Archive for May, 2024

In posters presented at theISPORThe Professional Society for Health Economics and Outcomes Researchmeeting held in Atlanta, Georgia, researchers explored Duchenne muscular dystrophy (DMD) caregiver experiences through cross-sectional surveys,1,2 and an economic analysis examined gene therapys impact on work opportunities for caregivers.3

DMD is an inherited neuromuscular disorder that leads to progressive muscle degeneration and weakness.4 It primarily affects boys, and symptom onset is typically in early childhood. Life expectancy for those with DMD has increased in recent years, and survival into the early 30s is becoming more common.

As DMD progresses, affected individuals rely more heavily on their caregivers, the authors of one poster wrote.1 Their cross-sectional survey aimed to characterize the experiences of caregivers in the US, as contemporary data are lacking.

The analysis included 106 US-based caregivers who completed an online survey between March and May 2023. The survey included questions capturing the use of formal (paid) and informal (unpaid) care; informal burden on caregivers rated on a scale from 0 to 10, 10 being the most challenging; and how accessibility barriers impact family plans. The survey results were stratified by patient ambulatory status.

The mean caregiver age was 46 years, and the mean care recipient age was 14.5 years. Eighty-one percent of the caregivers were mothers, and 11% were caregivers for 2 individuals with DMD. Out of 118 total patients with DMD being cared for, 47% (n = 55) were nonambulatory. Caregivers of ambulatory patients reported spending a median of 4.5 hours per day caregiving, while caregivers of nonambulatory patients reported a median of 8 hours per day. The median amount of time spent giving care per day in the overall cohort was 6 hours per day.

Caregivers reported a median burden of 5 overall, with those caring for nonambulatory patients reporting a burden of 6 and caregivers of ambulatory recipients reporting a burden rating of 4. Overall, 75% of caregivers reported utilizing additional informal caregiving, and 26% used additional formal caregiving. Of those using formal caregiving, 13% were caregivers for ambulatory patients and 42% were caregivers for nonambulatory patients. Accessibility barriers led to frequent changes in everyday plans for 74% of families.

Overall, the findings show the significant amounts of time and energy required of caregivers for individuals with DMD, as well as the increasing demands associated with disease progression.

Muscular dystrophy | Image credit: Lemau Studio - stockadobe.com

Another poster highlighted the impacts of caregiving on paid work, including the extent of DMD caregivers paid work accommodations and lost productivity based on survey results.2 The investigators recruited survey participants through a US-based DMD advocacy group and included questions from the Work Productivity and Activity Impairment (WPAI) questionnaire for DMD caregivers, with higher scores indicating greater impairment.

Among 106 caregivers, 81% were mothers, and the mean age was 46, and 89% of caregivers reported caring for 1 individual with DMD. The annual household income was greater than $100,000 annually for 49% of households in the study.

Overall, 68% of respondents (n = 72) were employed, with 55% (n = 52) employed full-time. Based on WPAI scores, 40.7% of respondents had experienced overall activity impairment in the past week, and absenteeism among those employed was 8.4%. Presenteeism, or impairment at work, was reported by 30.5% of caregivers, and absenteeism plus presenteeism (work productivity loss) by 34.8%. Among the 11% of caregivers caring for 2 individuals with DMD, 67% (n = 8) were employed, and 62.5% (n = 5) reported work productivity was impacted by DMD.

Furthermore, 77% (n = 82) of caregivers reported work-related changes due to caregiving responsibilities. Twenty-five percent quit, 26% took lower paying jobs, 34% changed their job role or responsibilities, 29% reduced working hours, and 34% took time off from work.

The results demonstrate the considerable paid work impact associated with caregiving for one or two individuals with DMD, the authors concluded, noting that the findings are limited due to the low number of caregivers of 2 individuals included in the study.

In an economic analysis, investigators explored how delandistrogene moxeparvovec (Elevidys; Sarepta Therapeutics), a gene therapy approved for the treatment of ambulatory patients aged 4 to 5 years with DMD, could impact the work opportunity of those caring for patients with DMD.3 They developed a partitioned survival model including 5 statesearly ambulatory, late ambulatory, early nonambulatory, late nonambulatory, and deathand estimated outcomes and caregiver work opportunity with standard-of-care (SOC) treatment vs SOC plus gene therapy for a cohort of 4-year-old early ambulatory patients with DMD. The researchers applied 2.8% salary growth and 3% discount rates annually.

With SOC treatment alone, caregivers were estimated to lose 7194 (15.5%) hours and experience a lifetime income loss of $249,697 (16.1%)/undiscounted $431,911 (16.2%) compared with the general US population. Caregivers of patients treated with SOC plus gene therapy were estimated to lose 4564 (9.8%) hours, equating a lifetime income loss of $153,396 (9.9%)/undiscounted $318,375 (11.9%) compared with the general population.

DMD substantially impacts caregiver work opportunity and income, the authors concluded. Based on this model, delandistrogene moxeparvovec could potentially increase caregiver work opportunity.

Reference

1. Audhya IF, Dunne JS, Patel S, et al. Characterizing the experience of caregiving for those with Duchenne muscular dystrophy (DMD): results from a cross-sectional survey. Presented at: International Society for Pharmacoeconomics and Outcomes Research 2024; May 5-8, 2024; Atlanta, GA. Poster 6044.

2. Patel S, Dunne JS, Audhya IF, et al. The balancing act of paid work and caregiving in Duchenne muscular dystrophy (DMD): results from a cross-sectional survey. Presented at: International Society for Pharmacoeconomics and Outcomes Research 2024; May 5-8, 2024; Atlanta, GA. Poster 6018.

3. Innis B, Henry A, Nelson L, et al. Economic analysis of the impact of delandistrogene moxeparvovec gene therapy on work opportunity in caregivers of individuals with Duchenne muscular dystrophy. Presented at: International Society for Pharmacoeconomics and Outcomes Research 2024; May 5-8, 2024; Atlanta, GA. Poster 2050.

4. Duchenne muscular dystrophy (DMD). Muscular Dystrophy Association. Accessed May 9, 2024.https://www.mda.org/disease/duchenne-muscular-dystrophy

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Posters Characterize DMD Caregiver Experiences, Impact of Gene Therapy on Caregiving Demands - AJMC.com Managed Markets Network

Published: 09 May 2024

A girl born deaf can now hear unaided after participating in a world-first trial.

TheCHORD study is for children born with hearing loss due to a genetic condition called auditory neuropathy.Auditory neuropathy is a condition where the ear can detect sound normally, but has a problem sending signals to the brain.

This can be caused by a fault in the OTOF gene. The gene makes a protein called otoferlin that allows cells in the ear to communicate with the hearing nerve. Changes in this gene can reduce sound transmission from the inner hair cells to the hearing nerves.

Gene therapy aims to deliver a working copy of the faulty OTOF gene. The treatment is given using a neutralised virus, injected into the inner ear under general anaesthetic.

The study started in 2023 using a treatment made by Regeneronand is supported by NIHR Cambridge Clinical Research FacilityandNIHR Cambridge Biomedical Research Centre.

Opal Sandy is the first patient treated in the global gene therapy trial. Opal was born completely deaf because of neuropathy. She was treated shortly before her first birthday.

During surgery, while Opal was given the gene therapy in right ear, a cochlear implant was fitted in her left ear.

Opals mother, Jo Sandy, said: When Opal could first hear us clapping unaided it was mind-blowing - we were so happy when the clinical team confirmed at 24 weeks that her hearing was also picking up softer sounds and speech. The phrase near normal hearing was used, and everyone was so excited that such amazing results had been achieved.

Professor Manohar Bance is the chief investigator for the trial. He is also an ear surgeon at Cambridge University Hospitals NHS Foundation Trust. He said: These results are spectacular and better than I expected. Gene therapy has been the future of otology and audiology for many years and Im so excited that it is now finally here. This is hopefully the start of a new era for gene therapies for the inner ear and many types of hearing loss.

Dr Richard Brown, Consultant Paediatrician at CUH, who is an investigator on the CHORD trial, said: The development of genomic medicine and alternative treatments is vital for patients worldwide, and increasingly offers hope to children with previously incurable disorders. It is likely that in the long run such treatments require less follow up so may prove to be an attractive option, including within the developing world. Follow up appointments have shown effective results so far with no adverse reactions and it is exciting to see the results to date.

Doctors in other countries, including China, are exploring very similar treatments for the OTOF gene mutation.Around 20,000 people across the US, UK, Germany, France, Spain and Italy are thought to have auditory neuropathy due to OTOF mutations, which shows the potential significance of a successful treatment. Patients are being enrolled in the study in the US, UK and Spain.

Addenbrookes Hospital in Cambridge is participating in the trial. Read more on the Cambridge University Hospitals website.

Photo of Opal Sandy taken byCambridge University Hospitals

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Baby born deaf can hear after breakthrough gene therapy - National Institute for Health Research

The companys presentation at ASGCT includes preliminary data results for a child who received the gene therapy.

Regeneron presented results from an ongoing Phase I/II clinical trial for its investigational gene therapy, DB-OTO, at the annual American Society of GeneandCell Therapy (ASGCT) meeting, being held in Baltimore, Md. from May 711. DB-OTO, a gene therapy for genetic deafness, improved hearing in one child, treated at 11 months old to normal levels within 24 weeks. A second child, treated at 4 years old, also showed hearing improvements at a six-week assessment, according to the company (1). Both children were born with genetic deafness due to variants of the otoferlin gene.

The results are from the ongoing Phase I/II CHORD (NCT# 05788536) first-in-human, multicenter, open-label trial. The trial evaluates the safety, tolerability, and preliminary efficacy of DB-OTO in infants, children, and adolescents with otoferlin (OTOF) variants in the United States, United Kingdom, and Spain. CHORD is a two-part study where participants will receive a single intracochlear injection of DB-OTO in one ear in Part A of the study. In Part B, participants receive simultaneous single intracochlear injections of DB-OTO in both ears at the selected dose from Part A.

Congenital deafness impacts approximately 1.7 out of every 1000 children born in the United States, according to Regeneron (1).Otoferlin-related hearing loss is especially rare and caused by variants in the otoferlin gene, which impairs the production of theOTOFprotein that is critical for the communication between the sensory cells of the inner ear and the auditory nerve.

Study data presented at ASGCT showsat the 24-week assessment the first participant, a 16-month-old child, had improvement of hearing to normal levelsacross key speech frequencies, with an average 84 dB improvement from baseline and one frequency measure reaching 10 dB in hearing level per PTA. Across all tested frequencies, an average 80 dB improvement from baseline was observed. There was also positive ABR responses, with best frequency reaching 45 dB.

The second participant, a four-year-old child, experienced consistent results to the first participant, including initial improvement of hearing with responses to loud sounds,which was observed across key speech frequencies, with an average 19 dB improvement from baseline and one frequency measure reaching 80 dB in hearing level per PTA. Across all tested frequencies, an average 16 dB improvement from baseline was observed. Positive ABR responses had best frequency reaching 75 dB.

The opportunity of providing the full complexity and spectrum of sound in children born with profound genetic deafness is a phenomenon I did not expect to see in my lifetime, saidLawrence R. Lustig, MD, chair of Columbia UniversitysDepartment of OtolaryngologyHead & Neck Surgery and a clinical trial investigator, in a press release. These impressive results showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness, and we are excited to see how this translates into an individuals development, especially [because] early intervention is associated with better outcomes for speech development. With the DB-OTO CHORD trial now enrolling participants in sites across theUS andEurope, were part of the beginning of a new era of gene therapy research that looks to create treatment options that address the root cause of profound genetic deafness.

1. Regeneron. Latest DB-OTO Results Show Dramatically Improved Hearing to Normal Levels in a Child with Profound Genetic Deafness Within 24 Weeks and Initial Hearing Improvements in a Second Child at 6 Weeks. Press Release. May 8, 2024.

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Regeneron Presents Update on Gene Therapy for Genetic Deafness at ASGCT - Pharmaceutical Technology Magazine

A new study published in New England Journal of Medicine has described the effect of gene editing in a group of patients with Leber congenital amaurosis (LCA).

The clinical trial involved two children and 12 adults with the genetic eye condition. Participants received an experimental gene editing therapy called Edit-101.

Outcomes used to evaluate the clinical trial were: visual acuity; full-field test results; the ability of participants to navigate a research maze containing obstacles and varied lighting levels; and self-reported improvements in quality of life.

The researchers found that 11 of the participants (79%) showed improvements in at least one of the four outcome measures, while 6 participants (43%) showed improvement in two or more outcomes. Four patients (29%) experienced improvements in visual acuity.

The scientists reported that there were no serious adverse effects linked to the treatment.

Dr Mark Pennesi, of Oregon Health & Science University, shared how rewarding it was to hear about vision improvements among patients who took part in the trial.

One of our trial participants has shared several examples, including being able to find their phone after misplacing it and knowing that their coffee machine is working by seeing its small lights, he said.

While these types of tasks might seem trivial to those who are normally sighted, such improvements can have a huge impact on quality of life for those with low vision, he added.

More:
Gene therapy improves vision in Leber congenital amaurosis patients - Association of Optometrists (AOP)

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At four

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weeks, when we initially heard her

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turning to clapping, that was like

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I was mind-blown that had worked.

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Id sat behind Opal countless times

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when she's had, to us, ridiculously

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loud noises

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blared through speakers in a sound booth

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and she's never once turned, so to

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see that happen is mind-blowing.

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Good girl! Yippee!

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Clever girl!

