical researchestablishing the safety profile of NSC in various animal species includingnon-human primates. In June 2016 we published the results of a 12-monthpre-clinical non-human primate study, which demonstrated the safety, efficacyand mechanism of action of the ISC- hpNSC. In 2017 we dosed four patients inour Phase I trial of ISC-hpNSC, human parthenogenetic stem cell-derived neuralstem

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cells for the treatment of Parkinson's disease. We reported 12-month resultsfrom the first cohort and 6-month interim results of the second cohort at theSociety for Neuroscience annual meeting (Neuroscience 2018) in November 2018. InApril 2019, we announced the completion of subject enrollment, with the 12thsubject receiving a transplantation of the highest dose of cells. There havebeen no safety signals or serious adverse effects seen to date as related to thetransplanted ISC-hpNSC cells.

In August 2014 we announced the launch of a stroke program, evaluating the useof ISC-hpNSC transplantation for the treatment of ischemic stroke using arodent model of the disease. The Company has a considerable amount of safetydata on ISC-hpNSC from the Parkinson's disease program and, as there isevidence that transplantation of ISC-hpNSC may improve patient outcomes as anadjunctive therapeutic strategy in stroke, having a second program that can usethis safety dataset is therefore a logical extension. In 2015 the Companytogether with Tulane University demonstrated that NSC can significantly reduceneurological dysfunction after a stroke in animal models.

In October 2016 we announced the results of the pre-clinical rodent study,evaluating the use of ISC-hpNSC transplantation for the treatment of TBI. Thestudy was conducted at the University of South Florida Morsani College ofMedicine. We demonstrated that animals receiving injections of ISC-hpNSCdisplayed the highest levels of improvements in cognitive performance and motorcoordination compared to vehicle control treated animals. In February 2019, wepublished the results of the pre-clinical study in Theranostics, a prestigiouspeer-reviewed medical journal. The publication titled, "Human parthenogeneticneural stem cell grafts promote multiple regenerative processes in a traumaticbrain injury model," demonstrated that the clinical-grade neural stem cells usedin our Parkinson's disease clinical trial, ISC-hpNSC, significantly improvedTBI-associated motor, neurological, and cognitive deficits without any safetyissues.

Anti-Aging Cosmetic Market - Skin Care Products

Our wholly-owned subsidiary LSC develops, manufactures and offers for saleanti-aging skin care products based on two core technologies: encapsulatedextract derived from hpSC and specially selected targeted small molecules. LSC'sproducts include:

LSC's products are regulated as cosmetics. LSC's products are sold domesticallythrough a branded website, Amazon, ecommerce partners and through theprofessional channel (including dermatologists, plastic surgeons, medical, dayand resort spas).

Biomedical Market - Primary Human Cell Research Products

Our wholly-owned subsidiary LCT develops, manufactures and commercializesapproximately 200 human cell culture products, including frozen human "primary"cells and the reagents (called "media") needed to grow, maintain anddifferentiate the cells. LCT's scientists have used a standardized, methodical,scientific approach to basal medium optimization to systematically produceoptimized products designed to culture specific human cell types and to elicitspecific cellular behaviors. These techniques can also be used to produceproducts that do not contain non-human animal proteins, a feature desirable tothe research and therapeutic markets. Each LCT cell product is quality testedfor the expression of specific markers (to assure the cells are the correcttype), proliferation rate, viability, morphology and absence of pathogens. Eachcell system also contains associated donor information and all informed consentrequirements are strictly followed. LCT's research products are marketed andsold by its internal sales force, OEM partners and LCT brand distributors inEurope and Asia.

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Results of Operations

Comparison of the Years Ended December 31, 2021 and 2020

Product sales revenue for the year ended December 31, 2021 was $7.2 million,compared to $7.1 million for the year ended December 31, 2020. The increase wasprimarily attributable to a $342 thousand increase in sales in our biomedicalmarket segment, largely offset by a $294 thousand decrease in sales in ouranti-aging market during 2021 compared to 2020.

Our biomedical product sales continue to recover from the impacts of COVID-19 aspurchasing activity from our largest original equipment manufacturer customersincreases.

Our professional skin care products, which are largely marketed to medicalprofessionals and spas that offer walk-up retail, experienced a significantdecline in customer demand due to COVID-19 and the related restrictions as thesebusinesses have continued with limited or reduced operations during the yearended December 31, 2021. The impact of these restrictions was mitigated in-partby expanding our offering of professional skin care products through ourecommerce channel. Anti-aging product sales through our ecommerce channelremained consistent year-over-year.

Cost of Sales

Cost of sales for the year ended December 31, 2021 was $2.9 million, compared to$2.8 million for the year ended December 31, 2020. The increase was primarilyattributable to an increase in costs as a result of an increase in productsales. Profit margins have deteriorated for the year ended December 31, 2021 ascompared to 2020, largely as a result of rising raw materials and labor relatedcosts, and a scarcity of certain materials, principally plastics. In response,we have increased our supply of raw materials on hand and have, where possible,sourced materials from alternative vendors.

Cost of sales consists primarily of salaries and benefits associated withemployee efforts expended directly on the production of the Company's products,as well as related direct materials, general laboratory supplies and anallocation of overhead. We aim to continue refining our manufacturing processesand supply chain management to improve the cost of sales as a percentage ofrevenue for both LCT and LSC.

General and Administrative Expenses

General and administrative expenses for the year ended December 31, 2021 was$4.1 million, compared to $4.4 million for the year ended December 31, 2020. Thedecrease was primarily attributable to a decrease in personnel-related costs andstock-based compensation of $522 thousand, a $87 thousand decrease in consultingand servicing fees, and a $26 thousand decrease in investor relations fees,partially offset by an increase in impairment of intangible assets of$184 thousand, a $57 thousand increase in director and officer liabilityinsurance premiums, a $24 thousand increase in human resource related expenses,a $16 thousand gain on foreign currency exchange rate conversion, and a$15 thousand increase in filing fees.

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Selling and Marketing Expenses

Selling and marketing expenses for the year ended December 31, 2021 was$1.4 million, compared to $1.8 million for the year ended December 31, 2020. Thedecrease was primarily attributable to a $178 thousand decrease inpersonnel-related costs, sales commissions and stock-based compensation,primarily as a result of headcount reductions and grants from 2018 which wereissued and fully vested in 2021, and a $211 thousand decrease in marketing,advertising, and building related expenses, partially offset by a $17 thousandincrease in consulting and creative service fees. The reduction in marketing,advertising, and building related expenses was largely attributable to travelrestrictions as a result of COVID-19.

Research and Development Expenses

Research and development expenses for the year ended December 31, 2021 was$0.7 million, compared to $1.0 million for the year ended December 31, 2020. Thedecrease was primarily attributable to a $247 thousand decrease inpersonnel-related costs and stock-based compensation primarily as a result ofheadcount reductions and grants from 2018 which were issued and fully vested in2021, a $89 thousand decrease in materials and supplies related to clinicaltrial expenses, a $46 thousand decrease in consulting services, partially offsetby a $45 thousand increase in building and utilities related expenses and a$44 thousand decrease in our research and development tax credit related toqualifiable expenditures from our research and development activities of ourAustralia subsidiary, Cyto Therapeutics, which reduced research and developmentexpenses for years ended December 31, 2021 and 2020.

Our research and development efforts are primarily focused on the development oftreatments for Parkinson's disease, traumatic brain injury, liver diseases,stroke, and the creation of new GMP grade human parthenogenetic stem cell lines.These projects are long-term investments that involve developing both new stemcell lines and new differentiation techniques that can provide higher puritypopulations of functional cells. Research and development expenses are expensedas incurred and are accounted for on a project-by-project basis. However, muchof our research has potential applicability to each of our projects. As wecompleted Phase 1 of our clinical in June 2021, we do not anticipate significantinvestment in research and development efforts related to therapeutic andclinical product development efforts for the foreseeable future, or until suchtime that we initiate a Phase 2 clinical trial.

Other Income, Net

Other income, net, for the year ended December 31, 2021 was $1.0 million,compared to other income, net, of $94 thousand for the year endedDecember 31, 2020. The increase was primarily attributable to forgiveness of ourFirst Draw Loan and Second Draw Loan from the PPP, collectively totaling$1.1 million, partially offset by a decrease of $207 thousand for the change inthe fair value of the warrant liability during the prior year period. Thewarrants expired unexercised in March 2021 and, as such, no further change inthe fair value of the warrant liability will be recognized.

Liquidity and Capital Resources

As of December 31, 2021, we had an accumulated deficit of approximately$110 million and have, on an annual basis, incurred net losses and negativeoperating cash flows since inception. Substantially all of our operating losseshave resulted from the funding of our research and development programs andgeneral and administrative expenses associated with our operations. We incurrednet losses of $0.9 million and $2.7 million for years ended December 31, 2021and 2020, respectively. As of December 31, 2021, we had cash of $171 thousand,compared to $689 thousand as of December 31, 2020.