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So this particular trial was for children

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who have the OTOF gene variant

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that does not produce

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a particular protein

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that they need for hearing.

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And the surgery involves

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approaching the ear

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like a cochlear implant, infusing a virus

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that makes the cells

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produce the protein that they're missing.

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So one thing that we've been

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really excited about here

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is that we've been able to use

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a really small dose of gene therapy

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delivered directly to the cochlear,

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and what that means is

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that we're not delivering

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a large dose of gene therapy

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to the rest of the body.

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So it means that we see

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fewer side effects.

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And for Opal,

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this is a very big change,

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because before the gene therapy,

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she had profound hearing loss.

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That meant she couldn't

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hear any sounds in that ear at all,

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even when they were very loud.

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And now she can hear

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sounds at a very soft level,

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almost in the normal range for children

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her age.

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Can I have a kiss?

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Aw, good girl, daddy kiss, mummy kiss.

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Yeah, if she doesn't have her implant

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on, she acts exactly the same

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as if she did have it on,

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because she can hear so well with this

Continued here:
Baby born deaf can hear after breakthrough gene therapy - Cambridge University Hospitals

Revolutionizing Treatment: ASGCTs Clinical Trials Spotlight on Immunotherapy, Cancer Vaccines, and Auditory Diseases

At this years ASGCTs 27th Annual Meeting in Baltimore, groundbreaking clinical trials took center stage, illuminating the latest advancements in gene therapy research. These trials presented innovative approaches ranging from targeted cell and gene therapies to advancements in AAV gene therapy and novel findings in cell therapy. Here we dive deeper into immunotherapy and cancer vaccines, alongside novel treatments for auditory diseases. With a focus on cutting-edge treatments and promising outcomes, these presentations underscore the transformative potential of gene and cell therapy in addressing diverse medical challenges.

Generating Antitumor T Cells: Personalized Neoantigen Vaccine and Pembrolizumab in Advanced Hepatocellular Carcinoma

Customized cancer vaccines targeting neoantigens from a patients tumor may boost the effectiveness of PD-1 inhibitors by stimulating tumor-specific immune responses. Findings from a single-arm Phase Ib/2a study investigate the use of a personalized therapeutic cancer vaccine (PTCV), designed to target specific mutations in an individuals tumor, in combination with pembrolizumab, a PD-1 inhibitor, for the treatment of advanced hepatocellular carcinoma (HCC). The results indicate that this combination therapy induces a robust immune response, involving both CD8+ and CD4+ T cells targeting tumor-specific neoantigens. These findings suggest a potential mechanism for the observed clinical activity and provide insight into improving treatment outcomes for patients with advanced HCC.

Long-Term Safety and Integration Site Analysis of T Cells Modified with Lentiviral or Gammaretroviral Gene Addition

No adverse events related to insertional mutagenesis were detected in a large patient cohort treated with CART therapy. Here, the long-term safety of CAR T cell therapy was assessed by analyzing data from 780 patients treated between 2001 and 2023. While 21 patients developed secondary malignancies, none were directly linked to the CAR T cell product. Integration site sequence analysis revealed insights into the behavior of transduced cell clones, with no evidence of pathogenic insertional mutagenesis. Overall, the study provides reassurance regarding the safety of CAR T cell therapy, despite recent concerns about secondary T cell malignancies.

CHORD Trial: DB-OTO Gene Therapy for Pediatric Hearing Loss

This trial highlights the significance of biallelic otoferlin gene mutations in causing severe-to-profound sensorineural hearing loss, emphasizing the potential for OTOF gene replacement therapy to restore physiological hearing. Subsequently, this investigation introduces DB-OTO, a novel adeno-associated virus vector designed for intracochlear delivery of the OTOF gene, and outlines the objectives of the CHORD trial (NCT05788536) evaluating its safety and efficacy in pediatric patients with profound hearing loss due to OTOF mutations. Initial results from the trial demonstrate promising outcomes, with no dose-limiting toxicities or DB-OTO-related adverse events reported. Significant improvements in hearing, as indicated by behavioral pure tone audiogram thresholds and auditory brainstem response, were observed in the DB-OTO-treated ear. Additionally, parental reports and auditory skills assessments further support the positive impact of DB-OTO on auditory function and development. These findings underscore the potential of DB-OTO gene therapy as a viable treatment option for patients with profound hearing loss caused by OTOF mutations, warranting further investigation in larger patient cohorts.

In conclusion, the presentations from the ASGCT annual conference in Baltimore showcase significant strides in immunotherapy, gene therapy, and treatments for ophthalmic and auditory diseases. The studies on personalized neoantigen vaccines, CAR T cell therapy safety, and DB-OTO gene therapy offer promising insights into improving outcomes for patients with advanced hepatocellular carcinoma, hematologic malignancies, and hearing loss due to genetic mutations. These findings underscore the potential of innovative cell and gene therapies in addressing unmet medical needs and enhance patient care. Moving forward, continued research and development in these areas will be instrumental in advancing precision medicine and improving the lives of individuals affected by these conditions. ASGCT 2024, gene therapy, gene therapy definition, cell and gene therapy, AAV gene therapy, Cell Reports impact factor, cell therapy, American, Baltimore, therapy, cell

Advancing Health: ASGCTs Clinical Trials Spotlight on Cell Therapy and Cell-Based Gene Therapy

2024-05-09

Profluent Achieves Human Genome Editing Milestone Using OpenCRISPR-1: The First AI-Generated, Open-Source Gene Editor

2024-05-08

The Gene & Cell Therapy Landscape: Recent Approvals and Upcoming Therapeutics of Interest

2024-05-06

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Revolutionizing Treatment: ASGCT's Clinical Trials Spotlight on Immunotherapy, Cancer Vaccines, and Auditory ... - geneonline

Ace Therapeutics announced the unveiling of its gene therapy development services to advance glaucoma research. To advance glaucoma research, Ace Therapeutics, an integrated biotechnology company with a broad research scope and comprehensive services, has announced the unveiling of its gene therapy development services. The company's innovative gene therapy approach holds promise in providing a new, effective treatment option for individuals suffering from this eye disease that damages the optic nerve.

Glaucoma is a leading cause of irreversible blindness worldwide, and currently available treatments only offer temporary relief of symptoms. Studies have found the main risk factor for glaucoma is high IOP, primarily due to RGC injury and death. For this reason, Ace Therapeutics offers glaucoma gene therapy development [https://www.acetherapeutics.com/glaucoma/gene-therapy-development-for-glaucoma.html] services, targeting IOP and RGC-associated candidate genes, as well as many other related genes and pathways. By delivering therapeutic nucleic acids directly to the affected cells, the company's gene therapy has the potential to halt the progression of glaucoma and preserve vision for patients.

Considering the great potential of stem cells as a possible therapy for glaucoma, the expert team at Ace Therapeutics can provide specialized services in glaucoma drug development, offer the opportunity to develop drugs for glaucoma using stem cell technology and stem cell-based therapies to restore vision loss due to glaucoma. In addition, the company also utilizes siRNA-based gene silencing strategies to treat glaucoma, providing researchers with development services to study the composition and mechanisms of siRNA drugs, offering solutions to the fundamental challenges faced during development.

"We are excited to collaborate with worldwide researchers to develop a more effective treatment for glaucoma using our gene therapy expertise and technologies," said the senior scientist at Ace Therapeutics. "We can provide genomic analysis or directly select appropriate genes from candidate genes that are genetically linked to glaucoma to those involved in the relevant pathway. Also, we can develop gene delivery systems for glaucoma gene therapy to ensure the transfer of nucleic acid drugs to target cells and to advance the translational application of gene therapy."

About Ace Therapeutics

Ace Therapeutics Glaucoma [https://www.acetherapeutics.com/glaucoma/] is an innovative ophthalmic disease research company that offers a wide range of services in basic research, drug development and preclinical studies, delivering innovative and high-quality solutions to global clients. Ace Therapeutics' mission is to be a leader in the field of glaucoma research, providing unique drug development, and preclinical research solutions to advance researchers' project development.

Media Contact Company Name: Ace Therapeutics Contact Person: Daisy Mostert Email:Send Email [https://www.abnewswire.com/email_contact_us.php?pr=ace-therapeutics-unveils-gene-therapy-development-services-to-fuel-glaucoma-research] Country: United States Website: https://www.acetherapeutics.com/

This release was published on openPR.

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Ace Therapeutics Unveils Gene Therapy Development Services to Fuel Glaucoma Research - openPR

- Company announces clearance of IND application with FDA for anti-tau antibody VY-TAU01 for the treatment of Alzheimers disease; expect to begin single ascending dose trial in the coming weeks -

- Development candidates selected for Neurocrine-partnered GBA1 and Friedreichs Ataxia gene therapy programs; potential for three gene therapies, including SOD1-ALS, to enter the clinic in 2025 -

- Appointed neurology clinical development expert Toby Ferguson, M.D., Ph.D., as Chief Medical Officer -

- Strong cash position of approximately $400 million as of March 31, 2024; expected to provide runway through multiple clinical data readouts into 2027 -

LEXINGTON, Mass., May 13, 2024 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (Nasdaq: VYGR), a biotechnology company dedicated to advancing neurogenetic medicines, today reported first quarter 2024 financial and operating results.

We have obtained IND clearance for our anti-tau antibody VY-TAU01 for Alzheimers disease, and we expect to dose the first subject in our single ascending dose trial in healthy volunteers in the coming weeks, said Alfred W. Sandrock, Jr., M.D., Ph.D., Chief Executive Officer of Voyager. Our gene therapy pipeline is also advancing, with development candidates selected in the GBA1 and Friedreichs Ataxia programs partnered with Neurocrine, as well as in our wholly-owned SOD1-ALS program. We expect to achieve IND filings for all three of these gene therapy programs in 2025. We maintain a strong cash position of approximately $400 million at quarter-end, with runway into 2027, which we anticipate will enable us to reach multiple data readouts in 2025 and 2026.

First Quarter 2024 and Recent Highlights

Anticipated Upcoming Milestones

First Quarter 2024 Financial Results

Financial Guidance

Voyager is committed to maintaining a strong balance sheet that supports the advancement and growth of its platform and pipeline. Voyager continues to assess its planned cash needs both during the current period and in future periods. We expect our cash, cash equivalents, and marketable securities, along with amounts expected to be received as reimbursement for development costs under the Neurocrine and Novartis collaborations, certain near-term milestones, and interest income, to be sufficient to meet Voyagers planned operating expenses and capital expenditure requirements into 2027.

Conference Call

Voyager will host a conference call and webcast today at 4:30 p.m. ET to discuss first quarter 2024 financial and operating results. To participate via telephone and join the call live, please register in advance here: https://register.vevent.com/register/BI1f6af80e7a614ca7925cbad2f35a55c6. Upon registration, telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number and a unique passcode. A live webcast of the call will also be available on the Investors section of the Voyager website at ir.voyagertherapeutics.com, and a replay of the call will be available at the same link approximately two hours after its completion. The replay will be available for at least 30 days following the conclusion of the call.

About the TRACER Capsid Discovery Platform

Voyagers TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) capsid discovery platform is a broadly applicable, RNA-based screening platform that enables rapid discovery of novel AAV capsids to enable gene therapy. Voyager has leveraged TRACER to create multiple families of novel capsids that, following intravenous delivery in preclinical studies, harness the extensive vasculature of the central nervous system (CNS) to cross the blood-brain barrier and transduce a broad range of CNS regions and cell types. In cross-species preclinical studies (rodents and multiple non-human primate species), intravenous delivery of TRACER-generated capsids resulted in widespread payload expression across the CNS at relatively low doses, enabling selection of multiple development candidates in Voyagers wholly-owned and partnered gene therapy programs for neurologic diseases.

About Voyager Therapeutics

Voyager Therapeutics, Inc. (Nasdaq: VYGR) is a biotechnology company dedicated to leveraging the power of human genetics to modify the course of and ultimately cure neurological diseases. Our pipeline includes programs for Alzheimers disease, amyotrophic lateral sclerosis (ALS), Parkinsons disease, and multiple other diseases of the central nervous system. Many of our programs are derived from our TRACER AAV capsid discovery platform, which we have used to generate novel capsids and identify associated receptors to potentially enable high brain penetration with genetic medicines following intravenous dosing. Some of our programs are wholly owned, and some are advancing with partners including Alexion, AstraZeneca Rare Disease; Novartis Pharma AG; Neurocrine Biosciences, Inc.; and Sangamo Therapeutics, Inc. For more information, visit http://www.voyagertherapeutics.com.

Voyager Therapeutics is a registered trademark, and TRACER is a trademark, of Voyager Therapeutics, Inc.

Forward-Looking Statements

This press release contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as expect, will, believe, anticipate, potential, trigger or continue, and other similar expressions are intended to identify forward-looking statements.

For example, all statements Voyager makes regarding Voyagers ability to advance its AAV-based gene therapy programs and tau antibody program, including expectations for Voyagers achievement of preclinical and clinical development milestones for its potential development candidates such as IND filings, the initiation of clinical trials, and generation of clinical data and proof-of-concept; Voyagers ability to advance gene therapy product candidates under the Neurocrine and Novartis collaborations; Voyagers anticipated financial results, including the anticipated receipt by Voyager of revenues or reimbursement payments from collaboration partners; and Voyagers cash runway and ability to generate sufficient cash resources to enable it to continue its business and operations are forward looking.

All forward-looking statements are based on estimates and assumptions by Voyagers management that, although Voyager believes such forward-looking statements to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Voyager expected. Such risks and uncertainties include, among others, the expectations and decisions of regulatory authorities; the timing, initiation, conduct and outcomes of Voyagers preclinical and clinical studies; the availability of data from clinical trials; the availability or commercial potential of product candidates under collaborations; the willingness and ability of Voyager's collaboration partners to meet obligations under collaboration agreements with Voyager; the continued development of Voyagers technology platforms, including Voyagers TRACER platform and its antibody screening technology; Voyagers scientific approach and program development progress, and the restricted supply of critical research components; the development by third parties of capsid identification platforms that may be competitive to Voyagers TRACER capsid discovery platform; Voyagers ability to create and protect intellectual property rights associated with the TRACER capsid discovery platform, the capsids identified by the platform, and development candidates for Voyagers pipeline programs; the possibility or the timing of Voyagers receipt of program reimbursement, development or commercialization milestones, option exercise, and other payments under Voyagers existing licensing or collaboration agreements; the ability of Voyager to negotiate and complete licensing or collaboration agreements with other parties on terms acceptable to Voyager and the third parties; the success of programs controlled by third party collaboration partners in which Voyager retains a financial interest, and the success of Voyagers product candidates; the ability to attract and retain talented directors, employees, and contractors; and the sufficiency of cash resources to fund its operations and pursue its corporate objectives.

These statements are also subject to a number of material risks and uncertainties that are described in Voyagers most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission. All information in the press release is as of the date of this press release, and any forward-looking statement speaks only as of the date on which it was made. Voyager undertakes no obligation to publicly update or revise this information or any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

Contacts

Trista Morrison, NACD.DC, tmorrison@vygr.com Investors: Adam Bero, Ph.D., abero@kendallir.com Media: Brooke Shenkin, brooke@scientpr.com

GAAP vs. Non-GAAP Financial Measures Voyagers financial statements are prepared in accordance with generally accepted accounting principles in the United States, or GAAP, and represent revenue and expenses as reported to the Securities and Exchange Commission. Voyager has provided in this release certain financial information that has not been prepared in accordance with GAAP, including net collaboration revenue and net research and development expenses, which exclude the impact of reimbursement by Neurocrine Biosciences (Neurocrine) for expenses we incur in conducting preclinical development activities under our collaboration agreements. Management uses these non-GAAP measures to evaluate the Companys operating performance in a manner that allows for meaningful period-to-period comparison and analysis of trends in its business. Management believes that such non-GAAP measures are important in comparing current results with prior period results and are useful to investors and financial analysts in assessing the Companys operating performance. Non-GAAP financial measures are not required to be uniformly applied, are not audited and should not be considered in isolation. The non-GAAP measures give investors and financial analysts a better understanding of our net revenue and net research and development expenses without the pass-through impact of Neurocrine costs. The non-GAAP financial information presented here should be considered in conjunction with, and not as a substitute for, the financial information presented in accordance with GAAP. Investors are encouraged to review the reconciliation of these non-GAAP measures to their most directly comparable GAAP financial measures set forth below.

Note 1: Under the Company's existing collaboration agreements with Neurocrine and Novartis, Neurocrine and Novartis have agreed to be responsible for all costs the Company incurs in conducting preclinical development activities for certain collaboration programs, in accordance with joint steering committee agreed upon workplans and budgets. Reimbursable research and development services performed during the period are captured within collaboration revenue and research and development expenses in the Company's consolidated statements of operations. During the three months ended March 31, 2024, we incurred $3.2 million of reimbursable research and development services recorded within collaboration revenue and research and development expenses. During the three months ended March 31, 2023, we incurred $0.3 million of reimbursable research and development services recorded within collaboration revenue and research and development expenses.

Link:
Voyager Therapeutics Reports First Quarter 2024 Financial and Operating Results - GlobeNewswire

Mesenchymal Stem Cells Market

Major Highlights of TOC: Chapter 1: Overview of the Global Mesenchymal Stem Cells Market in 2024 1.1 GREEN HYDROGEN Industry Analysis 1.2 Key Companies and Product Profiles 1.3 Mesenchymal Stem Cells Market Segments 1.4 Industry Value Chain Analysis 1.5 Market Dynamics- Trends, Drivers, and Opportunities 1.6 Pricing Analysis 1.7 Porter's Five Forces Analysis 1.8 SWOT Profile 1.9 Macro-Economic and Demographic Impact Analysis 1.10 Scenario Analysis

Chapter 2: Global GREEN HYDROGEN Demand Forecasts 2.1 Overview of the Segment 2.2 Global Historic Mesenchymal Stem Cells Market Size (2018-2023) by Types, Applications, and Other Segments 2.3 Global Forecast Mesenchymal Stem Cells Market Size (2024-2030) by Types, Applications, and Other Segments

Chapter 3: Segment-wise Mesenchymal Stem Cells Market Forecasts 3.1 Key Market Segments 3.2 Premium Insights- Largest Types, Applications and Segments 3.3 Premium Insights- Most Lucrative Types, Applications, and Segments

Chapter 4: Mesenchymal Stem Cells Market Outlook by Country 4.1 Mesenchymal Stem Cells Market by Regions 4.2 Mesenchymal Stem Cells Market Revenue Share by Region 4.3 North America (US, Canada, Mexico) 4.4 Europe (Germany, UK, France, Spain, Italy, Russia, Others) 4.5 Asia Pacific (China, Japan, India, South Korea, Australia, South East Asia, Others) 4.6 Latin America (Brazil, Argentina, Chile, Others) 4.7 Middle East and Africa (Saudi Arabia, UAE, Qatar, South Africa, Nigeria, Egypt, Others)

Player Analysis in Chapter Five 5.1 Players' Market Share Analysis (2023) 5.2 Regional Market Concentration Rates 5.3 Business Profiles, SWOT Analysis, Financial Details, Product Portfolio of Companies ..........continued For a comprehensive competitive analysis, Buy this report now and gain access to a detailed table of contents @ https://www.usdanalytics.com/payment/report-9048 Why should you purchase this report? USD Analytics offers essential historical and analytical data on the global Mesenchymal Stem Cells Market. The report thoroughly evaluates future market trends and potential changes in market behavior. It provides various strategic business methodologies to support informed business decisions. Gain a competitive advantage in the market with this detailed research report, which covers competitive landscape analysis, growth drivers, applications, market dynamics, and other In conclusion, the Mesenchymal Stem Cells Market report is a genuine source for accessing the research data which is projected to exponentially grow your business. The report provides vital information including economic scenarios, benefits, limits, trends, market growth rates, and figures. Further, SWOT analysis and PESTLE analysis are also incorporated in the report. Review the Executive Report: @ https://www.usdanalytics.com/industry-reports/mesenchymal-stem-cells-market Thanks for reading this article; You can also get individual chapter-wise sections or region-wise report versions like North America, Middle East, Africa, Europe, MENA, LATAM, and Southeast Asia.

Contact Us: Harry (Business Consultant) USD Analytics Market Phone: +1 213-510-3499 sales@usdanalytics.com

About Author: USD Analytics is a leading information and analytics provider for customers across industries worldwide. Our high-quality research publications are connected market. Intelligence databases and consulting services support end-to-end support our customer research needs.

This release was published on openPR.

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Mesenchymal Stem Cells Market to Witness an Outstanding Growth by 2030 - openPR

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Excerpt from:
Are any specific respiratory viruses more severe than others in recipients of allogeneic stem cell transplantation? A ... - Nature.com

Roughly 20 years ago, a biologist named Caroline Gargett went in search of some remarkable cells in tissue that had been removed during hysterectomy surgeries. The cells come from the endometrium, which lines the inside of the uterus. When Gargett cultured the cells in a petri dish, they looked like round clumps surrounded by a clear, pink medium. But examining them with a microscope, she saw what she was looking for two kinds of cells, one flat and roundish, the other elongated and tapered, with whisker-like protrusions.

Gargett strongly suspected that the cells were adult stem cells rare, self-renewing cells, some of which can give rise to many different types of tissues. She and other researchers had long hypothesized that the endometrium contained stem cells, given its remarkable capacity to regrow itself each month. The tissue, which provides a site for an embryo to implant during pregnancy and is shed during menstruation, undergoes roughly 400 rounds of shedding and regrowth before a woman reaches menopause. But although scientists had isolated adult stem cells from many other regenerating tissues including bone marrow, the heart, and muscle no one had identified adult stem cells in the endometrium, Gargett says.

Such cells are highly valued for their potential to repair damaged tissue and treat diseases such as cancer and heart failure. But they exist in low numbers throughout the body and can be tricky to obtain, requiring surgical biopsy or extracting bone marrow with a needle. The prospect of a previously untapped source of adult stem cells was thrilling on its own, says Gargett. And it also raised the exciting possibility of a new approach to long-neglected womens health conditions such as endometriosis.

Before she could claim that the cells were truly stem cells, Gargett and her team at Monash University in Australia had to put them through a series of rigorous tests. First, they measured the cells ability to proliferate and self-renew and found that some of them could divide into about 100 cells within a week. They also showed that the cells could indeed differentiate into endometrial tissue and identified certain telltale proteins that are present in other types of stem cells.

Gargett, who is now also with Australias Hudson Institute of Medical Research, and her colleagues went on to characterize several types of self-renewing cells in the endometrium. But only the whiskered cells, called endometrial stromal mesenchymal stem cells, were truly multipotent, with the ability to be coaxed into becoming fat cells, bone cells, or even the smooth muscle cells found in organs such as the heart.

Around the same time, two independent research teams made another surprising discovery: Some endometrial stromal mesenchymal stem cells could be found in menstrual blood. Gargett was surprised that the body would so readily shed its precious stem cells. Since they are so important for the survival and function of organs, she didnt think the body would waste them by shedding them. But she immediately recognized the findings significance: Rather than relying on an invasive surgical biopsy to obtain the elusive stem cells shed identified in the endometrium, she could collect them via menstrual cup.

More detailed studies of the endometrium have since helped to explain how a subset of these precious endometrial stem cells dubbed menstrual stem cells end up in menstrual blood. The endometrium has a deeper basal layer that remains intact and an upper functional layer that sloughs off during menstruation. During a single menstrual cycle, the endometrium thickens as it prepares to nourish a fertilized egg, then shrinks as the upper layer sloughs away.

Gargetts team has shown that these special stem cells are present in both the lower and upper layers of the endometrium. The cells are typically wrapped around blood vessels in a crescent shape, where they are thought to help stimulate vessel formation and play a vital role in repairing and regenerating the upper layer of tissue that gets shed each month during menstruation. This layer is crucial to pregnancy, providing support and nourishment for a developing embryo. The layer and the endometrial stem cells that produce its growth also appear to play an important role in infertility: An embryo cant implant if the layer doesnt thicken enough.

Endometrial stem cells have also been linked to endometriosis, a painful condition that affects roughly 190 million women and girls worldwide. Although much about the condition isnt fully understood, researchers hypothesize that one contributor is the backflow of menstrual blood into a womans fallopian tubes, the ducts that carry the egg from the ovaries into the uterus. This backward flow takes the blood into the pelvic cavity, a funnel-shaped space between the bones of the pelvis. Endometrial stem cells that get deposited in these areas may cause endometrial-like tissue to grow outside of the uterus, leading to lesions that can cause excruciating pain, scarring, and, in many cases, infertility.

Researchers are still developing a reliable, noninvasive test to diagnose endometriosis, and patients wait an average of nearly seven years before receiving a diagnosis. However, studies have shown that stem cells collected from the menstrual blood of women with endometriosis have different shapes and patterns of gene expression than cells from healthy women. Several labs are working on ways to use these differences in menstrual stem cells to identify women at higher risk of the condition, which could lead to faster diagnosis and treatment. Menstrual stem cells may also have therapeutic applications. Some researchers working on mice, for example, have found that injecting menstrual stem cells into the rodents blood can repair the damaged endometrium and improve fertility.

Other research in lab animals suggests that menstrual stem cells could have therapeutic potential beyond gynecological diseases. In a couple of studies, for example, injecting menstrual stem cells into diabetic mice stimulated the regeneration of insulin-producing cells and improved blood sugar levels. In another, treating injuries with stem cells or their secretions helped heal wounds in mice.

A handful of small but promising clinical trials have found that menstrual stem cells can be transplanted into humans without adverse side effects. Gargetts team is also attempting to develop human therapies. She and her colleagues are using endometrial stem cells those taken directly from endometrial tissue rather than menstrual blood to engineer a mesh to treat pelvic organ prolapse, a common, painful condition in which the bladder, rectum, or uterus slips into the vagina due to weak or injured muscles.

The condition is often caused by childbirth. Existing treatments use synthetic meshes to reinforce and support weak pelvic tissues. However, adverse immune reactions to these materials have led these meshes to be withdrawn from the market. Gargetts research so far conducted only in animal models suggests that using a patients own endometrial stem cells to coat biodegradable meshes could yield better results.

Despite the relative convenience of collecting adult multipotent stem cells from menstrual blood, research exploring and utilizing the stem cells power and their potential role in disease still represents a tiny fraction of stem cell research, says Daniela Tonelli Manica, an anthropologist at Brazils State University of Campinas. As of 2020, she found, menstrual stem cell research accounted for only 0.25 percent of all mesenchymal cell research, while bone marrow stem cells represented 47.7 percent.