In May 2020, we received a first draw loan of $654 thousand from the PPP ("FirstDraw Loan") which provided additional liquidity to support our currentoperations. In March 2021, we received a second draw loan of $474 thousand fromthe PPP ("Second Draw Loan"). In June 2021, we applied for and receivedforgiveness of unpaid principal and accrued interest from our First Draw Loan inthe amount of $661 thousand. In August 2021, we applied for and receivedforgiveness of unpaid principal and accrued interest from our Second Draw Loanin the amount of $476 thousand. As of December 31, 2021, we are not eligible toreceive any additional funding, or have any further obligations, related to thePPP.

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Cash Flows

Comparison of the Years Ended December 31, 2021 and 2020

The following table provides information regarding our cash flows for the yearsended December 31, 2021 and 2020 (in thousands):

Net cash used in operating activities $ (1,297 ) $ (341 )Net cash used in investing activities

Operating Cash Flows

For the year ended December 31, 2021, net cash used in operating activities was$1.3 million, resulting primarily from our net loss of $899 thousand and netchanges in operating assets and liabilities of $823 thousand, consistingprimarily of an increase in accounts receivable of $441 thousand, inventory,net, of $268 thousand, and decrease in operating lease liabilities of $342thousand, partially offset by net non-cash adjustments of $425 thousand. For theyear ended December 31, 2020, net cash used in operating activities was$341 thousand, resulting primarily from our net loss of $2.7 million and changein fair value of warrant liability of $207 thousand, offset by non-cashadjustments of stock-based compensation expense of $1.3 million, operating leaseexpense of $265 thousand and depreciation and amortization of $253 thousand,coupled with net changes in operating assets and liabilities of $623 thousand.

Investing Cash Flows

Net cash used in investing activities for the year ended December 31, 2021 was$45 thousand, compared to $108 thousand for the year ended December 31, 2020.The decrease was attributable to a decrease in payments for patent licenses of$58 thousand and purchases of property and equipment of $5 thousandyear-over-year.

Financing Cash Flows

Net cash provided by financing activities for year ended December 31, 2021 was$0.8 million, compared to $0.7 million for the year ended December 31, 2020. Forthe year ended December 31, 2021, net cash provided by financing activitiesconsisted of $474 thousand in proceeds from our second draw loan under thePaycheck Protection Program, coupled with proceeds from a note payable from arelated party of $350 thousand. For the year ended December 31, 2020, net cashprovided by financing activities consisted of $654 thousand in proceeds from ourfirst draw loan under the Paycheck Protection Program.

Liquidity and Going Concern

Management continues to evaluate various financing sources and options to raiseworking capital to help fund our current research and development programs andoperations. We will need to obtain significant additional capital from sourcesincluding exercise of outstanding warrants, equity and/or debt financings,license arrangements, grants and/or collaborative research arrangements tosustain our operations and develop products. Unless we obtain additionalfinancing, we do not have sufficient cash on hand to sustain our operations atleast through one year after the issuance date. The timing and degree of anyfuture capital requirements will depend on many factors, including:

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Our failure to raise capital or enter into applicable arrangements when neededwould have a negative impact on our financial condition. Additional debtfinancing may be expensive and require us to pledge all or a substantial portionof its assets. Further, if additional funds are obtained through arrangementswith collaborative partners, these arrangements may require us to relinquishrights to some of its technologies, product candidates or products that we wouldotherwise seek to develop and commercialize on its own. If sufficient capital isnot available, we may be required to delay, reduce the scope of or eliminate oneor more of its product initiatives.

We currently have no revenue generated from our principal operations intherapeutic and clinical product development through research and developmentefforts. In addition, as we completed Phase 1 of our clinical in June 2021, wedo not anticipate significant investment in research and development effortsrelated to therapeutic and clinical product development efforts for theforeseeable future, or until such time that we initiate a Phase 2 clinicaltrial. There can be no assurance that we will be successful in maintaining ournormal operating cash flow and obtaining additional funds and that the timing ofour capital raising or future financing will result in cash flow sufficient tosustain our operations at least through one year after the issuance date.

Based on the factors above, there is substantial doubt about our ability tocontinue as a going concern. The consolidated financial statements were preparedassuming that we will continue to operate as a going concern. The consolidatedfinancial statements do not include any adjustments to reflect the possiblefuture effects on the recoverability and classification of assets or the amountsand classification of liabilities that may result from the outcome of thisuncertainty. Management's plans in regard to these matters are focused onmanaging our cash flow, the proper timing of our capital expenditures, andraising additional capital or financing in the future.

Critical Accounting Policies and Estimates

Our discussion and analysis of our financial condition and results of operationsis based upon our consolidated financial statements, which have been prepared inaccordance with accounting principles generally accepted in the United States.The preparation of these financial statements requires us to make estimates andassumptions that affect the reported amounts of assets, liabilities, revenues,expenses and related disclosures. On an on-going basis, we evaluate ourestimates and assumptions and we base our estimates on historical experience andon various other assumptions that are believed to be reasonable under thecircumstances, the results of which form the basis for making judgments aboutthe carrying values of assets and liabilities that are not readily apparent fromother sources. Actual results may differ from these estimates under differentassumptions and conditions.

Our significant accounting policies are more fully described in Note 1 to ourconsolidated financial statements included elsewhere in this Annual Report onForm 10-K. Our most critical accounting estimates include current andnon-current inventory, intangible assets, and stock-based compensation. Wereview our estimates and assumptions periodically and reflect the effects ofrevisions in the period in which they are deemed to be necessary. We believethat the following accounting policies are critical to the judgments andestimates used in preparation of our consolidated financial statements.

Intangible Assets

Our intangible assets consist of acquired patent licenses and capitalized legalfees related to the acquisition, filing, maintenance, and defense of patents andtrademarks. Amortization begins once the patent is issued by the appropriateauthoritative bodies. In the period in which a patent application is rejected orefforts to pursue the patent are abandoned, all the related accumulated costsare expensed. Our patents and other intangible assets are amortized on astraight-line basis over the shorter of the useful life of the underlyingpatent, which is generally 15 years, or when the intangible asset is rejected orabandoned. All amortization expense and impairment charges related to intangibleassets are included in general and administrative expense in our consolidatedstatements of operations.

Allowance for Excess and Obsolete Inventory

Our inventory, particularly within our biomedical market, consists of certainproducts that have a long or, when frozen, indefinite shelf life. In addition,future demand for our products is uncertain. Accordingly, at each reportingperiod, we estimate a reserve for allowance for excess and obsolete inventory.This estimate is computed using historical sales data and inventory turnoverrates, which are subjective in nature and fluctuate between periods. Theestablishment of a reserve for excess and obsolete inventory establishes a

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new cost basis in the inventory with a corresponding adjustment to cost ofsales. If we are unable to sell such inventory, any related reserves are reducedin the period of sale.

Stock-Based Compensation

We are required to measure and recognize compensation expense for allstock-based payment awards made to employees and consultants based on estimatedfair value. We estimate the fair value of stock options granted using theBlack-Scholes option-pricing model.

The determination of fair value of stock-based awards using the Black-Scholesoption-pricing model requires the use of certain estimates and subjectiveassumptions that affect the amount of stock-based compensation expenserecognized in our consolidated statements of operations. These include estimatesof the expected volatility of our stock price, expected option life, expecteddividends and the risk-free interest rate. Estimated volatility is a measure ofthe amount by which our stock price is expected to fluctuate each year duringthe expected life of the award. The expected option life is calculated using themid-point method as prescribed by accounting guidance for stock-basedcompensation. We determined expected dividend yield to be 0% given that we havenever declared or paid any cash dividends on our common stock, and we currentlydo not anticipate paying such cash dividends. The risk-free interest rate isbased upon United States Treasury securities with remaining terms similar to theexpected term of the share-based awards. If any of the assumptions used in theBlack-Scholes model change significantly, stock-based compensation expense maydiffer materially from what we have recorded in the current period.

Recently Issued Accounting Pronouncements

A description of recently issued accounting pronouncements that may potentiallyimpact our financial position and results of operations is disclosed in Note 1to our consolidated financial statements included in this Annual Report on Form10-K.

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Edgar Online, source Glimpses

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INTERNATIONAL STEM CELL CORP MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com

Recommendation and review posted by Bethany Smith

Cell therapy research is the process of developing and testing whole cells that can be delivered to a patient to treat or cure a disease. Bone marrow transplants are one of the earliest cell therapies developed where bone marrow cell from a healthy person are used to repopulate the bone marrow of patients with some cancers. Newer cell therapies are cells that may be harvested from altered to target a disease or may be cells that are produced in a laboratory. The cell therapy is infused or transplanted into the patient as a treatment for a disease.

Genes are responsible for creating the proteins that control cellular processes. In many diseases, genetic instructions to code for the protein are missing or defective. Gene therapy research is the process by which scientists develop and test a DNA or RNA molecule that could be delivered back to the patient to treat the disease. Scientists first identify the impacted gene and the nature of the defect in patient cells. Depending on the nature of the defect, a gene therapy can be developed that is a proper copy of the gene or suppresses the defective copy of the gene from being used by the cell. The gene therapy is then put inside of a vector or a nanoparticle that can target the therapy to the proper cells when it is administered to the patient. Once delivered to the patient, the gene therapy provides genetic instructions for that can be used by the cell to correct or minimize the impact of the defect.