Manica attributes the slow adoption of menstrual stem cells in part to misogynistic ideas that uteruses are outside the norm and to reactions of disgust. Theres certainly something of an ick factor associated with menstrual blood, agrees Victoria Male, a reproductive immunologist at Imperial College London who coauthored an article about uterine immune cells in the 2023 Annual Review of Immunology.

Cultural taboos surrounding menstruation and a general lack of investment in womens health research can make it difficult to get funding, says Gargett. Immunologist Male has faced similar challenges it was easier to obtain funding when she used to study immune cells in liver transplantation than it is now that she works on immune cells in the uterus, she says.

If we want more research on menstrual fluid, we need more funding, says Male, noting that the logistics of collecting menstrual fluid over multiple days can be expensive. For that to happen, we have to tackle sex and gender bias in research funding. Through more equitable investments, she and others hope, menstruation will be recognized as an exciting new frontier in regenerative medicine not just a monthly inconvenience.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.

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The Real Reason Studying Menstrual Blood Is So Important - Inverse

At the 50th Annual EBMT Meeting, clinicians and researchers highlighted advancements in the blood and bone marrow transplant field, including significant advances centering on criteria for donor selection in allogeneic stem cell transplantation (ASCT) and ongoing efforts to refine outcomes and reduce complications in patients with graft-versus-host disease (GVHD), according to Mohamad Mohty, MD, PhD.

In an interview with OncLive, Mohty highlighted key takeaways from the meeting, emphasizing the discussions that revolved around donor selection criteria, as well as the impact that haploidentical donors and other donor sources may have on patients' needs.

The 2024 EBMT Meeting was a very exciting meeting; we celebrated the 50th anniversary of the European Society for Blood and Marrow Transplantation [EBMT], which was originally founded in 1974, Mohty said. This EBMT Annual Meeting proved to be very successful, and we [saw] the greatest advances in this field.

In the interview, Mohty discussed the implementation of post-transplant cyclophosphamide for GVHD prophylaxis, highlighted efforts to optimize cyclophosphamide dosing to minimize complications when treating this disease, and noted future directions for this research.

Mohty is a professor of hematology, as well as the head of the Hematology and Cellular Therapy Department at the Saint-Antoine Hospital and Sorbonne University in Paris, France. He is also a member and lead of the translational research team at the Saint-Antoine Research Center and is the chairman of the Acute Leukemia Working Party for the EBMT.

Mohty: What was striking for me were the criteria for choosing donors [and] the implementation and [expansion] of the use of posttransplant cyclophosphamide [PTCy] for GVHD prophylaxis. There are also novelties in the management of acute, especially steroid-refractory, but also ruxolitinib-refractory, GVHD. Weve seen some great advances when it comes to cGVHD, and overall, this was a memorable EBMT meeting where milestone data were presented.

When it comes to choosing a suitable stem cell donor [for] ASCT, there is a lot of excitement about the use of haploidentical donors. When combining matched sibling donors, fully matched unrelated donors, mismatched unrelated donors, and now haploidentical donors, youre able to find a suitable donor for approximately 95% of patients who need an ASCT. Although the use of cord blood cells has decreased over the past few years in the adult population, if you use cord blood cells [with] the new technologies and platforms for cord blood expansion, you would be able to cover approximately 100% of [patient] needs.

Interestingly, when it comes to living donors, the age of the donor remains an important parameter. Favoring a young donor, whether in the setting of haploidentical or unrelated donors, is likely to be an important parameter. Also, having a female donor to a male recipient remains an important risk factor for alloreactivity, especially in cGVHD. What remains controversial is how to choose between a young haploidentical donor, if available, and a young, fully matched, unrelated donor. Here we dont have a final response to this question.

There are teams who now rely almost exclusively on family donors, and this would include matched sibling donors and haploidentical donors. There are still teams who prefer to have fully matched 10 out of 10 unrelated donors. This is proving to be very exciting, and despite the debates, the good news is [there is a possibility of] finding a donor for almost everybody who needs an ASCT.

Age of the donor is important when selecting a given donoron the other hand, you must take into account the age of the recipient [too]. When it comes to the recipients age, it is very important to consider the comorbidities, which will play an important role in the final outcome. We know from daily clinical experience that a patient who is 60 years oldbut has comorbidities such as hypertension, diabetes, a heavy smoking history, and cardiovascular complications[will be affected by] these comorbidities. [They will] negatively impact the incidence of nonrelapse mortality.

However, a patient whos 70 years old but also fit and without any comorbidities [will] have a lower likelihood of developing toxicities. We can see an important separation between biological age vs physiological age, which is correlated with comorbidities. The development of comorbidity indexes and trying to use new electronic artificial intelligence tools to try to predict outcomes are going to be major [focuses] of future research.

The use of posttransplant high-dose cyclophosphamide has, in the past 15 years, proved to be a major breakthrough in ASCT because it has allowed safe haploidentical stem cell transplantation [to be performed for the first time, thus] allowing for engraftment while reducing the risk of severe aGVHD and cGVHD.

The use of PTCy has rapidly spread because it is a relatively cheap drug and physicians are quite familiar with the use of cyclophosphamide, as it is a very common drug in hematology and oncology. It has great efficacy in depleting the alloreactive T cells. Now there is an accumulating body of evidence explaining the mechanism of action that allows PTCy to effectively prevent GVHD.

[Although] the initial experience started in the haploidentical setting, use of PTCy is spreading beyond haploidentical transplant and is being used increasingly in the mismatched unrelated setting. Some teams are also using it in the unrelated matched sibling setting. These are the positives with use. We also know with some long-term follow-up and greater experience that high-dose PTCymay not be suitable or safe for everybody because there is a risk of cardiac complications, which were described especially in patients with cardiovascular risk factors. We also know [there is] the high risk of hemorrhagic cystitis related to the BK virus.

At the EBMT meeting, we saw very nice translational work showing that PTCy can impact the immune repertoire and immune anti-infectious controlthat can explain the higher incidence of infectious and opportunistic infections after PTCy. With this background, efforts are aiming to test lower doses of PTCy, and our team presented data on reducing the dose by 20% or even 30%.

For instance, [we used] 35 mg/kg per day for 2 days on day 3 and day 4 or day 3 and day 5. You can achieve similar GVHD prevention while reducing the risk of complications, especially cardiac [and] infectious complications, but also shortening the duration of neutropenia and thrombocytopenia. This needs to be validated in prospective future randomized trials, but the use of PTCywill continue to grow. This is something that will make the ASCT procedure safer and more feasible, especially in older and frail patients.

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Mohty Shares Key Takeaways From the 50th Annual EBMT Meeting, Highlighting Advances in GVHD - OncLive

In an interview with OncLive, Mohamad Mohty, MD, PhD, discussed advancements in the management of graft-vs-host disease (GVHD) and highlighted unmet needs for patients with chronic (cGVHD) or acute GVHD (aGVHD), for whom standard-of-care therapies often fall short.

Mohty also expanded on ongoing research in GVHD reported at the 50th Annual EBMT Meeting. This included 3-year follow-up findings from the phase 2 ROCKstar trial (NCT03640481), which investigated belumosudil (Rezurock) in patients with cGVHD. The study showed that treatment with this agent yielded sustained responses, and no new safety signals were observed in eligible patients.1

Although challenges remain, advancements showcased at the EBMT meeting continue to underscore a new era for the treatment of patients with GVHD, Mohty noted. He provided further insights and key takeaways from the EBMT Annual Meeting in another interview with OncLive.

Mohty is a professor of hematology and the head of the Hematology and Cellular Therapy Department at Saint-Antoine Hospital and Sorbonne University in Paris, France. He is also head of the translational research team at the Saint-Antoine Research Center and the chairman of the Acute Leukemia Working Party of the EBMT.

Mohty: GVHD remains a matter of concern after transplant. Weve seen some major improvements over the past few years with the advent of posttransplant high-dose cyclophosphamide in particular. However, some patients are still [experiencing] aGVHD. Unfortunately, our first-line therapy remains focused on high-dose corticosteroids with deleterious adverse effects [AEs]; we also know that approximately 50% to 60% of patients are not going to respond to corticosteroids or are going to become corticosteroid dependent, which is not a good scenario.

Weve been lucky over the past 3 to 4 years to have the approval of the JAK2 inhibitor ruxolitinib, which proved to be a very good drug for patients who have steroid-refractory aGVHD. We are also struggling with a smaller group of patients who are becoming ruxolitinib refractory, resistant, or dependent. If you use ruxolitinib for salvage [therapy] after corticosteroids, a small group of patients may not be able to receive ruxolitinib, not everybody will respond, and some patients will lose their initial response to ruxolitinib. We then end up with a new group of patients who are ruxolitinib refractory. This is a new category of patients. Were fortunate that were now seeing research in this subgroup of patients. During the EBMT meeting, I was very excited to see some novel data on modulation of the microbiota in these patients with advanced and refractory aGVHD.

An important piece of information regarding the use of MaaT013 as salvage treatment based on the early-access program is its excellent safety profile. We didnt see severe AEs in the 140 patients who were treated. It is a single-shot treatment, which is important, instead of a treatment that is received and given to the patient on a chronic basis every day for several weeks or months.

Most importantly, the responses are very quickwithin 1 week. Patients who are responding are [doing so] in an excellent manner and very rapidly. Now based on this early-access program, we have very important follow-up that gives us some confidence in these results, which I consider quite reliable.

cGVHD incidence and severity have decreased over the past 10 years thanks to the efficacy of PTCy. However, we should bear in mind that were [performing transplant in] older patients. We are frequently using peripheral blood stem cells as well as donor lymphocyte infusion, including in the prophylaxis setting. At the end of the day, we still have a significant proportion of patients, at approximately 20%, who are continuing to experience moderate or severe cGVHD, which would require systemic immunosuppressive therapy.

Although cGVHD is not an immediate life-threatening condition, it dramatically alters the patients quality of life. Therefore, we still need to make progress in this arena. When it comes to the first-line therapy today, we dont have options better than corticosteroids. Thats the bad news because we dont like to use high-dose corticosteroids due to their deleterious AEs. We do have some good news about ruxolitinib because it was validated in the steroid-refractory cGVHD setting in the phase 3 REACH3 trial [NCT03112603].

But we have patients who may not be able to tolerate ruxolitinib; they may develop cytopenias over the long term or infections, or they may not respond to ruxolitinib. Therefore, novel options are needed, and this is where belumosudil, which was [granted regulatory] approved in 2021, is proving to be an excellent option. This drug has a new mechanism of action, as its a ROCK2 inhibitor. This mechanism of action is extremely interesting because when we look to the pathophysiology of cGVHD, we do have different phases. For instance, it is likely that ruxolitinib is acting well on the inflammatory component, which is an earlier phase, especially with the Th17 inflammatory response. But the use of a ROCK2 inhibitor such as belumosudil can also act not only on the inflammatory process but mainly on the fibrotic process. This is what makes it very attractive. This is what we saw in the ROCKstar trial, which allowed the approval of belumosudil in the United States and many other countries across the globe.

We can see more than a 70% response rate with belumosudil, and responses are in all organs usually involved with cGVHD, including the lung. [I stress] lung cGVHD because this is a terrible localization and [represents] a huge unmet need. Having a drug that [leads to] responses in the lung for cGVHD is most welcome. We are now getting closer to having better control of cGVHD. These drugs have been developed for the patient population with the most advanced, severe [disease]. The next step, and my wish, is to try to move these agents into earlier lines of use, even first-line treatment of cGVHD.

During the EBMT meeting we heard about the launch of a randomized trial with belumosudil in the first-line setting in combination with corticosteroids. The field is moving positively and, in my opinion, in the right direction.

Biomarkers in the field of GVHD, whether acute or chronic, are highly desired. I dont think anyone would question the need to have biomarkers to be able to predict the responses [and] also the failures, and maybe identify when to start treatment. Unfortunately, despite a lot of research and some very nice studies, Im not aware of 100% reliable, robust biomarkers in acute or chronic GVHD.

There have been some great work and results, for instance, with the Mount Sinai Acute GVHD International Consortium criteria and biomarker [research], but I still dont believe this is part of routine clinical practice. Its also true that in cGVHD, we dont have reliable biomarkers; maybe we will, but it will be difficult to find these biomarkers because cGVHD is a very heterogeneous condition. Clinically, cGVHD of the lungs or scleroderma may be different from dry eyes or dry mouth with cGVHD. In the ideal world, we would love to see these biomarkers. However, in the real world today, I dont see them ready for primetime yet.

Cutler C, Lee SL, Pavletic S, et al. Belumosudil for chronic graft-versus-host disease after 2 prior lines of systemic therapy: 3-year follow-up of the ROCKstar study. Presented at: 50th Annual Meeting of the EBMT; April 14-17, 2024; Glasgow, Scotland. Abstract OS13-01.

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Derivation of HOs from hiPSCs

We previously generated hiPSC-derived cardiac organoids (COs), and the CO formation resulted in the enhanced maturity of hiPSC-derived cardiomyocytes [18]. However, these COs could not mimic the diverse cellular composition of the human heart. Thus, we refined our differentiation protocol to generate heart organoids (HOs) designed to accommodate the coexistence of various cardiac lineage cells by modulating BMP, VEGF, FGF, and TGF signaling during differentiation (Fig. 1A).

A Overall schematic diagram of differentiation from hiPSC into COs and HOs. B Comparison of beating efficiency of COs and HOs at day 830 of differentiation. C The morphology of COs and HOs for 30 days, including the differentiation period.

An assessment of organoid beating efficiency spanned the entire differentiation period from day 8 to day 30 for both COs and HOs (Fig. 1B). On day 810 of differentiation, both COs and HOs initiated discernible beating (Fig. 1B). Notably, COs showed a beating efficiency of 68.1%, whereas HOs exhibited a lower rate of 34.5% on day 8 of differentiation. However, although the beating efficiency at the beginning of differentiation was higher in COs than in HOs, HOs displayed an ascending trend in their beating rate post-differentiation initiation, culminating in a 100% beating efficiency by day 30 (Fig. 1B), and resulted in similar beating efficiency to COs on day 30 (Fig. 1C, Videos 1 and 2).

Moreover, we validated the cardiomyocyte subtypes in the organoids by confirming the expression levels of MLC-2v and MLC-2a, indicative of ventricular and atrial types of cardiomyocytes, respectively. We observed that the expression of MLC-2a initiated early in differentiation (from D5 to D10), while MLC-2v expression gradually increased over the differentiation period. At D24, the majority of cardiomyocytes in both COs and HOs exhibited strong expression of MLC-2v (Fig. S1A and B).

To assess the cellular distribution in the COs and HOs, FACS analysis was performed (Figs. 2A, B and S2). Within COs, the mean distribution of cTnT, CD90, and VE-cadherin was 92.232.62%, 6.241.55%, and 4.731.48%, respectively (Figs. 2A, B and S2). Conversely, in HOs, these distributions were determined to be 51.095.92%, 24.634.08%, and 14.033.34%, respectively (Figs. 2A, B and S2).

A Representative pie chart showing the distribution of cTnT, a cardiomyocyte (CM)-specific marker, CD90, a cardiac fibroblast (CF)-specific marker, and VE-Cad, an endothelial cell (EC)-specific marker, in CO and HO. B The graph displays the mean cellular compositions of cardiomyocytes, fibroblasts, and endothelial cells across 11 different batches of COs and HOs. C Representative z-stack image of HOs and COs using confocal microscopy (left). Staining for cTnT (green) and VE-cad (red) in 2D monolayer culture of cells dissociated from HOs and COs (right). Scale bar: 100m. D Z-stack image of co-staining for Vimentin (fibroblast marker, green), -actinin (cardiomyocyte marker, red), and DAPI (blue) in COs and HOs. Scale bar: 100m. E Comparison of the gene expression levels for various cell types in COs and HOs. Quantitative analysis of gene expression levels as performed with real-time PCR. The expression levels of cardiomyocyte markers (NKX2.5, TNNT2, MYL2, and MYL7), endothelial cell markers (CD34, PECAM1, SOX17, and FOXA2), fibroblast markers (CD90, PDGFR, Vimentin, and TCF21) normalized to that of GAPDH. Data were shown as fold-change relative to COs, as meanSD, by 2-way ANOVA (n=3). A significant difference is indicated by #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001 compared with COs and ns (non-significant).

Immunostaining was also performed to visualize the distribution of cardiac lineage cells (Fig. 2C and D). Consistently with FACS analysis, COs prominently displayed cTnT expression within the organoids, while HOs displayed VE-cadherin expression on the surface of HOs (Fig. 2C, Videos 3, 4). The distinct distribution of blood vessel cells in HOs was further verified through the culture of dissociated organoids, and the dissociated cells from HOs exhibited a composition of both cTnT-positive cells and VE-Cad-positive cells (Fig. 2C). In contrast, the dissociated cells from COs exclusively displayed cTnT-positive cells (Fig. 2C). In addition, the HOs exhibited notable expression of Vimentin, a fibroblast marker, in comparison to COs (Fig. 2D).

The differences were further validated through qPCR analysis, and this analysis substantiated that COs exhibited a relatively increased expression of NKX 2.5, a transcription factor governing heart development, in addition to TNNT2, MYL2, and MYL7 (Fig. 2E). In contrast, HOs displayed significant upregulation in genes related to cardiac fibroblasts (CD90 and PDGFR), Vimentin, and TCF21, all in comparison to COs (Fig. 2E). Furthermore, endothelial-related genes including CD34, PECAM1, SOX17, and FOXA2 exhibited elevated expression levels in HOs relative to COs (Fig. 2E).

To gain a deeper understanding of the intricate gene expression within HOs, we utilized single-cell RNA sequencing (Fig. 3). Utilizing UMAP clustering and marker identification, the pool of 2587 cells from HOs was effectively categorized into distinct groups, encompassing cardiomyocytes, fibroblasts, and endothelial cells (Fig. 3A). To compare the representative gene expression patterns by cell type in both COs and HOs, we selected genes with p-values below 0.05 and visualized their expression using violin plots. Additionally, a comparative examination of gene expression patterns between COs and HOs was presented through violin plots. Notably, representative genes linked to cardiomyocytes, such as MYL2, MYL7, MYH7, TNNC1, MYBP3, and CACNA1C, exhibited enhanced expression in COs when compared to HOs (Fig. 3B). Similarly, an analysis was also extended to endothelial cells. Endothelial-related genes such as APOLD1, GIMAP4, PECAM1, PRSS23, STC1, and VEGFC exhibited an upregulation in HOs compared to COs (Fig. 3C). Shifting the focus to cardiac fibroblasts, the violin plots highlighted genes like AGT, CLU, and HMGA1 illustrating disparities between COs and HOs (Fig. 3D).

A Uniform manifold approximation and projection (UMAP) plots of HOs. Winseurat data sets labeled with Winseurat clusters. Detailed clustering within CMs (pink), CFs (green), and ECs (purple) clusters. BD Violin plots of representative genes for CMs (MYL2, MYL7, MYH7, TNNC1, MYBPC3, and CACNA1C), ECs (APOLD1, GIMAP4, PECAM1, PRSS23, STC1, and VEGFC), and CFs (AGT, CLU, and HMGA1). These genes were selected fold-change about 2-fold, average expression about 4 or more, and p-value 0.05 or less.

Clusters where unselected genes were grouped under the unclassified category in HOs were further analyzed (Fig. 3A). To predict cell types within the populations, we made use of databases such as pangiaoDB and GeneCard. These predictions revealed that the unclassified population mainly comprised pericytes, epithelial cells, neurons, and other cell types. These findings collectively indicate that HOs possess a more comprehensive genetic repertoire of heart constituent cells in comparison to COs.

With the established HOs, we mimicked the pathological conditions of acute myocardial infarction (AMI) and subsequent cardiac fibrosis to model human heart disease (Fig. 4A). To replicate hypoxia-induced ischemic conditions, we introduced 50M of cobalt chloride (CoCl2) [19] to the organoids along with glucose-depleted culture medium. This approach effectively elevated the expression of hypoxia-inducible factor-1 (HIF-1) in both COs and HOs (Figs. 4B and S3).

A Schematic of an experiment mimicking the heart disease in organoids by ischemia-reperfusion injury mechanism that occurs in the human adult heart and followed fibrogenesis. B Expression of the HIF-1 through western blots. Quantitative analysis of HIF-1 performed using Image J software. The expression of HIF-1 normalized to that of GAPDH. Data were shown as fold-change, and a significant difference is indicated by ****, ####p<0.0001, and ns (non-significant). C Immunofluorescence images of the expression levels of apoptotic marker (cleaved caspase-3, green) and cardiomyocyte marker (cTnT, red) in COs and HOs after IR injury. The scale bar represents 100m. D Representative western blot image and quantitative analysis of cleaved caspase-3. Data normalized to that of caspase-3. Equal protein loading amounts were confirmed by GAPDH expression. The corresponding density ratio was calculated by the average intensity of the bands from Image J software. Data were shown as fold-change, and a significant difference is indicated by ****, ####p<0.0001 and ns (non-significant). E Representative image and quantitative analysis of TUNEL assay (green). Data were shown as fold-change, as meanSD, by 2-way ANOVA (n=3). Significant difference is indicated by #p<0.05, ***p<0.001, ****, ####p<0.0001 (*compared to control group; #compared to COs), and ns (non-significant). The scale bar represents 100m.

In the clinical condition, the rapid reintroduction of blood flow post-reperfusion can lead to an immediate supply of oxygen and nutrients, triggering heightened inflammation and oxidative stress, thereby potentially causing tissue damage. A study suggested that high glucose sensitizes cardiomyocytes to ischemia-reperfusion (IR) injury [20]. Another study proposed that intracellular and mitochondrial calcium overload may contribute to reperfusion injury by exacerbating oxidative stress [21]. Based on these findings, we hypothesized that these factors could mimic reperfusion injury in CoCl2-treated HOs. To test this hypothesis, we applied a culture condition in which high glucose and calcium ion levels, then CoCl2-treated COs and HOs were exposed to a reperfusion medium rich in glucose and calcium ions for 72h.

To verify the induction of apoptosis in both COs and HOs following IR injury, we performed co-staining of cTnT and cleaved caspase-3 in organoid sections (Fig. 4C). This co-staining provided confirmation of the reduction in cardiomyocytes and the increase in apoptosis were more pronounced in HOs compared to COs (Fig. 4C). Western blot analysis against the cleaved caspase-3 further confirmed the more effective induction of apoptosis in HOs relative to COs (Figs. 4D and S4). Validation of apoptosis in the IR-injured organoids was also carried out using the TUNEL assay, and the findings demonstrated the more increased apoptotic cells within the HOs than that of COs (Fig. 4E). Additionally, Western blot analysis unveiled a more substantial increase in the Bax/Bcl2 signaling in HOs compared to COs (Fig. S5).

IR injury in humans leads to the disruption of sarcomere structures and a reduction in cardiac markers, including cTnT and cTnI, within heart tissue [22]. Furthermore, in clinical practices, markers such as cTnI, Myoglobin (MB), and Creatine kinase M (CKM) are quantified in blood to diagnose myocardial infarction resulting from IR injury [23].

Consistent with previous findings, we observed a more pronounced disintegration of sarcomere structures in HOs following IR injury, in contrast to COs (Fig. 5A). Simultaneously, the intracellular expression of cTnT and cTnI showed a marked reduction in HOs compared to COs (Figs. 5B and S6). Moreover, the release of cTnI, MB, and CKM from HOs began to be released from the organoids 24h post-IR injury, with the highest levels observed at 72h and exhibited significantly higher levels than those from COs (Fig. 5C).

A Immunofluorescence images of the expression levels of sarcomeric -actinin and DAPI in the control and IR groups. White dotted line in IR-induced HOs indicates the disintegrated sarcomere structure in the organoids. The scale bar represents 100m and magnified image scale bar represents 20m. B Western blot analysis in cell lysates from COs and HOs in control and IR groups. The protein expression of cTnT and cTnI, which are essential for cardiac structure was calculated by the average intensity of the bands from Image J software. The comparison of the fold change between the COs and HOs was normalized by the control group. C Extracellular secretion levels of cTnI, myoglobin (MB), and creatine kinase M type (CKM), which AMI indicators in control and IR group during culture periods. Secretion of cTnI, MB, and CKM was measured by ELISA. All data were shown as meanSD by 2-way ANOVA (n=3). Significant difference is indicated by ***, ###p<0.001, ****, ####p<0.0001(*compared to control group; #compared to COs), and ns (non-significant).

In addition, an analysis of inflammatory responses and necrosis-related mRNA levels in both COs and HOs following IR injury revealed a more notable increase in gene expressions within HOs in comparison to COs (Fig. S7A). Furthermore, HOs subjected to IR injury displayed a more significant upregulation of NF-B, a crucial transcription factor involved in inflammation and processes related to cardiac-vascular damage, in comparison to IR-injured COs (Figs. S7B and S8). The expression levels of phosphorylated ERK, phosphorylated JNK, and phosphorylated p38, which are indicative of increased signaling pathways in cardiac remodeling post-AMI [24, 25], were also significantly elevated in IR-injured HOs compared to COs (Figs. S7C and S8).

Intracellular calcium overload and subsequent mitochondrial calcium accumulation are observed in acute myocardial ischemia, and these phenomena are exacerbated during reperfusion, ultimately leading to mitochondrial permeability transition pore (mPTP) opening [26]. Furthermore, within a physiological environment, the bulk of calcium during cycles of contraction and relaxation is released from and taken up by the sarcoplasmic reticulum (SR) [27]. Therefore, quantifying SR calcium content is essential in elucidating the pathophysiological mechanisms of calcium overload.

We first observed calcium overload in the organoids by measuring the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA), which significantly influences SR calcium storage [28], to infer the SR calcium content. Before IR injury, there were no significant differences in basal and peak intracellular calcium concentrations between COs and HOs during the contractionrelaxation cycle (Fig. 6A and B). However, after IR injury, both the basal and peak calcium concentrations were significantly higher in HOs compared to COs (Fig. 6A and B). Subsequently, we measured the activity of SERCA (kSERCA) by calculating the time constant after inhibiting SERCA and observed that the SERCA activity was notably increased in IR-injured HOs compared to IR-injured COs (Fig. 6C). In the same context, the phosphorylated phospholamban (PLN) expression was significantly elevated in IR-injured HOs, confirming the accelerated SERCA activity (Fig. 6D and S9). This suggests that SERCA activity preferentially increases during IR induction in HOs, leading to a significant increase in SR calcium storage in IR-injured HOs compared to IR-injured COs.