Researchers work with contract research organizations, like Charles River, by using gene and cell therapy services to prove efficacy and safety through various study types prior to submitting to agency for approval for first-in-human clinical trials. During and after approval of human trials, researchers continue to work with contract research organizations for clinical trial support, extended nonclinical safety studies and manufacturing support. Additional steps and studies are taken following clinical trials to ensure safety in the manufacturing stages before market release.

Link:
Cell and Gene Therapy Services | Charles River

Recommendation and review posted by Bethany Smith

Professor Rachel Lennon, Professor of Nephrology at the University of Manchester said: Rare diseases have an enormous impact on an individuals life, and they do not attract the critical mass of researchers required to enable rapid improvements in treatment. This Kidney Research UK-Stoneygate award to establish a UK hub for Alport Research is fabulous news and it will transform our ability to increase awareness, improve understanding of the condition and to accelerate new treatment options for patients. By bringing together expertise in cell and matrix biology, genetics and clinical practice, we aim to improve genetic testing and to progress a range of therapy options to extend kidney survival in patients with Alport syndrome.

Sandra Currie, chief executive of Kidney Research UK said: Rare diseases offer a unique challenge to charities such as ours and the overall scientific community. Often, there are limited resources attributed to sourcing new treatments as well as an overall lack of understanding into the causes, impacts and ways to treat them. Embarking on this new collaborative way of working, we are tackling this issue head on by bringing together a wealth of facilities and expertise. With this new Hub, we have the potential to accelerate the discovery and testing of new treatments and possibly even a cure through gene therapy.

The diagnosis and treatment of Alport syndrome have improved in the last decade. However, more progress is urgently needed. With the additional resources and funding, researchers are optimistic that results and transformative treatments could begin to emerge from the hub within the next five years.

See the rest here:
Collaborative research approach set to accelerate treatment of rare kidney condition - The University of Manchester

Recommendation and review posted by Bethany Smith

This article was originally posted on genetherapylive.

Cell and gene therapies are currently being evaluated as possible avenues of treatment for multiple inherited retinal diseases in the field of ophthalmology. Here we highlight the most promising therapies currently in development.

GT005 is a gene therapy by Gyroscope Therapeutics currently being evaluated in the recruiting phase 1/2 FocuStrial (NCT03846193) for the treatment of dry AMD. The company announced positive interim data in February 2021.

Regenerative Patch Technologies is developing the cell therapy CPCB-RPE1 for the treatment of geographic atrophy (GA) in dry AMD. It is being evaluated in 16 participants in a phase 1/2 trial (NCT02590692), positive data from which were presented in June 2021.

The cell therapy ASP7317 (Astellas Pharma) is being developed for GA in dry AMD and is being evaluated in 18 participants in a phase 1 trial (NCT03178149).

AAVCAGsCD59/HMR1002, a gene therapy developed by Hemera Biosciences for the treatment of wet AMD, is being evaluated in 25 participants enrolled in an ongoing phase 1 clinical trial (NCT03585556).

Regenxbios gene therapy RGX-314 is being evaluated in the recruiting phase 2/3 ATMOSPHERE trial (NCT04704921) for the treatment of wet AMD. Regenxbio presented positive initial data at the Retina Society 54th Annual Scientific Meeting in October 2021.

Adverum Biotechnologies is developing the gene therapy ADVM-022 for wet AMD, which is being evaluated in the phase 1 OPTIC trial (NCT03748784). The company plans to initiate a phase 2 trial after observing positive results in the OPTIC trial presented at the Retina Society meeting. The therapy was also being evaluated in diabetic macular edema, but that development was halted after serious adverse events, including irreversible vision loss, were seen in participants in the phase 2 INFINITY trial (NCT04418427).

Editas Medicines gene editing therapy, EDIT-101, is being evaluated in LCA type 10 in the phase 1/2 BRILLIANCE trial (NCT03872479). Data presented at the XIXth International Symposium on Retinal Degeneration demonstrated efficacy in some patients as well as safety concerns such as retinal tears and hemorrhage.

The gene therapy rAAV2-CBSB-hRPE65 is being developed by University of Pennsylvania and National Eye Institute. The therapy is being evaluated in 15 participants ina phase 1 trial (NCT00481546).

Sepofarsen (QR-110) is an RNA antisense oligonucleotide in development by ProQR Therapeutics. The therapy is being evaluated in the phase 2/3 ILLUMINATE trial (NCT03913143), results from which were published in Nature Medicine in April 2021. The last patient completed their last, 12-month visit in January 2022.

MeiraGTX's gene therapy cevaretigene ritoparvovec/AAV RPE65 met the primary endpoints in the phase 1/2 OPTIRPE65 trial (NCT02781480) in 2019. Additional clinical progress is expected in 2022.

Gensight Biologics gene therapy GS010 has so far demonstrated positive data in 90 participants in the phase 3 REFLECT trial (NCT03293524), including statistically significant improvements in visual acuity.

4D-110 is 4D Molecular Therapeutics gene therapy currently being evaluated in a recruiting phase 1 study (NCT04483440). The therapy has been well-tolerated in the low-dose cohort but serious adverse events (AEs) were observed in the high-dose cohort.

The University of Alberta is studying the gene therapy RAAV2.REP1 in 6 participants in a phase 1/2 (NCT02077361). Positive 5-year results were presented at The Association for Research in Vision and Ophthalmology (ARVO) 2021 meeting.

The University of Oxford is studying a similar RAAV2.REP1 gene therapy in 30 participants in a phase 2 trial (NCT02407678).

STZ eyetrials gene therapy RAAV.hCNGA3 is being evaluated in the recruiting phase 1/2 Colourbridge trial (NCT02610582).

Applied Genetic Technologies is developing AGTC-401 (NCT02599922) and AGTC-402 (NCT02935517) for CNGB3 and CNGA3 achromatopsia, respectively. Both phase 1/2 trials have demonstrated tolerable safety profiles for the gene therapies.

MeiraGTX is also developing gene therapies for both CNGB3 and CNGA3 achromatopsia. AAV CNGB3 (NCT03001310) and AAV CNGA3 (NCT03758404) are both in phase 1/2 studies.

QR-1123 is another antisense oligonucleotide from ProQR Therapeutics being evaluated in the recruiting phase 1/2 AURORA trial (NCT04123626) for RHO-RP.

MeiraGTXs gene therapy AAV2-RPGR has demonstrated positive data in X-linked RP (XLRP) in a phase 1/2 study (NCT03252847). The therapy will be further evaluated in the phase 3 Lumeos trial (NCT04671433).

Positive efficacy data from Applied Genetics phase 1/2 trial (NCT03316560) of the gene therapy AGTC-501/rAAV2tYF-GRK1-RPGR was presentedat the American Academy of Ophthalmology (AAO) 2021 Annual Meeting. The therapy is being further evaluated in the phase 2/3 VISTA trial(NCT04850118) for XLRP.

4Ds gene therapy 4D-125 was well-tolerated for XLRP in a phase 1/2 trial(NCT04517149), according to data presented at the 2021 American Society of Retina Specialists (ASRS) 39th Annual Meeting.

The National Eye Institute is evaluating RS1 AAV in a phase 1/2 trial (NCT02317887) for XLRP.

Coave Therapeutics gene therapy CTx-PDE6b (AAV2/5-hPDE6B)is being evaluated for PDE6b-RP in a phase 1/2 trial (NCT03328130).

GenSights GS030-DP gene therapy in combination with the GS030-MD optogenetic device has shown positive efficacy and safety data in treating end-stage blindness in RP. These data, from a phase 1/2 trial (NCT03326336), were presented at the 2021 AAO meeting.

Novartis is evaluating their gene therapy CPK805 in RLBP1-RP in a first in-human phase 1/2 trial (NCT03374657) that is currently recruiting.

ProQRs ulteversen/QR-421a gene therapy showed efficacy in the phase 1/2 Stellar trial (NCT03780257) for Usher syndrome and RP in March 2021. ProQR plans to soon advance the program into finalstage clinical testing.

The gene therapy RST-001 is being evaluated in a phase 1/2 trial (NCT02556736). Updates have been sparse for the therapy, which was developed by RetroSense Therapeutics, which was acquired by Allergan in 2016, which was then acquired byAbbvie in 2020.

The first 4 patients treated in the phase 1/2 trial (NCT04278131) of BS01 are able to detect light and motion,Bionic Sight announced in March 2021. The trial continues to enroll participants.

Nanoscope Therapeutics vMCO-I/MCO-010is being evaluated in a phase 1/2 trial (NCT04919473). Positive data in participants with autosomal recessive RP were presented at the ASRS 2021 meeting.

STZ eyetrials gene therapy rAAV.hPDE6A is being evaluated for PDE6A-RP in the recruiting phase 1/2 Pigment trial (NCT04611503).