A Representative trace of calcium transient in COs and HOs before and after IR injury. control and IR groups. B Basal and peak Ca2+ concentrations were measured using calcium imaging. All data were shown as meanSD by 2-way ANOVA (n=1820). A significant difference in all graphs are indicated by *, #p<0.05, **, ##p<0.01, ***, ###p<0.001, ****, ####p<0.0001 (*compared to control group; #compared to COs), and ns (non-significant). C The SERCA rate constant, reflecting the activity of SERCA, was calculated by subtracting the reciprocal of the time constant measured after inhibiting SERCA from the reciprocal of the time constant measured in the transient. All data were shown as meanSD by 2-way ANOVA (n=1820). A significant difference in all graphs are indicated by *, #p<0.05, **, ##p<0.01, ***, ###p<0.001, ****, ####p<0.0001 (*compared to control group; #compared to COs), and ns (non-significant). D Western blot analysis of phospholamban and phosphorylated phospholamban in COs and HOs before and after IR injury. Quantitative analysis of all western blot data was calculated by the average intensity of the bands in Image J software. Equal protein loading amounts of western blot data were confirmed by GAPDH expression. A significant difference of all graphs is indicated by #,*p<0.05, ##,**p<0.01 ###,***p<0.001, ####,****p<0.0001(*Compared to control group; #compared to COs), and ns (non-significant). E Representative immunofluorescence images of MPTP opening (calcein, green) in control and IR groups. The scale bar represents 200m. F MPTP opening (calcein) ratio in each group was calculated by image J software. This data was normalized to the control of COs. G Beating characteristics of COs and HOs in IR and control groups. Beating analysis was performed by monitoring calcium fluorescence over a period of 20s under control and IR conditions. A comparison of BPM (beat per minute), peak-to-peak duration, and time-to-peak was performed on COs and HOs in each group. All data were shown as meanSD by 2-way ANOVA (n=3). A significant difference in all graphs is indicated by **, ##p<0.01, ***, ###p<0.001, ****, ####p<0.0001 (*compared to the control group; #compared to COs), and ns (non-significant). H Schematic summary of findings in (AF).

To determine whether the IR condition facilitates mPTP opening in HOs, we directly measured fluorescence intensity using an mPTP assay kit in the IR-injured organoids and found a more significant reduction in fluorescence intensity within IR-injured HOs compared to COs (Fig. 6E and F), suggesting that IR injury in HOs leads to a greater increase in mPTP opening than IR injury in COs.

Moreover, the real-time calcium transient assay allowed for an analysis of calcium handling properties in IR-injured organoids (Figs. 6G and S10). Amplitudes showed no significant difference between COs and HOs during ischemia and IR injury (Fig. 6G). However, HOs subjected to ischemia-injury exhibited aberrant beating properties (Fig. 6G) with a significant change in beating rate (peak-to-peak) and systolic time (time-to-peak), indicated a disease-like model. Consistent with the ischemia results, the IR-injury condition induced further detrimental calcium handling properties in HOs, resulting in a decrease in beating and systolic parameters compared to those of COs (Fig. 6G). Collectively, these results indicate that multicellular HOs effectively mimic clinically observed AMI pathologies, such as calcium overload and mPTP opening under IR conditions, as well as the mimicking defects in calcium handling function (Fig. 6H).

Cardiac fibrosis is a consequential outcome of cardiac remodeling following AMI [29]. To replicate the cardiac fibrosis within IR-injured HOs, we cultured the organoids with 10M TGF-1 for 7 days. Staining for COL1A1, a marker indicating fibrosis progression, revealed a more pronounced accumulation of collagen in IR-injured HOs after fibrosis induction compared to IR-injured COs (Fig. 7A and S12A). This substantial collagen accumulation in IR-injured HOs was further confirmed through western blot analysis and Massons trichrome (MT) staining (Fig. 7B, C and S12B). Additionally, we assessed increased expression levels of mRNA associated with fibrosis-related genes (ACTA2, POSTN, Vimentin, MMP2) and collagen-related genes (PAI1, COL1A1, COL1A2, COL3A1) in IR-injured HOs after fibrosis induction using quantitative PCR (Fig. S12C).

A Representative immunofluorescence images of COL1A1 (green) and DAPI (blue) in each group. The scale bar represents 100m. B The protein expression of COL1A1 and -SMA, which are fibroblast activation and fibrosis indicators using western blot in cell lysates from COs and HOs in each group. Equal protein loading amounts were confirmed by GAPDH expression. C The morphologies of the IR-Fibrosis organoid by Massons Trichrome staining. The scale bar represents 40m. D Evaluation of the electrophysiological function of COs and HOs on the electrode of the MEA plate in each group. Magnified image to show a heatmap of a representative MEA recording. The spike activity of each active electrode is color-coded: white/red represents high spike activity; blue/black represents low spike activity. E Beating rate (BPM), Spike amplitude, FPDcF, and conduction velocity of COs and HOs in each group through MEA recording. All data were shown as fold-change, as meanSD, by 2-way ANOVA (n=3). A significant difference of all graphs is indicated by #,*p<0.05, ##,**p<0.01, ###,***p<0.001, ####,****p<0.0001(*Compared to control group; #compared to COs) and ns (non-significant). F Comparison of contraction in control COs versus IR-fibrosis COs and control HOs versus IR-fibrosis HOs.

To validate the alterations in calcium handling in HOs under the IR-fibrosis condition, we conducted a calcium transient assay. Real-time video recordings allowed for an analysis of beating properties (Fig. S13A and Videos 11, 12) of the organoids, and HOs subjected to IR-fibrosis displayed an increase in amplitude and beating (peak-to-peak) but a decrease in systolic (time-to-peak) compared to IR-fibrosis COs (Fig. S13B), reflecting a form of arrhythmic event in the human heart.

Heart disease also leads to alterations in electrophysiological properties [30, 31]. To demonstrate the defect of electrophysiological characteristics in IR-fibrosis HOs, multielectrode arrays (MEA) were utilized (Fig. 7D). Consistent with the analysis of beating properties in calcium transient, the beating rate (BPM) was significantly increased in IR-fibrosis HOs compared to IR-fibrosis COs, and the BPM exceeded 100, a characteristic of tachycardia (Fig. 7E). The spike amplitude, indicative of action potential height, demonstrated a decline in both COs and HOs within the IR-fibrosis group, but HOs displayed a particularly significant difference compared to COs (Fig. 7E). Measurement of the field potential duration corrected by Fridericias formula (FPDcF) unveiled a twofold increase in HOs subjected to IR-fibrosis (Fig. 7E), mirroring the prolongation of the period between the onset of the Q wave and the conclusion of the T wave. The cardiac conduction velocity exhibited a significant slowing in IR-fibrosis HOs compared to IR-fibrosis COs, resulting from an elevated risk of re-entrant excitation attributing to collagen accumulation in HOs (Fig. 7E). Additionally, induction of fibrosis subsequent to IR injury resulted in reduced contractility of COs but maintained normal cardiac rhythms, whereas, in HOs, it led to both diminished contractility and irregular cardiac rhythms (Fig. 7F).

The QuantSeq 3 mRNA-Sequencing analysis provided further support for the modeling of AMI and cardiac fibrosis in HOs (Fig. 8). In comparing the up-regulated KEGG pathways between control HOs and IR-injured HOs (Fig. 8A), it was observed that the FoxO signaling pathway, known to be activated in cardiomyocytes under ischemic stress [32], was predominantly up-regulated. Additionally, pathways associated with cancer, which share common systemic pathology and mechanisms with heart failure [33], were also up-regulated in IR-injured HOs. Furthermore, pathways related to extracellular matrix (ECM)-receptor interaction, PI3K-Akt signaling, and HIF-1 signaling were up-regulated in IR-injured HOs compared to control HOs which are known to play crucial roles in cardiac remodeling [34], alleviating negative post-infarct changes in myocardium [35], and modulating post-infarct healing after myocardial ischemic injury [36], respectively. Interestingly, pathways associated with human papillomavirus, insulin resistance, efferocytosis, longevity genes, and focal adhesion kinase (FAK) inhibition were also found to be up-regulated in IR-injured HOs. These pathways are implicated in various processes such as the diagnosis of myocardial infarction [37], hypoxia-induced inhibition of angiogenesis [38], macrophage-mediated clearance of dead cells during myocardial infarction [39], modulation of cardiovascular function [40], and regulation of cardiac fibrosis post-MI [41].

A Visualized graphs of up-regulated KEGG pathways in IR-injured HOs compared to control HOs. B Visualized graphs of up-regulated KEGG pathways in IR-fibrosis HOs compared to control HOs. The pathways were selected based on criteria including a fold change >2 and a p-value less than 0.05.

The comparison between control HOs and IR-fibrosis HOs revealed up-regulated pathways associated with cardiac fibrosis (Fig. 8B). One of the pathways identified as up-regulated in IR-fibrosis HOs, is the calcium signaling pathway, known to play a role in fibroblast activation by increasing intracellular calcium concentration, promoting fibroblast proliferation and migration, and inducing the synthesis of extracellular matrix proteins [42]. Extracellular matrix (ECM) remodeling is closely linked to cardiac remodeling and the development of heart failure [43]. Furthermore, the renin-angiotensin-aldosterone system (RAAS) pathway, Wnt signaling pathway, and adrenergic signaling pathway were also identified as up-regulated in IR-fibrosis HOs. These pathways are known to promote myocardial fibrosis and cardiac remodeling, contributing to the progression of heart failure [44,45,46,47], respectively. Additionally, conditions such as Cushing syndrome, circadian disruption, and cardiomyopathy, which are associated with increased myocardial fibrosis [48,49,50], were found to be relevant to the up-regulated pathways in IR-fibrosis HOs. Cortisol is also experimentally shown to induce cardiomyocyte hypertrophy [51].

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Injections of cardiac spheroids into primate ventricles improved left ventricular ejection after four weeks.

Researchers from Shinshu University and Keio University School of Medicine have tested a novel strategy for regenerative heart therapy. They transplanted cardiac spheroids derived from human induced pluripotent stem cells (HiPSCs) into damaged ventricles and observed very positive outcomes in primate models. These results could expand treatment options for people suffering from heart problems.

The prevalence of myocardial infarction is rising. These destroy millions of cardiac muscle cells, leaving the heart in a weakened state. Currently, as mammals cannot regenerate cardiac muscle cells on their own, heart transplants are the only clinically viable option for patients suffering heart failure. However, full heart transplants are expensive and donors are rare, so alternative therapies are highly sought after.

The team cultivated HiPSCs in a medium that led to their differentiation into cardiomyocytes. Following the extraction and purification of cardiac spheroids, they injected approximately 6 107cells into the damaged hearts of crab-eating macaques and monitored the condition of the animals for twelve weeks, taking regular measurements of cardiac function.

Analysis of the monkeys hearts at the tissue level was then conducted to assess whether cardiac spheroids could regenerate the damaged heart muscles. The researchers verified the correct reprogramming of HiPSCs into cardiomyocytes first, observing at cellular-level electrical measurements that the cultured cells showed patterns typical of ventricular cells. Also, the cells responded as expected to numerous known drugs. Significantly, they discovered that the cells abundantly expressed adhesive proteins like connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart.

Furthermore, this approach is less expensive and easier to adopt because the cells were transported from the production facility at Keio University to Shinshu University, located 230km away. The cardiac spheroids were preserved at 4C in standard containers and withstood the four-hour journey, meaning extreme cryogenic measures would not be required when transporting the cells to clinics.

The monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. The team noted that arrhythmias were very uncommon, with only two individuals experiencing transient tachycardia in the first two weeks among the treatment group. Echocardiography and computed tomography exams confirmed that, compared to the control group, the hearts of monkeys that received treatment had better left ventricular ejection after four weeks, demonstrating a superior blood pumping capability.

Ultimately, it was revealed through the histological analysis that the cardiac grafts were mature and properly connected to pre-existing existing tissue, confirming the results of previous observations. HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for heart regeneration, given their straightforward generation process and effectiveness, explained first author Dr Hideki Kobayashi. We believe that the results of this research will help solve the major issue of ventricular arrhythmia that occurs after cell transplantation and will greatly accelerate the realisation of cardiac regenerative therapy.

Despite this cardiac spheroid production protocol being tested in monkeys, it was designed for clinical application in humans. The favourable results obtained thus far are sufficient to provide a green light for our clinical trial, called the LAPiS trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy, concluded Dr Kobayashi.

This study was published in Circulation.

Read the original:
Accelerating cardiac regenerative therapy with HiPSC spheroids - Drug Target Review

In December 2014, Dr. Stephen Coles, a UCLA professor who studied aging, passed away from pancreatic cancer. While for many years Coles had made his home in Los Angeles, he chose to enter hospice care in Scottsdale, Arizona. That way, he could be close to the team of doctors who would

Once Coles was pronounced dead, that team arrived at his bedside. They restored his breathing and blood circulation with a heart-lung resuscitator, also known as a thumpera mechanical device used in emergency medicine to perform CPRand injected his body with anticoagulants to keep the blood flowing. All of this was done to protect the brain from damage that can occur after too long without oxygen. Next, the body was cooled in an ice water bath, the blood replaced with an organ preservation solution.

Finally, Coles body arrived at its final destination: Alcor, the nations oldest provider of cryonics, the freezing of human corpses and brains in liquid nitrogen that will one daytechnology willinglive again.

There, surgeons performed a neuroseparation, removing Coles head at the sixth cervical vertebra, and pumped cryoprotectants (medical-grade anti-freeze) into the now severed head. Then, a forensic pathologist opened the skull and removed the brain.

Coles had died around 10 a.m.; by dinner time, his brain was in a silver dewar, its thermostat set to -140 degrees Celsius.

The Patient Care Bay at Alcor holds a number of Bigfoot dewars, which are custom-designed to contain four whole-body patients and five neuropatients each. The dewar is an insulated container which consumes no electric power. Liquid nitrogen is added periodically to replace the small amount that evaporates.

Coles was Alcors 131st patient but one of its first to select brain-only cryopreservation, sometimes called neuropreservation or neurosuspension. A company announcement called Cole an unusual brain-only patient, and revealed that the unfamiliar nature of the procedure created several major challenges, with procedures being revised even as the surgery and perfusion were underway.

Ten years later, according to Emil Kendziorra, M.D., CEO of Tomorrow Bio, a German biotech firm that specializes in human cryopreservation, brain removal is not a big issue, and becoming more popular among those interested in cryonics. Storing a brain is faster, cheaper, anddespite the human taboo of decapitationpoised for a higher degree of social acceptance, Dr. Kendiziorra says, since anatomy departments and research institutions have been storing brains for years.

But what about the rest of the body? Wont future humans need their legs and arms when they wake up from their cryonic suspension?

While the brain is unique and cannot be recreated, the fundamental logic is that all the rest of the body can be recreated, Dr. Kendziorra tells Popular Mechanics. This means that by the time technology exists to cure death and reanimate the human brain, slapping together a real or virtual vessel should be a cinch.

These ideas may seem far-fetched, but Dr. Kendziorra is quick to point out that there was a time in the past when heart transplantationtaking one heart and connecting into another bodysounded pretty science fiction as well.

But as neuropreservation grows in popularity, the question remains: what will we do with all of these frozen brains in the future?

***

Dr. Kendziorra is a trained medical doctor-turned-cryonics evangelist. As a former cancer researcher, he was frustrated by the agonizingly slow pace of progress and never found it acceptable to tell a 25-year-old that they have incurable cancer and theyre going to die, he says. I think that everybody should live as long as they choose to.

Its important to point out that no human brain (or whole human for that matter) has ever been revived after death. The hope behind cryonics is that, eventually, very smart people using technology that hasnt been invented yet will figure out how to conquer death. For anyone with an untreatable diseaseor anyone who would like to live beyond their average lifespanto elongate their lives, they just need to freeze themselves, and then wait for those smart (and hopefully benevolent) people to wake us up.

Its also important to point out that freeze is the wrong word. Technically, cryonically preserved bodies arent frozen, theyre vitrified. Youve probably heard that the human body is 70 percent water; if you popped a corpse in the freezer, there would be a lot of cracking when ice crystals formed in the cells and damaged the body beyond revival. Upon thawing, the body would be mushy, thanks to the ruptured cell walls caused by cracking.

The Alcor operating theater in Scottsdale, Arizona. Here, surgeons perform initial procedures to gain access to the patients vascular system, replacing the blood with a cryoprotectant solution to prevent the formation of ice crystals during subsequent cooling.

Instead, cryopreservation involves vitrification, replacing the blood with a medical antifreeze, called cryoprotectant, then cooling the body gradually until it resembles glass.

The cost of these proceduresas well as transporting the body and storing it for untold yearsis not cheap. For full-body suspension, Tomorrow Bio charges 200,000. Thats why, although he always recommends full-body cryopreservation, Dr. Kendziorra says that, at the bargain price of 75,000, brain-only cryopreservation is an attractive option to those hoping to extend their time on Earth.

Dr. Kendziorra says he feels strongly about making cryopreservation possible at more price points, but its not just humans hoping to live forever that will benefit from increasing affordability. The field of cryonics needs an infusion of cash and research funding if it is going to maintain long-term storage facilities and figure out how to cure death. Theoretically, more bodiesor brainsin more tanks will lead to a greater investment in these endeavors by the scientific community.

Today, Alcors membership is split nearly evenly between whole-body and neuro cryopreservation. While neurosuspension is easier and less expensive, there are still some compelling reasons to consider whole-body cryopreservation.

For one thing, no one can be sure that the brain contains everything we would need to feel like ourselves upon reanimation. Without the central nervous system, the spine, the endocrine glands, and microbiome, would we recognize ourselves upon waking in the distant future?

Its a concern that led Becca Ziegler, a 23-year-old Tomorrow Bio member, to opt for whole-body preservation. From my understanding, everything that makes me me is in the brain, she says, but there are still some unknowns about consciousness and memories and how the brain interacts with the rest of the body. So I chose whole-body cryopreservation to ensure that there are no essential parts of my consciousness and memories that arent cryopreserved.

Dr. Kendziorra says that out of an abundance of caution, his company always recommends whole-body cryopreservation, unless its not within the budget of a perspective member. After all, rousing from a cryonic state hundreds of years in the future with only half of your identity would be a real disappointment. Better safe than sorry, says Dr. Kendziorra.

***

According to Dr. Kendziorra, there are currently four working theories for what future generations will do with thawed-out human brains. All of this is very speculative, he warns, but they have potential.

The first and perhaps most realistic, based on existing technology, is 3D printing.

We could 3D print all the other organs and connect the brain, Dr. Kendziorra says. This technology isnt there quite yet, but its probably not that far away anymore. Indeed, 3D organ bioprintingthe use of human cells to create three-dimensional tissueis a quickly evolving field, fueled by the hundreds of thousands of people who need organ transplants. Jennifer Lewis, a professor at Harvard Universitys Wyss Institute for Biologically Inspired Engineering, predicts the technology could be ready in a decade.

Another possibility will be the development of clones using DNA taken from brain tissue. The clone, of course, will need to be created without a brain, so that the old one can be transplanted. Since the birth of Dolly the sheep in 1996, scientists have cloned 22 animal species as well as a human embryo. Could brainless vessels be next?

Some scientists believe clones wont be necessary, and that reanimated brains could be transplanted in donor bodies, a method neurosurgeon Sergio Canavero called technically feasible, in a recent paper (published in a journal he is an editor of, it should be mentioned). After detailing how the cranial nerve and vascular system could theoretically be reconnected to the brain, the controversial scientist admitted there was lots of work still ahead, including cadaveric rehearsals, tests in brain-dead organ donors, and the development of new surgical tools. With appropriate funding, he argued, a long-held dream may finally come true.

The third way a reanimated brain could once again express itself is by being placed in an artificial body. In simpler terms, a robot body, says Dr. Kendziorra. Elon Musk thinks its possible and so does Michael S.A. Graziano, a Princeton neuroscientist. Graziano argued in a Wall Street Journal essay that uploading a mind into a robot body would take only two pieces of technology: an artificial brain and a scanning device with the ability to measure exactly how [a brains] neurons are connected to each other, to be able to copy that pattern in the artificial brain.

Then again, the robot might not even be necessary. We could reinstantiate the brain by connecting it to a computer, and all sensation inputs and outputs would be virtual, Dr. Kendziorra explains. On some abstract level, maybe theres not much a difference between real and virtual. Hes got a point; some scientists already believe were living in a simulation.

Regardless of just what future humans do with cryonically preserved brains, Dr. Kendziorra believes its going to take a long time to figure it out. Medically and technologically we are not there yet, and we will not be there for many, many decades. Its going to take a significant amount of time. And in fact, it might never work.

But if theres a reason to stay hopeful about cryonics, Dr. Kendziorra says its because the other option isnt so great either. The alternative, he laments, is death.

Ashley Stimpson is a freelance journalist who writes most often about science, conservation, and the outdoors. Her work has appeared in the Guardian, WIRED, Nat Geo, Atlas Obscura, and elsewhere. She lives in Columbia, Maryland, with her partner, their greyhound, and a very bad cat.

Original post:
The Science of Frozen Heads: How the First Cryonic Brains Will Rise Again - Popular Mechanics

Cell culture

Human MSCs from bone marrow were purchased from Riken BioResource Research Center (Ibaraki, Japan)and cultured in Dulbeccos Modified Eagles Medium (DMEM: Sigma-Aldrich, St. Louis, MO, USA) with 10% fetal bovine serum (FBS, Sigma-Aldrich). Cells were passaged four to five times before use for transplantation. HK-2 cells, a human proximal tubular cell line, were obtained from the American Type Culture Collection (Manassas, VA). These cells were cultured as described previously47.

MSCs were pretreated with or without recombinant human IFN- (PeproTech, Cranbury, NJ, USA) by the following method. When MSCs reached 70% confluence, IFN- was added to the medium to achieve a final concentration of 10ng/mL. After 48h, cells were collected and subjected to in vivo and in vitro analyses.

Male Sprague Dawley (SD) rats (8weeks old) were purchased from Charles River Laboratories Japan (Yokohama, Japan). Experimental procedures were approved by the Institutional Animal Care and Use Committee of Hiroshima University (Hiroshima, Japan) (Permit Nos. A15-66 and A17-75) and conducted in accordance with the Guide for the Care and Use of Laboratory Animals, 8th ed, 2010 (National Institutes of Health, Bethesda, MD, USA). This study is reported in accordance with ARRIVE guidelines. To establish the animal model, SD rats were randomly divided in 6 groups (n=5 in each group): sham, PBS (control), MSCs, IFN- MSCs, NC siRNA/IFN- MSCs and IDO1 siRNA/IFN- MSCs groups. All procedures were performed under anesthesia with injection of agents composed of midazolam, medetomidine, and butorphanol. Right nephrectomy was performed 7days prior to IRI of the left kidney. Renal IRI was induced by transiently clamping the unilateral renal artery. After a laparotomy was performed, the left kidney was exposed. Next, the renal pedicle was clamped by atraumatic vascular clamps for 45min, followed by reperfusion on a heating blanket. After reperfusion, phosphate-buffered saline (PBS, vehicle), control MSCs, or IFN- MSCs (5105 cells/rat) were injected through the abdominal aorta clamped above and below the left renal artery bifurcation. At 7 or 21days post-injection, rats were sacrificed and their kidneys were collected to evaluate inflammation and fibrosis.

Immunohistochemical staining was performed according to previously described methods47 using the following primary antibodies: mouse monoclonal anti-Foxp3 (Abcam, Cambridge, UK), rabbit polyclonal anti-CD3 (Dako, Glostrup, Denmark), mouse monoclonal anti-rat CD68 (Serotec, Oxford, UK), and rabbit polyclonal anti-collagen type I (Abcam). FOXP3-, CD3- and CD68-positive cells, as well as areas positive for -SMA and collagen type I staining, were assessed using ImageJ software (version 1.53s, NIH) by examining five randomly selected fields (100magnification) of the cortex.

Double immunostaining was performed according to the following methods. Sections of formalin-fixed, paraffin-embedded tissues (4m thick) were de-paraffinized, subjected to heat-mediated antigen retrieval in citric acid buffer at 98C for 40min, and then blocked in 5% skim milk at room temperature for 1h. They were incubated with anti-FOXP3 antibody (Abcam) overnight at 4C, followed by incubation with the appropriate secondary antibody (DAKO) at room temperature for 1h, and then incubated with 3,3-diaminobenzidine (Sigma-Aldrich) at room temperature for 5min. After that, they were heated again in EDTA buffer (pH 9.0) in the same way. They were then blocked in 2.5% normal horse serum (ImmPRESS Horse Anti-Rabbit IgG Polymer kit; Vector Laboratories, Riverside, CA, USA) at room temperature for 20min, followed by incubation with anti-CD3 antibody (Abcam) overnight at 4C. They were incubated with the secondary antibody (ImmPRESS Horse Anti-Rabbit IgG Polymer kit; Vector Laboratories) at room temperature for 30min and then incubated with working solution prepared with Vector SG Peroxidase (HRP) Substrate Kit (Vector Laboratories) at room temperature for 5min.

Sections of formalin-fixed, paraffin-embedded tissues (2m thick) were stained with Massons trichrome to assess fibrosis. Areas of interstitial fibrosis were assessed using Lumina Vision (Mitani, Osaka, Japan) by examining five randomly selected fields (100magnification) of the cortex.

Sample collection and western blotting were performed as previously reported36,47 with the following primary antibodies: anti-VEGFA antibody (Abcam), mouse monoclonal anti--SMA (Sigma-Aldrich), rabbit monoclonal anti-TGF-1 (Abcam), IDO1 polyclonal antibody (Proteintech, Rosemont, IL, USA), mouse monoclonal anti-Foxp3 (Abcam), rabbit polyclonal anti-CD4 (Abcam), and mouse monoclonal anti-GAPDH (Sigma-Aldrich). Horseradish peroxidase-conjugated goat anti-rabbit immunoglobulin G (Dako) or goat anti-mouse immunoglobulin G (Dako) were used as secondary antibodies. SuperSignal West Dura or Pico Systems (Thermo Fisher Scientific, Waltham, MA, USA) were used to detect signals. The intensity of each band was analyzed by ImageJ software and standardized to the level of GAPDH.

To generate conditioned medium (CM) from untreated MSCs (control MSCs-CM) and IFN- MSCs (IFN- MSCs-CM), human MSCs (3105 cells/dish) were seeded in 10-cm dishes and cultured in DMEM containing 10% FBS. When the cells reached at least 70% confluence, the medium was replaced with fresh medium with or without 200ng/mL recombinant human IFN- (PeproTech). After 48h, the culture medium was replaced with DMEM containing 0.1% FBS, which was collected after 48h.

RNA extraction and real-time reverse-transcription PCR were conducted according to previously described methods47. Specific primers and probes for human IDO1 (assay ID: Hs00984148_m1), and human -actin (assay ID: Hs99999903_m1) were obtained as TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA, USA). mRNA levels were normalized to the level of -actin.