More here:
A Wrap-Up of Ophthalmologic Cell And Gene Therapies Currently in Development - MD Magazine

Recommendation and review posted by Bethany Smith

REDWOOD CITY, Calif. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)--Kriya Therapeutics, Inc., a fully integrated company pioneering novel technologies and therapeutics in gene therapy, today announced an exclusive agreement with the Medical University of South Carolina (MUSC) Foundation for Research Development to license next generation complement-targeted gene therapies for the treatment of geographic atrophy and other ocular diseases.

Geographic atrophy, also known as atrophic age-related macular degeneration (AMD), is an advanced form of AMD, a progressive retinal disease affecting millions of adults worldwide. Patients with geographic atrophy experience irreversible loss of vision with significant impact on quality of life due to the chronic and progressive nature of the disease. There are currently no FDA-approved treatments available for geographic atrophy.

"This partnership highlights the broad potential of Kriyas technology and R&D platforms to drive innovation in diseases with established biology, and furthers our mission of developing transformative gene therapies for diseases with high unmet need," said Theresa Heah, M.D., M.B.A., President and Chief Medical Officer of Kriyas ophthalmology division. "We believe that complement hyperactivity is a clinically validated target implicated in the pathogenesis of retinal degeneration in geographic atrophy, and has the potential to address other ocular diseases. We are excited to develop gene therapies that precisely target this pathway, in collaboration with academic partners who have been at the forefront of characterizing the biology underlying these diseases.

The complement system plays a crucial role in the bodys innate immune system by enhancing its ability to clear pathogens and damaged cells, and regulating inflammatory immune responses through complement control proteins. Dysregulation and hyperactivity of the complement system is associated with the onset and progression of serious inflammatory diseases, including geographic atrophy and other ocular conditions. Through this agreement, Kriya is advancing gene therapies that are designed to durably express engineered molecules that selectively reduce complement hyperactivity at the site of pathology following one-time administration.

Geographic atrophy due to age-related macular degeneration is a devastating disease with a profound impact on patients, as there are no approved treatments for the irreversible loss of central vision that often occur, said Peter K. Kaiser, M.D., Professor of Ophthalmology, Cole Eye Institute, Cleveland Clinic. Recent advances in complement inhibitor therapies have provided important additional evidence that targeting complement holds great promise in treating geographic atrophy. I am excited by the potential of restoring balance to the complement system with a one-time gene therapy that can deliver a meaningful long-term solution and a major advancement in the field of retinal disease.

By targeting the inhibition of complement proteins directly involved in complement activation, our approach has the potential to deliver a selective and profound biological effect, said Dr. Brbel Rohrer, Ph.D., Professor of Ophthalmology at the Medical University of South Carolina, and co-inventor of the technology. After having confirmed the potential of this gene therapy strategy in mouse models of age-related macular degeneration, we are very excited to take the next step towards a clinical application for patients with geographic atrophy by partnering with Kriya, a leader in the development of novel gene therapies.

About Kriya

Kriya is a fully integrated company pioneering novel technologies and therapeutics in gene therapy. The company aims to revolutionize how gene therapies are designed, developed, and manufactured, improving speed to market, and delivering significant reductions in cost. Kriya is organized into four principal business units: Kriya Technologies, Kriya Therapeutics, Kriya R&D, and Kriya Manufacturing. The company is advancing a deep and diversified pipeline of innovative gene therapies in multiple therapeutic area divisions, with current pipeline programs in ophthalmology, oncology, rare disease, and chronic disease. Kriya was founded by pioneers in the biopharmaceutical industry and is backed by leading life sciences and technology investors. The company has core operations in Silicon Valley, California and Research Triangle Park, North Carolina. For more information, please visit http://www.kriyatx.com and follow on LinkedIn.

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Kriya Licenses Next Generation Complement-Targeted Gene Therapies for the Treatment of Geographic Atrophy and Other Ocular Diseases - Business Wire

Recommendation and review posted by Bethany Smith

Gene therapies have yielded promising results for individuals experiencing rare diseases. However, these groundbreaking therapies come with their own unique set of challenges regarding who will be able to access them, how much they will cost, and how the policymaking and scientific processes will conflict as more and more therapies undergo clinical trials.

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Last week, we convened a panel of experts to address these questions and discuss potential solutions in our latest 5 Slides Were Watching conversation, led by State of Reforms DJ Wilson. The panel featured Danny Seiden, president & CEO of the Arizona Chamber of Commerce and Industry, Dr. Jennifer Hodge, U.S. DMD Gene Therapy Lead at Pfizer, Dr. Rafael Fonseca, chief innovation officer at Mayo Clinic, and Dr. Sharon Hesterlee, chief research officer at the Muscular Dystrophy Association.

Hesterlee brought a slide showing the prevalence of rare diseases in Arizona, noting that 5,500 Arizonans were estimated to be living with rare genetic neuromuscular diseases that were potentially treatable with gene therapy. She highlighted that Charcot-Marie-Tooth disease and Myotonic dystrophy were the most prominent, and that both diseases currently have gene therapy treatments in preclinical development.

She emphasized that ethics need to be an important part of the conversation, and that it will be critical to educate patients and families about the treatments irreversible implications as more and more therapies begin to launch.

Its a permanent change to someone. What we see in particular with parents of a child who has a pediatric disease, they are put in a very difficult position because they have to make a decision without always understanding all of the science and all of the implications.

So I think there is a huge requirement for the physician [who does the informed consent] to be very clear, and then the parents have to decide if it doesnt work, my child cannot be redosed, my child may not be eligible for another trial I think thats been a big challenge and something that weve tried to help our community in the neuro-muscular disease space navigate.

Seiden brought a slide displaying the economic benefits that would come with the increased prevalence of gene therapies. He noted that outdated systems of payment would not be applicable to this kind of treatment, and that these therapies would allow for one-time costs as opposed to a lifetime of treatment for patients with rare diseases.

When you deal with rare diseases, you need to look at it on an annualized basis over the cost of a lifetime, because gene therapy has the potential to save money and a lot of heartache for the patients and the families involved with it Arizona is one of a handful of states that allows for value-based purchasing when it comes to Medicaid contracts With the [Arizona Health Care Cost Containment System (AHCCCS)], which is by far the largest provider, theyve recognized that you have to look at patient outcomes. Its not just about that initial upfront cost.

Hodge presented a slide illustrating the unmet needs of individuals with rare diseases and the potential impacts that gene therapies can have on these individuals. She emphasized the urgent need for innovative treatments for these diseases, as 95% of rare diseases worldwide have limited or no approved treatment options, and 80% of those rare diseases have a genetic cause. She said this makes patients with rare disease collectively one of the most underserved communities in medicine today.

She said educating every organization involved in the process of developing these therapies on the stories of real patients affected by these diseases will be critical as gene therapies move through both scientific and legislative processes.

Its really to address the underlying cause of rare diseases at the root, meaning the genetics, not the symptoms It cant be a line item in a bill, it cant be something on a piece of paper that you hear about, it has to be someone telling their story [and] thinking about the patient and what theyre going through.

You can learn so much by just sitting and talking and just hearing their story, and little things that you didnt even know affected them We need to bring that to more of the audience thats involved in making some of these decisions so they can see it as more than just a line on a piece of paper when theyre deciding something.

Fonseca showed a slide explaining some specific uses of gene therapy that could potentially provide individualized, life-saving treatment to people with red blood cell diseases, as well as preventive genetic interventions for diseases like cancer.

When you think about this approach in looking at the rare disorders, it turns out that by extrapolation, a lot of the diseases that we consider common also become more and more individualized, and therefore, theyre more and more unique. More and more, we see approaches that have to be very, very much [a] tailored design for patients

To have someone who is born with [a red-blood cell disorder] return to normal red blood cell function is just enormous. This is a worldwide problem, its a problem thats associated with pain, serious medical problems, a shorter lifespan, and great expenditures for the health system, and so [Im very excited about where were at with this].

Wilson highlighted that while few gene therapies have been officially launched in the market, many are currently in pre-clinical and clinical trials and are expected to provide promising health solutions for the future.

Continued here:
5 Slides We're Discussing: Gene therapy and the promise for rare disease - State of Reform - State of Reform

Recommendation and review posted by Bethany Smith

Cell lines

Human PC cell lines LNCaP and PC-3 obtained from JCRB Cell Bank (Osaka, Japan), and 22Rv1 purchased from The European Collection of Authenticated Cell Cultures were maintained in RPMI-1640 (FUJIFILM Wako Pure Chemical, Osaka, Japan) containing penicillin, streptomycin and 10% fetal bovine serum (Equitech-Bio, Kerrville, TX). The docetaxel-resistant 22Rv1 cell line, 22Rv1DR, was previously described18. All cell culture experiments were performed using cells within less than 20 passages except for PC-3PRF cells stably transfected with Tet-on tetracycline-inducible perforin expression vector and docetaxel-resistant 22Rv1DR cells.

Docetaxel was purchased from Selleckchem (Houston, TX, USA).

The perforin expression vector for Tet-On system (pT-Rex-DEST30-perforin) was purchased from Thermo Fisher Scientific (Waltham, MA, USA). The pcDNA6/TR regulatory vector (Thermo Fisher Scientific) and pT-Rex-DEST30-perforin vector were transfected to PC-3 cells using Lipofectamine 2000 (Thermo Fisher Scientific). Transfected cells were selected under 500g/ml G418 and 10g/ml Blasticidin (Thermo Fisher Scientific). Perforin was induced by 1g/ml of tetracycline. The human PSA promoter-driven perforin expression vector (pDRIVEperforin-psa-hpsa) was purchased from InvivoGen (San Diego, CA, USA).

Whole cell lysates were harvested and lysed in RIPA buffer containing the protease inhibitor cocktail (Sigma-Aldrich St. Louis, MO, USA). Western blot analysis was performed as described previously19. The anti-PSA and anti--actin antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). The immunoreactive proteins were detected using horseradish peroxidase-conjugated anti-rabbit antibody (Cell Signaling Technology) and ImmunoStar (FUJIFILM Wako Pure Chemical).

Perforin expression in conditioned medium, mouse serum and harvested xenograft tumors was measured by human perforin ELISA kit according to manufacturers instruction (Abcam, Cambridge, UK).

SS-cleavable and pH-activated lipid-like material (ssPalmM), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), cholesterol and 1,2-Dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000) were purchased from NOF Corporation (Tokyo, Japan). Encapsulation of plasmid vector in lipid nano-particles was conducted according to a previous report20. First, plasmid DNA and protamine solutions (0.3mg/mL and 0.144mg/mL) were prepared in 10mM HEPES buffer (pH5.3). Plasmid DNA/protamine core particle was prepared by the drop-wise addition of 1mL of the protamine solution into the 1mL of the DNA solution with vortexing. Liposome was composed of ssPalmM, DOPE, cholesterol and DMG-PEG2000 in a molar ratio of 3:4:3:0.5. Lipids (3.3mol of total lipids) were dissolved in 2mL of ethanol and the lipid solution (2mL) was rapidly diluted with an equal volume of the plasmid DNA/protamine core particle suspension with vortexing. The solution was further diluted with 36mL of 10mM HEPES (pH 5.3) to obtain 5% ethanol(v/v) concentration. The diluted solutions were concentrated to ten times by Amicon 8400 ultrafiltration stirred cell with a Biomax membrane (Merck Millipore, Allen, TX, USA) following further serial ultrafiltration with 100mM HEPES (pH 7.4) and 10mM HEPES (pH 7.4) using Amicon 8050 ultrafiltration stirred cell with a Biomax membrane. Finally, the liposome solution was filtrated by 0.45m of pore size Millex HV (Merck Millipore).

Liposome concentration was measured as total cholesterol concentration in the presence of sodium dodecyl sulfate using a Cholesterol E test Wako (FUJIFILM Wako Pure Chemical) and the total amount of fatty acids was calculated based of the molar ratio of each lipid. DNA concentration in liposomes was determined using Quant-iT Picogreen dsDNA Assay Kit (Thermo Fisher Scientific) in the presence of Triton X-100. Particle size and -potential were measured at 25C using Zetasizer Nano-S90 (Malvern Panalytical, Worcestershire, UK) after 50 times dilution of samples with distilled water.

This study was approved by the Medical Review Board of Gifu University, Graduate School of Medicine (No. 2018219). A written informed consent was obtained from participants and blood was collected from male volunteers without clinically detectable cancer. All methods were performed in accordance with the relevant guidelines and regulations in compliance with the Declaration of Helsinki. Human PBMCs were isolated by Ficoll-Paque density gradient centrifugation according to the manufacturers instructions (Amersham Biosciences, Piscataway, NJ).

Cells were seeded on 96-well plates. Twenty-four h after seeding, agents with or without PBMCs were added. Cell viability was determined using WST-1 assay kit (Roche Diagnostics, Mannheim, Germany). The mean value obtained from PBMCs alone was deducted from the values obtained from co-culture of prostate cancer cells and PBMCs.

All animal experiments were approved by the Gifu University Animal Experiment Approval Committee (No. 2019116) and carried out in accordance with the approved guidelines. This study is compliant with the ARRIVE guidelines. Six-week-old male athymic nude mice (BALB/cSlc-nu/nu) were purchased from Japan SLC, Inc. (Shizuoka, Japan). A suspension of 22Rv1DR cells (1107) cells in PBS was mixed with Matrigel (1:1) in a final volume of 0.2mL. The mixture was subcutaneously injected to generate tumors. Two weeks after the injection, tumor volume was measured and mice were randomly assigned to 2 groups (n=5). Agents were intravenously administrated via tale vein. The tumor volume and body weight were monitored and measured once a week. Four weeks after treatment, mice were sacrificed and the resected tumors were weighed.

Statistical analysis was performed using Graph Pad Prism 7 version 7.03 (Graph Pad Software, CA, USA). Comparison of 2 groups was made using t-test or MannWhitney U test. Comparison among 4 groups was made using one-way ANOVA with Tukeys post hoc for multiple comparisons. Differences were considered significant if p<0.05.

More here:
Gene therapy of prostate cancer using liposomes containing perforin expression vector driven by the promoter of prostate-specific antigen gene |...

Recommendation and review posted by Bethany Smith

SAN DIEGO--(BUSINESS WIRE)--Excellos, Incorporated, a cell therapy Contract Development and Manufacturing Organization (CDMO), announces its official corporate launch and closing of $15M in growth funding from Telegraph Hill Partners (THP).

Built on the foundation of the San Diego Blood Bank (SDBB), Excellos is focused on supplying cGMP cellular products and services, together with process development and manufacturing expertise to scientists and clinicians working with cell and gene therapies. The companys collection network consists of nine SDBB centers in the San Diego area that see an average of over 70,000 diverse donors annually, as well as exclusive access to select, consented material from SDBBs public cord blood bank. Excellos also has access to a nationwide collection network giving it one of the largest cellular material procurement portfolios. Uniquely connecting its broad collection network to state-of-the-art cGMP and R&D facilities in San Diego, Excellos provides a full suite of innovative end-to-end capabilities to facilitate the development and manufacture of autologous and allogeneic cell therapies. Excellos experience includes working with therapeutic companies developing chimeric antibody receptor-engineered T cells (CAR-T), tumor-infiltrating lymphocytes (TILs), and providing isolated immune cells that are integral to the advancement of immunotherapies.

Excellos will create highly characterized, standardized cell products and custom services that are essential for advanced therapeutics, said David Wellis Ph.D., CEO of Excellos. The SDBB had been incubating Excellos for a number of years, but fully capitalizing on the rapidly growing opportunity required significantly more resources than the SDBB was able to provide. We will now be able to focus exclusively on the needs of the expanding cell and gene therapy industry through the development of our data-driven platform to enable the characterization of cellular therapeutics starting at the donor level. The funding from THP will allow a significant facility expansion and overall growth in the capabilities of our organization.

The growth in the cell and gene therapy industry is driving a surge in demand for critical human cells, tissues, and services to support the development and commercialization of new products, said Paul Grossman, Ph.D., J.D., Partner at THP. We look forward to partnering with Excellos and their proven leadership team. Their exclusive access to one of the industrys largest donor bases, coupled with their technology-focused research and development activities, will help to accelerate the advancement of cell and gene therapies for those patients in need. Paul Grossman, Alex Herzick, and Deval Lashkari from THP have joined the Excellos Board concurrent with the financing.

Excellos founding leadership team brings a wealth of commercial and industry experience to bear. Chief Executive Officer David Wellis Ph.D., previously served as CEO of SDBB for nine years where he foresaw the need for products and services to serve the then nascent cell and gene therapy industry. His guidance allowed the organization to meet these needs, a path that ultimately led to the formation of Excellos. David has also held senior leadership roles at both Illumina and GenVault Corporation. Chief Commercial Officer George Eastwood, brings significant experience in the cell and gene therapy space, with a focus on cGMP materials and cell manufacturing. He served as VP, Global Sales and Business Development for HemaCare, and in his over five years there, he saw the company through a period of dramatic expansion that culminated in its acquisition by Charles River in 2020. Chief Scientific Officer Rob Tressler Ph.D., brings vast experience in R&D for advanced cell-based therapies. Most recently, as CSO of SDBB, he led the cell therapy, immunohematology, components manufacturing, and cord blood banking labs. Rob also has extensive drug development experience, both as Head of Preclinical Oncology at Geron Inc. and VP of R&D at Cellerant Therapeutics.

About Excellos: Built on the foundation of the San Diego Blood Bank, Excellos is focused on supplying cGMP cellular products and services, together with process development and manufacturing expertise to scientists and clinicians working with cell and gene therapies. Excellos is dedicated to improving human life by providing critical products and services to life science research and the next generation of cell and gene therapies. Learn more at http://www.excellos.com

About Telegraph Hill Partners: Telegraph Hill Partners, founded in 2001 and based in San Francisco, CA, invests in commercial stage life science, medical technology, and healthcare companies. For more information, please see http://www.telegraphhillpartners.com

Excerpt from:
Excellos Launches to Accelerate Innovation in the Cell and Gene Therapy Industry - Business Wire

Recommendation and review posted by Bethany Smith

MaxHggblom Distinguished Professor and ChairDepartment of Biochemistry and MicrobiologySchool of Environmental and Biological SciencesRutgers-New BrunswickHonored for distinguished contributions to understanding both the fundamental and application components of microbialbiotransformationsof pollutants, especially chlorinated aromaticcompoundsand metalloids.

MaxHggblomis a renowned research scientist and educator with a large body of microbial ecology and environmental biotechnology research that has expanded our understanding of how the biodegradation of environmental pollutants, such as dioxins and PCBs,impact our planet.

His research interests revolve around thebioexploration, cultivation and characterization of novel microbes.His research on bacteria has provided a foundation for applications that address the pollution problems facing impacted industrialized and urbanized environments.

Hggblomslab is also actively studying microorganisms that degrade pharmaceutical and personal care products in aquatic environments.

Over the past decadesthediverse chemicalsin pharmaceutical and personal care productshave emerged as a major group of environmental contaminants in numerous watersheds around the world; therefore, it is important to understand how microbes can degrade them.There is much to explore and learn,Hggblomadded.

Hggblomswork also touches climate change, particularly the roles and responses of microbes in rapidly changing environments, such as the Arctic.In his lab at Rutgers, students have the unique opportunity to exploreareas of research such asthe biodegradation and detoxification of anthropogenic pollutant chemicals, including certainpesticides;respiration of rare metalloids; or life in the frozen tundra soils.

For several years,my lab has worked on studying the microbial ecology of Arctic tundra soils to understand how the changing conditions impact microbial activity and turnover of soil organic matter, and consequently enhanced greenhouse gas flux,Hggblomsaid. This is an important area of research as the threat of microbial contribution to positive feedback of greenhouse gas flux is substantial.

His lab recently received funding from the National Science Foundation to studyhowdiverse microbial communitiesare established insoils.Hggblomwill work with an international research team of scientists from the U.S., China, South Africa and Finland to study soils from the three differentregionsacross Arctic, Tibetan Plateau and Antarctic habitats to expand our understanding of how soil ecosystems respond in critical polar regions.

Emily EversonLayden

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Twelve Rutgers Professors Named Fellows of the American Association for the Advancement of Science - Rutgers Today

Recommendation and review posted by Bethany Smith

The switch design works solely for certain subsets of cancers, specifically non-small-cell lung cancer cells with an EGFR gene mutation, where drugs that target mutated proteins in the cancer cell are already on the market.

We are taking a careful approach to design and testing, Pritchard said. We will look specifically for failures within the switch, and analyze what we find, sort of like when civil engineers analyze a building or bridge failure after the fact. Failures help us understand where our ideas about cancer therapy are incomplete, and what we can do to fix them and increase our knowledge.

After initial tests on cancer cell lines, the researchers will test the dual-switch gene drives on human organoids, provided by the University of Massachusetts Medical School, which are patient-derived cancer cells that more closely mimic real tumors.

Co-investigator Shelly Peyton, Armstrong Professional Development Professor at University of Massachusetts Amherst and expert in tissue engineering, will lead the design of microenvironments to determine how the gene therapy functions under different conditions. Peytons team will study how certain switches or parameters fail, or why they function well in some environments but not others.

The research here is trying to take the challenge of cancer treatment and flip it on its head, said Scott Leighow, fifth-year doctoral student in biomedical engineering, who gathered the preliminary data that were key to securing the grant. If we can do that, we'll have a therapy that can handle resistant forms of cancer a lot better than what's currently in our arsenal.

If the study is successful, the researchers will test their treatments on animal models to show proof-of-concept, Leighow said. Far in the future, the technology has the potential to offer a cellular gene therapy that might assist cancer patients who are not candidates for surgery.

The grant is part of a new consortia created by the NCI to promote collaborative approaches to synthetic biology for cancer applications.

See the original post here:
$2.5M grant awarded to flip the switch on lung cancer drug resistance - Penn State News

Recommendation and review posted by Bethany Smith

WASHINGTON, Jan. 25, 2022 (GLOBE NEWSWIRE) -- The GlobalHemophilia Market size is expected to reachUSD 14.2 Billionby 2028, exhibiting a CAGR of5.3%during the forecast period. Hemophilia is a bleeding condition, which leads to the prolonged bleeding after injury or a surgery due to a delay in the blood clotting, The Global Hemophilia Market is anticipated to grow at a substantial rate in coming years because of increasing cases of genetic abnormalities and prevalence of Hemophilia, states Vantage Market Research, in a report, titledHemophilia Market by Type (Hemophilia A, Hemophilia B, Hemophilia C, Others), by Treatment (On-demand, Prophylaxis), by Therapy (Replacement therapy, ITI therapy, Gene therapy), by Region (North America, Latin America, Europe, Asia Pacific) - Global Industry Assessment (2016 - 2021) & Forecast (2022 - 2028).The market size valued atUSD 12.1 Billionin 2021.

Click Here To Access The Free Sample Report @ https://www.vantagemarketresearch.com/hemophilia-market-1216/request-sample

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(Please note that the sample of this report has been updated to include the COVID-19 impact study prior to delivery.)

Market Overview:

Increasing Establishment of Hemophilia Treatment Centers to Drive the Market

The availability of limited treatment therapy options and growing burden on regulatory bodies towards the treatment is resulted to increase R&D efforts. The public as well as private healthcare bodies are heavily investing in development of specialized clinics that are established to meet the targeted needs of patients. In this regard, there is increasing number of Hemophilia treatment centres that also aims at proving treatment to underprivileged patients.It is recommended by authorities that people who are suffering from Hemophilia should visit a treatment center for optimal care and health education to stay healthy. The establishment of healthcare centres is anticipated to fuel theHemophilia Market growth.Additionally, efforts are been undertaken by regulatory bodies for spreading awareness regarding the disease and providing information about the effective treatment.

The COVID-19 outbreak has affected various industries worldwide. TheHemophilia Marketis no exception. Governments across the world took severe actions like border seals, lockdown, and implementing strict social distancing measures, in order to stop swift spread of COVID-19. These actions led to severe impact on the global economy impairing various industries. The impact of COVID-19 on the market demand is considered while estimating the current and forecast market size and growth trends of the market for all the regions and countries based on the following data-points:

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Benefits of Purchasing Hemophilia Market Reports:

The Report on Hemophilia Market Highlights:

Various Supportive Initiatives to Drive Market Growth in Asia Pacific

Asia Pacificis anticipated to witness fastest CAGR over the forecast period. The awareness campaigns and supportive initiatives taken by the government to commence the early screening of neonates, is about to boost the demand for diagnostic tools related to Hemophilia in the region. Some other factors such as advanced healthcare ecosystem and capacity of people to spend on such expensive medical services are defining the regional business growth. Additionally, easy medical reimbursement schemes are promoting the market growth.

List of Prominent Players in the Hemophilia Market:

Read Full Research Report @ https://www.vantagemarketresearch.com/industry-report/hemophilia-market-1216

Recent Developments:

December, 2021:The European Medicines Agency (EMA) has approved an accelerated assessment request for etranacogene dezaparvovec, an experimental gene therapy for Hemophilia B. The decision means that, once an application is submitted seeking approval for marketing authorization of etranacogene dezaparvovec, it will be reviewed more quickly than normal which could allow patients in Europe to access the therapy sooner,

December, 2021:Global biotherapeutics leader CSL Behring announced that the Committee for Medicinal Products for Human Use (CHMP), the chief scientific body of the European Medicines Agency (EMA) accepted its request for an accelerated assessment of the etranacogene dezaparvovec Marketing Authorisation Application (MAA). Etranacogene dezaparvovec (also known as EtranaDez), currently being studied in the Phase 3 HOPE-B clinical trial, is an investigational gene therapy for people living with hemophilia B, a life-threatening bleeding disorder.

December, 2021:Patients with severe Hemophilia can develop inhibitors against factor VIII or IX, preventing factor replacement therapy from working, said Dr. Guy Young (University of Southern California, CA, USA). A quarter of patients develop these inhibitors, leading to a worse prognosis. Novel agents are needed to protect these patients from bleeding events and arthropathy and improve their quality of life. In addition, the current IV therapies need to be administered multiple times per week, resulting in venous access issues and poor adherence.

December, 2020:Pfizer Inc. and Sangamo Therapeutics, Inc., a genomic medicines company, announced updated follow-up data from the Phase 1/2 Alta study of giroctocogene fitelparvovec, an investigational gene therapy for patients with moderately severe to severe Hemophilia A.

Browse the Report Hemophilia Market by Type (Hemophilia A, Hemophilia B, Hemophilia C, Others), by Treatment (On-demand, Prophylaxis), by Therapy (Replacement therapy, ITI therapy, Gene therapy), by Region (North America, Latin America, Europe, Asia Pacific) - Global Industry Assessment (2016 - 2021) & Forecast (2022 - 2028) @ https://www.vantagemarketresearch.com/blog/hemophilia-225379

This market titled Hemophilia Market will cover exclusive information in terms of Regional Analysis, Forecast, and Quantitative Data Units, Key Market Trends, and various others as mentioned below:

Treatment: - On-demand, Prophylaxis

Therapy: - Replacement therapy, ITI therapy, Gene therapy

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Global Hemophilia Market to Reach $14.2 Billion by 2028 - - GlobeNewswire

Recommendation and review posted by Bethany Smith

Patient 1 with Sandhoff disease realized normalization of Hex A enzyme activity by Month 1, achieving 58-fold above the presumed asymptomatic level of 5% of normal identified by natural history at Month 3

Patient 2 with Tay-Sachs disease achieved Hex A enzyme activity 5-fold above the presumed asymptomatic level of 5% of normal identified by natural history at Month 1

First-ever data supporting bicistronic vector approach in humans, TSHA-101 is designed to deliver both HEXA and HEXB genes in the endogenous ratio

Conference call and live webcast today at8:00 AM Eastern Time

DALLAS--(BUSINESS WIRE)-- Taysha Gene Therapies (Nasdaq: TSHA), a patient-centric, pivotal-stage gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system (CNS) in both rare and large patient populations, today reported positive initial serum -hexosaminidase A (Hex A) enzyme activity data for TSHA-101 in patients with Sandhoff and Tay-Sachs diseases, which represent two forms of GM2 gangliosidosis. Todays data are the first ever to support the bicistronic vector approach in humans delivering both HEXA and HEXB genes in the endogenous ratio.

TSHA-101 is the first bicistronic vector in clinical development, representing an important first for the field of gene therapy, noted RA Session II, President, Founder and CEO of Taysha. TSHA-101 demonstrated expression of both HEXA and HEXB genes in the endogenous ratio, providing the ability to restore and normalize enzyme activity in GM2 gangliosidosis. We expect to provide continued updates on the program, with additional clinical data anticipated by the end of 2022.

Based on natural history data, patients with asymptomatic GM2 gangliosidosis have Hex A enzyme levels that are at least 5% of normal activity. Key patient findings for Hex A enzyme activity following treatment with TSHA-101 include:

Patient 1 (Sandhoff disease)

Patient 2 (Tay-Sachs disease)

Suyash Prasad, MBBS, M.Sc., MRCP, MRCPCH, FFPM, Chief Medical Officer and Head of Research and Development at Taysha added, GM2 gangliosidosis is a progressive and life-limiting disease with no treatment options. Normalization of patient Hex A enzyme activity levels 58-fold above the presumed asymptomatic level of 5% of normal identified by natural history supports TSHA-101s ability to potentially make a meaningful difference in the lives of patients with Sandhoff and Tay-Sachs diseases after a single intrathecal administration. We look forward to submitting a protocol amendment to expand patient enrollment in the ongoing Phase 1/2 trial and providing additional updates later this year.

Preliminary data suggest that TSHA-101 was well-tolerated with no significant drug-related events.

Patient 1 (Sandhoff) demonstrated signs of clinical improvement at Month 3 and was deemed stable to travel home. Upon returning home, Patient 1 (Sandhoff), who was unvaccinated, was exposed to a family member symptomatic for an upper respiratory infection, possibly Covid-19, and was hospitalized with pneumonia before contracting a secondary hospital-acquired methicillin-resistant staphylococcus aureus (MRSA) infection. On January 14, 2022, the patient succumbed to pneumonia and pleural effusion with a concomitant hospital-acquired MRSA infection. The principal investigator has made the initial assessment that the death was unrelated to study drug. Final determination from the independent data safety monitoring board (DSMB) is anticipated in the near term.

TSHA-101 is an investigational gene therapy that delivers both the HEXA and HEXB genes that comprise the -hexosaminidase A enzyme. The two genes are driven by a single promoter within an AAV9 capsid ensuring that the two sub-units of Hex A are produced in the endogenous ratio within each cell, which is important to ensure efficient production of the enzyme. TSHA-101 is the first and only bicistronic vector currently in clinical development for GM2 gangliosidosis and has been granted Orphan Drug and Rare Pediatric Disease designations by the FDA and Orphan Drug Designation from the European Commission. TSHA-101 is administered intrathecally and is currently being evaluated in a single arm, open-label Phase 1/2 clinical trial for the treatment of infants with GM2 gangliosidosis sponsored by Queens University. Additional clinical safety and efficacy data are expected by the end of 2022.

GM2 gangliosidosis is a rare and devastating monogenic lysosomal storage disorder that is part of a family of neurodegenerative genetic diseases that includes Tay-Sachs and Sandhoff diseases. The disease is caused by defects in the HEXA or HEXB genes that encode the two subunits of the -hexosaminidase A (Hex A) enzyme. These genetic defects result in progressive dysfunction of the central nervous system. Residual Hex A enzyme activity determines the severity of the disease. The infantile form of the disease has an onset of symptoms usually before six months of age with residual Hex A enzyme activity of less than 0.1%. Juvenile onset occurs between 1.5 and five years of age with residual Hex A enzyme activity of approximately 0.5%. Early adult onset of the disease has residual Hex A enzyme activity of between 2% to 4%. There are no approved therapies for this disease, and current treatment is limited to supportive care.

Conference Call and Webcast Information

Taysha management will hold a conference call and webcast today at 8:00 am ET / 7:00 am CT to provide an update on the GM2 gangliosidosis program. The dial-in number for the conference call is 877-407-0792 (U.S./Canada) or 201-689-8263 (international). The conference ID for all callers is 13726741. The live webcast and replay may be accessed by visiting Tayshas website at https://ir.tayshagtx.com/news-events/events-presentations. An archived version of the webcast will be available on the website for 30 days.

About Taysha Gene Therapies

Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our teams proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platforman engine for potential new cureswith a goal of dramatically improving patients lives. More information is available at http://www.tayshagtx.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as anticipates, believes, expects, intends, projects, plans, and future or similar expressions are intended to identify forward-looking statements. Forward-looking statements include statements concerning the potential of our product candidates, such as TSHA-101 and including our preclinical product candidates, to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, and whether, if approved, these product candidates will be successfully distributed and marketed, the potential market opportunity for these product candidates, and our corporate growth plans. Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission (SEC) filings, including in our Annual Report on Form 10-K for the full-year ended December 31, 2020 and our Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, both of which are available on the SECs website at http://www.sec.gov. Additional information will be made available in other filings that we make from time to time with the SEC. Such risks may be amplified by the impacts of the COVID-19 pandemic. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

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Taysha Gene Therapies Announces Positive Initial Biomarker Data For TSHA-101 - BioSpace

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PHILADELPHIA--(BUSINESS WIRE)--SwanBio Therapeutics, a gene therapy company advancing AAV-based therapies for the treatment of devastating, genetically defined neurological conditions, today announced that its Investigational New Drug (IND) application for its lead candidate, SBT101, for the treatment of adrenomyeloneuropathy (AMN), was cleared by the U.S. Food and Drug Administration (FDA).

SBT101 is the first AAV-based gene therapy in development specifically designed for people living with AMN, an adult-onset degenerative spinal cord disease caused by mutations in the ABCD1 gene. SwanBio plans to initiate a randomized, placebo-controlled Phase 1/2 clinical trial designed to assess the safety and explore the efficacy of SBT101 in patients with AMN in the second half of 2022.

Todays IND clearance is a formative milestone for SwanBio, enabling us to evolve from a preclinical company to a truly integrated research and development organization, underscoring the expertise of our team and potential of our technology platform, said Tom Anderson, chief executive officer and director of SwanBio Therapeutics. SBT101 has the potential to become the first disease-modifying treatment for patients with AMN, a devastating and progressive disease with no approved treatments. We look forward to initiating clinical development of SBT101 later this year, bringing us closer to our ultimate goal of delivering life-changing treatments to patients.

The clinical program for SBT101 builds on SwanBios unique understanding of AMN, including new insights being gathered in an ongoing natural history study. SwanBio is deeply committed to the AMN community and has worked closely with patients, family members, and expert physicians including SwanBio Co-Founder Dr. Florian Eichler to ensure that its clinical programs are designed to meet their needs. SwanBio is supported by long-term investment partners Syncona Ltd. and Mass General Brigham Ventures, which both have proven track records in gene therapy, particularly in AAV-focused therapies.

About SBT101SBT101 is the first AAV-based gene therapy in development designed to compensate for the disease-causing ABCD1 mutation, to increase ABCD1 expression, and reduce very long chain fatty acid (VLCFA) levels specifically for people living with adrenomyeloneuropathy (AMN). In preclinical studies, treatment with SBT101 demonstrated dose-dependent improvement of AMN disease markers in mouse models and was shown to be well-tolerated in non-human primates at six months post-treatment.

About AdrenomyeloneuropathyAdrenomyeloneuropathy (AMN) is the adult-onset degenerative spinal cord disease that affects people living with adrenoleukodystrophy (ALD), a category of rare, genetic, and metabolic conditions. AMN is characterized by progressive loss of mobility, incontinence, and debilitating pain. It affects adults with mutations in the ABCD1 gene, which encodes a protein essential to the processing and breakdown of very long chain fatty acids (VLCFA). Without a functioning version of this protein there is an accumulation of VLCFA to toxic levels that leads to progressive dysfunction of the central nervous system. Between 8,000-10,000 men in the U.S. and E.U. are living with AMN. There are no approved therapies for the treatment of the disease; current standard of care is limited to symptom control.

About SwanBio TherapeuticsSwanBio Therapeutics is a gene therapy company that aims to bring life-changing treatments to people with devastating, genetically defined neurological conditions. SwanBio is advancing a pipeline of gene therapies, designed to be delivered intrathecally, that can address targets within both the central and peripheral nervous systems. This approach has the potential to be applied broadly across three disease classifications spastic paraplegias, monogenic neuropathies and polygenic neuropathies. SwanBios lead program is being advanced toward clinical development for the treatment of adrenomyeloneuropathy (AMN). SwanBio is supported by long-term, committed investment partners, including its primary investors Syncona, Ltd. (lead investor and majority shareholder) and Mass General Brigham Ventures. For more information, visit SwanBioTx.com.

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SwanBio Therapeutics Announces FDA Investigational New Drug Clearance for First AAV-Based Gene Therapy for the Treatment of Adrenomyeloneuropathy -...

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PARIS--(BUSINESS WIRE)--Regulatory News:

GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today reported that Leber Hereditary Optical Neuropathy (LHON) subjects treated with LUMEVOQ continued to experience significantly improved vision four years after a single injection of the gene therapy. The findings come from RESTORE (CLIN06), the long-term follow-up study to which participants in the RESCUE1 and REVERSE2 Phase III pivotal trials were invited.

When RESTORE subjects enrolled in the study, 2 years after the one-time injection, they had already experienced clinically meaningful improvements relative to the lowest point (the nadir) of their best-corrected visual acuity (BCVA): +18.8 ETDRS letters equivalent* in their LUMEVOQ-treated eyes and +17.3 letters equivalent in their sham-treated eyes. Four years after treatment, the bilateral improvement from nadir was sustained, with LUMEVOQ-treated eyes achieving a mean improvement against nadir of +22.5 letters equivalent and sham-treated eyes demonstrating a mean improvement of +20.5 letters equivalent.

The impact of such results on patients is demonstrated by increases in the self-reported quality of life (QoL) scores at Year 4 vs. baseline. Mean overall QoL increased by a clinically meaningful magnitude relative to baseline, driven by clinically meaningful increases in the sub-scores corresponding to mental health and the ability to carry out activities autonomously (e.g., role difficulties, dependency, near and far activities, general vision).

The 4-year RESTORE long-term extension study provides patients with Leber Hereditary Optic Neuropathy and their families as well as the neuro-ophthalmology community with highly informative data about both the efficacy and safety of intravitreal LUMEVOQ therapy, commented Dr. Robert Sergott, Director, Neuro-Ophthalmology Service, Wills Eye Hospital, and Founding Director and CEO, William H. Annesley EyeBrain Center, Thomas Jefferson University, Philadelphia, PA, USA. Compared to the natural history of LHON, the 4-year data extend and validate the 3-year observations by confirming that objective visual acuity improvement is sustained and is associated with improved functional visual quality of life without any long-term safety concern.

The RESTORE findings underline the therapeutic value of GenSights pioneering one-time treatment for LHON: durable and clinically significant improvement in visual function coupled with impressive safety, noted Bernard Gilly, Co-founder and Chief Executive Officer of GenSight. The body of evidence we have now accumulated is without doubt good news for patients needing an urgent solution for their brutal blinding condition, and consequently we are continuing to work vigorously with the relevant authorities to bring regulatory review process to a successful conclusion.

RESTORE is one of the largest long-term follow-up studies for a rare disease treatment, with 62 subjects accepting the invitation to enroll. All subjects, who were affected by LHON caused by a mutated ND4 mitochondrial gene, were treated with an intravitreal injection of LUMEVOQ in one eye and with sham injection in the other.

Table 1. BCVA Mean Improvement Vs. Nadir* In LUMEVOQ Long-Term Follow-Up (RESTORE)

2 Years Post-Injection

3 Years Post-Injection3

4 Years Post-Injection

LogMAR(Std Error)

LettersEquivalent**

LogMAR(Std Error)

LettersEquivalent**

LogMAR(Std Error)

LettersEquivalent**

LUMEVOQ-treated eyes

-0.375(0.306)

+18.8

-0.410(0.365)

+20.5

-0.453(0.440)

+22.5

Sham-treated eyes

-0.346(0.291)

+17.3

-0.387(0.369)

+19.4

-0.406(0.361)

+20.5

Note: The RESTORE sample consists of the RESCUE and REVERSE participants who accepted to be followed in the long-term follow-up study. Year 4 values were the LogMAR readings nearest to 1461 days post treatment recorded between 1461 +/- 273 days post- treatment. Missing values were imputed using the Last Observation Carried Forward (LOCF) method. *Nadir = worst best-corrected visual acuity recorded from baseline to Year 4. ** Assessments of best-corrected visual acuity (BCVA) were recorded in LogMAR. The change from nadir in LogMAR was converted to letters equivalent improvement by multiplying the LogMAR by -50 (ref. J.T. Holladay, J Refrac Surgery, 1997;13, 388-391).

Responder analyses at Year 4 indicate that improved BCVA was a benefit for a substantial proportion of the study participants. 71.0% of RESTORE subjects achieved Clinically Relevant Recovery (CRR)4 against nadir four years after treatment, and 80.7% of them had on-chart vision (BCVA 1.6 LogMAR) in one or both eyes.

Viewed against the trend in vision typically seen in untreated patients5, the findings represent a significant departure from the natural progression of LHON.

Safety findings at 4 years post-injection were consistent with previous readouts, which concluded that LUMEVOQ is well-tolerated: no serious adverse events were recorded among LUMEVOQ-treated eyes, and no discontinuations occurred due to ocular events. There were no systemic serious adverse events or discontinuations related to study treatment or study procedure.

The review of the European Marketing Authorisation Application for LUMEVOQ is ongoing, with the decision from the CHMP expected in Q4 2022.

References and notes:

About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics lead product candidate, GS010, is in Phase III trials in Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease that leads to irreversible blindness in teens and young adults. Using its gene therapy-based approach, GenSight Biologics product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery.

About Leber Hereditary Optic Neuropathy (LHON)

Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited mitochondrial genetic disease, characterized by the degeneration of retinal ganglion cells that results in brutal and irreversible vision loss that can lead to legal blindness, and mainly affects adolescents and young adults. LHON is associated with painless, sudden loss of central vision in the 1st eye, with the 2nd eye sequentially impaired. It is a symmetric disease with poor functional visual recovery. 97% of subjects have bilateral involvement at less than one year of onset of vision loss, and in 25% of cases, vision loss occurs in both eyes simultaneously. The estimated incidence of LHON is approximately 1,200-1,500 new subjects who lose their sight every year in the United States and the European Union.

About LUMEVOQ (GS010; lenadogene nolparvovec)

LUMEVOQ (GS010; lenadogene nolparvovec) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. LUMEVOQ was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018.

About RESCUE, REVERSE, and RESTORE

RESCUE and REVERSE were two separate randomized, double-masked, sham-controlled Phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in subjects affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene.

The primary endpoint measured the difference in efficacy of GS010 in treated eyes compared to sham-treated eyes based on BestCorrected Visual Acuity (BCVA), as measured with the ETDRS at 48 weeks post-injection. The patients LogMAR (Logarithm of the Minimal Angle of Resolution) scores, which are derived from the number of letters patients read on the ETDRS chart, were used for statistical purposes. Both trials were adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between drug-treated and sham-treated eyes, adjusted to baseline.

The secondary endpoints involved the application of the primary analysis to bestseeing eyes that received GS010 compared to those receiving sham, and to worseseeing eyes that received GS010 compared to those that received sham. Additionally, a categorical evaluation with a responder analysis was performed, including the proportion of patients who maintained vision (< ETDRS 15L loss), the proportion of patients who gained 15 ETDRS letters from baseline and the proportion of patients with Snellen acuity of >20/200. Complementary vision metrics included automated visual fields, optical coherence tomography, and color and contrast sensitivity, in addition to quality-of-life scales, biodissemination and the time course of immune response. Readouts for these endpoints were at 48, 72 and 96 weeks after injection.

The trials were conducted in parallel, in 37 subjects for REVERSE and 39 subjects for RESCUE, in 7 centers across the United States, the UK, France, Germany and Italy. Week 96 results were reported in 2019 for both trials, after which patients were invited to participate in a long-term follow-up study, RESTORE, for three additional years.

The primary objective is to assess the long-term safety of intravitreal LUMEVOQ administration up to 5 years post-treatment. The secondary objective is to assess the long-term treatment efficacy of the therapy and the quality of life (QoL) in subjects up to 5 years post-treatment. The first subject was enrolled on January 9, 2018. 61 subjects have enrolled.

ClinicalTrials.gov Identifiers:REVERSE: NCT02652780RESCUE: NCT02652767RESTORE: NCT03406104

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GenSight Biologics Reports Clinically Meaningful Vision Improvement is Maintained 4 Years After One-time Treatment with LUMEVOQ Gene Therapy -...

Recommendation and review posted by Bethany Smith