ELISA analysis of IDO (R&D Systems, Minneapolis, MN, USA) was performed according to the manufacturers protocol. Concentrations were normalized to the total protein content.

Human peripheral blood mononuclear cells (PBMCs; Biosciences, Berkeley, CA, USA) were suspended with the buffer formulated as MACS BSA Stock Solution (Miltenyi, Bergisch Gladbach, NRW, Germany) and autoMACS Rinsing Solution (Miltenyi). Cells were labelled with a Nave CD4+T Cell Isolation Kit II (Miltenyi) according to the manufacturers protocols. Nave CD4-positive T cells were sorted by negative selection using LS columns (Miltenyi) and MidiMACS (Miltenyi), and then collected.

Nave CD4 T cells (1106 cells/mL) were cultured in RPMI-1640 (Solarbio, Beijing, China) plus 0.1% FBS (Thermo Fisher Scientific) with MSCs-CM or IFN- MSCs-CM at a RPMI-1640:CM ratio of 1:1. Next, Dynabeads human T cell activator CD3/CD28 (Thermo Fisher Scientific) was added at a bead:cell ratio of 1:1, along with animal-free human recombinant IL-2 (ProteinTech) at a concentration of 300IU/mL, and cells were incubated in a humidified CO2 incubator. The medium, IL-2, and beads were exchanged on day 3, and then cells were collected on day 5.

MSCs were transfected with 20nM siRNA against IDO1 (s7426, Applied Biosystems) or negative control siRNA (4390843, Applied Biosystems) using Lipofectamine 2000 Transfection Reagent (Thermo Fisher Scientific). After 24h, transfected cells were washed and fresh complete medium was added. When cells reached 80% confluence, they were collected and subject to in vivo experiments.

Results are expressed as the meanstandard deviations (S.D.). For multiple group comparisons, one-way ANOVA followed by Bonferronis post-hoc test was applied. Comparisons between two groups were analyzed by Students t-test. P<0.05 was considered statistically significant.

All experimental procedures were approved by the Institutional Animal Care and Use Committee of Hiroshima University (Permit Nos. A15-66 and A17-75).

See original here:
Mesenchymal stem cells pretreated with interferon-gamma attenuate renal fibrosis by enhancing regulatory T cell ... - Nature.com

A placebo-controlled Phase 1/2 trial conducted in East Shanghai has found that administering umbilical cord-derived mesenchymal stem cells reduces frailty in older people.

These researchers begin by defining frailty as a state of heightened vulnerability to potential stressors as a consequence of reduction in physiological reserves across multiple systems [1]. This vulnerability destroys the strength and endurance of older people, exhausting their stamina and greatly increasing their risks of death and disability, and a metric has been determined to measure this [2]. However, while vitamin supplements may help people with nutritional deficiencies, there are no medically approved drugs to treat frailty [3].

As stem cell exhaustion has been pinpointed as a cause of frailty [4], replacement stem cells have been investigated as a possible treatment. In particular, mesenchymal stem cells (MSCs), which are naturally attracted to injury sites [5], appear to be the most promising. MSCs have multiple potential sources for derivation [6], and previous trials have been conducted to treat frailty by using MSCs derived from bone marrow (BM-MSCs), with positive results [7, 8].

This study, however, was conducted on stem cells that were originally derived from the human umbilical cord (HUC-MSCs). These cells are easy to mass produce [9], have been successfully clinically tested against other diseases such as heart failure [10] and arthritis [11], and fight inflammation [12]. This, however, is the first trial of HUC-MSCs for frailty.

All participants had to meet three criteria: to be between the ages of 60 and 80, to score between 1 and 4 on the Fried frailty scale [2], and to be expected to live another year. A large variety of co-morbidities were screened out, such as uncontrolled diabetes, serious cardiovascular problems, infections, and viral diseases. This was a double-blinded trial from which 80 potential candidates were excluded. 15 patients received placebo, and 15 received MSCs, for 6 months.

This study measured physical performance by testing grip strength, the timed up-and-go test, walking speed, and the ability to stand up and sit back down. Inflammatory cytokines such as interleukins were also measured, and sleep quality, quality of life, and mental health were also assessed.

There were no significant adverse effects. Three participants had suffered from ailments during the trial, two of which were in the placebo group and the third of which had dizziness not related to the MSCs.

Physical function, the primary endpoint of the study, was strongly affected by the MSCs. Even with only 30 total participants, not all of which participated in every assessment, the researchers were able to obtain, against baseline, a p-value of .003 after only one week of treatment and p-values under .001 for 1 and 6 months. Against placebo, the p-value at the end of the 6-month study was .042.

There were possible effects on mental health and sleep quality but those could be statistically attributed to the placebo effect. However, the treatment improved total quality of life with a p-value of 0.002 against placebo at the end of the study.

Cytokines had less clear effects; the placebo group spiked in TNF- and IL-17 at 6 months while the MSC group did not.

While not all of the endpoints were hit, this study was against frailty, and it is clear from these results that MSCs have beneficial impacts on frailty in human beings. However, this study was conducted in one country among 30 people. Further work, with a larger sample size and more testing sites, will need to be conducted to determine if these results hold up under further scrutiny.

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?

[1] Clegg, A., Young, J., Iliffe, S., Rikkert, M. O., & Rockwood, K. (2013). Frailty in elderly people. The lancet, 381(9868), 752-762.

[2] Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., Gottdiener, J., & McBurnie, M. A. (2001). Frailty in older adults: evidence for a phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 56(3), M146-M157.

[3] Dent, E., Morley, J. E., Cruz-Jentoft, A. J., Woodhouse, L., Rodrguez-Maas, L., Fried, L. P., & Vellas, B. (2019). Physical frailty: ICFSR international clinical practice guidelines for identification and management. The Journal of nutrition, health and aging, 23(9), 771-787.

[4] Schulman, I. H., Balkan, W., & Hare, J. M. (2018). Mesenchymal stem cell therapy for aging frailty. Frontiers in Nutrition, 5, 108.

[5] Golpanian, S., Wolf, A., Hatzistergos, K. E., & Hare, J. M. (2016). Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiological reviews, 96(3), 1127-1168.

[6] Zhang, J., Huang, X., Wang, H., Liu, X., Zhang, T., Wang, Y., & Hu, D. (2015). The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem cell research & therapy, 6, 1-7.

[7] Golpanian, S., DiFede, D. L., Khan, A., Schulman, I. H., Landin, A. M., Tompkins, B. A., & Hare, J. M. (2017). Allogeneic human mesenchymal stem cell infusions for aging frailty. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(11), 1505-1512.

[8] Tompkins, B. A., DiFede, D. L., Khan, A., Landin, A. M., Schulman, I. H., Pujol, M. V., & Hare, J. M. (2017). Allogeneic mesenchymal stem cells ameliorate aging frailty: a phase II randomized, double-blind, placebo-controlled clinical trial. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(11), 1513-1522.

[9] Sarugaser, R., Lickorish, D., Baksh, D., Hosseini, M. M., & Davies, J. E. (2005). Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem cells, 23(2), 220-229.

[10] Bartolucci, J., Verdugo, F. J., Gonzlez, P. L., Larrea, R. E., Abarzua, E., Goset, C., & Khoury, M. (2017). Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [randomized clinical trial of intravenous infusion umbilical cord mesenchymal stem cells on cardiopathy]). Circulation research, 121(10), 1192-1204.

[11] Wang, L., Huang, S., Li, S., Li, M., Shi, J., Bai, W., & Liu, Y. (2019). Efficacy and safety of umbilical cord mesenchymal stem cell therapy for rheumatoid arthritis patients: a prospective phase I/II study. Drug design, development and therapy, 4331-4340.

[12] Uccelli, A., Pistoia, V., & Moretta, L. (2007). Mesenchymal stem cells: a new strategy for immunosuppression?. Trends in immunology, 28(5), 219-226.

Read the original post:
Stem Cell Treatment Restores Strength in Trial - Lifespan.io News

27-year-old Kerri Paton was overjoyed to welcome her first child with husband Igor Topas, 28, a little over six years ago. Baby Amelia was born a healthy 6lbs 12oz. But shortly after Kerri gave birth, her doctor noticed the newborn had pale purple spots all over her body.

Once she was in my arms I just cried. I was so happy, Kerri recalls of the birth to UK news site yahoo!life.

Acute means that these types can progress rapidly.

RELATED: 11-Month-Old Baby Boy of Beloved Female Police Officer Is Diagnosed with AML Leukemia as Community Rallies in Support Fighting Pediatric Cancer

Amelia had to begin chemotherapy at just three weeks old. Luckily, after the first round of chemotherapy, Kerri saw that her babys lumps and spots were gone, though she still had a long way to go.

Amelia also endured a bone marrow transplant, or stem cell transplant, which is a procedure where healthy cells are transplanted into your blood or bone barrow.

After eight months of treatment, she was declared in remission by her medical team.

Six months later after hearing the joyous news of remission, during a routine follow-up, Kerri and Igor tragically learned that their baby girl had relapsed with AML. Igor had been on his way to the appointment when the doctor called Kerri and said she should come in as well.

I just knew it had come back, Kerry said.

What Are The Symptoms of Relapse in Acute Myeloid Leukemia (AML)?

In addition to more chemotherapy, Amelia needed another stem cell transplant.

Thankfully, the transplant worked, and Amelia has now been cancer free for five years. Just before Amelias recurrence, the Scottish couple had another baby, a son named Oscar, so theyre now a happy and healthy family of four.

Watching your kid sick it was horrible, Kerri said of all they have endured. At six years old, she noted that her daughter is just so funny and fiercely independent. Shes very strong-willed.

Added Kerri, Even though she went through cancer, her story doesnt end there.

Acute myeloid leukemia (AML) is a cancer that affects bone marrow, the spongy tissue inside of your bones. Its a rare cancer overall, but it is the most common type of leukemia in adults. Children rarely get AML.

Dr. Mikkael Sekeres, Director of the Cleveland Clinic Cancer Center Leukemia Program, Explains How AML Works

This disease is caused by DNA damage to the cells in your bone marrow that give rise to blood cells. Red blood cells carry oxygen to tissues, white blood cells fight infections as part of the immune system, and platelets help stop bleeding. Those cells are damaged in AML, and the damage results in an overproduction of unnecessary white blood cells.

Acute lymphoblastic leukemia (ALL) is a type of leukemia where the bone marrow makes too many immature lymphocytes, a type of white blood cell. It is also called acute lymphocytic leukemia, according to the National Cancer Institute.

Dr. Olalekan Oluwole, a hematologist with Vanderbilt University Medical Center, previously spoke with SurvivorNet about ALLs effect on the body and the type of treatments that work to fight it.

ALL is a type of cancer that is very aggressive, Dr. Oluwole told SurvivorNet. It grows very fast. Within a few weeks, a few months, the person will start to feel very sick. And thats why we will have to give it an equally aggressive type of treatment to break that cycle.

All About Acute Lymphoblastic Leukemia

Dr. Oluwole also says the leukemia often resides in the bone marrow, and because it is an abnormal growth, it just keeps dividing.

It doesnt follow rules, and it doesnt stop, he told SurvivorNet. Not only that, because this is part of the immune system, the immune system is sorta like the police of the body. So those abnormal cells that have now become cancer, they have the ability to go to many places. They go into the blood, and they often go into the tissue or the lining around the brain.

As parents navigate their young ones cancer journey, its important to remember that childrens bodies may react differently to treatments because their bodies are still growing.

They may receive more intense treatmentsand they may respond differently to drugs that control symptoms in adults, the National Cancer Institute informs. Be sure to ask a lot of questions.

RELATED: Why Do Pediatric Drugs Take So Long to Develop? A Look into the Lag Time on Drug Approvals for Childhood Cancer & Other Illnesses

Remember, youre not alone your childs oncologist and care team are there to guide you and provide information and answers. Oncological social workers can also be a vital resource to help you sort out the financial aspects of cancer treatment, as well as other cancer-related issues. Skilled psychologists and counselors can be accessed to help you maintain good mental health through your childs cancer journey, to the best of your ability.

Additionally, dont be afraid to reach out to your support system friends, relatives, etc. for help through this process. No one expects you to handle everything on your own.

Meanwhile, if youre wondering what you can do to ensure your child is getting the best treatment possible, consider the following recommendations from theNational Cancer Institute.

At SurvivorNet, we always encourage people to advocate for themselves when it comes to cancer and, more generally, healthcare. When it comes to a child, the parent must become the advocate.

RELATED: The Top Ten Childhood Cancer Symptoms That Can Be Missed

Its important to speak up about each and every issue that may concern you, no matter how minor, as even minor signs can sometimes clue doctors in on a potential cancer diagnosis. And catching it as early as possible is always ideal, as early detection may help with treatment and outcomes.

When It Comes to Health, Its Okay to Be a Little Pushy

Seeking multiple opinions is one way to make sure you or your child is getting the proper care and attention. You should also try to remember that not all doctors are in agreement. Recommendations for further testing or treatment options can vary, and sometimes its essential to talk with multiple medical professionals.

Every appointment you leave as a patient, there should be a plan for what the doc is going to do for you, and if that doesnt work, what the next plan is, Dr. Zuri Murell, director of the Cedars-Sinai Colorectal Cancer Center, previously told SurvivorNet. And I think that thats totally fair. And me as a health professional thats what I do for all of my patients.

Learn more about SurvivorNet's rigorous medical review process.

Read more:
Prayers For Baby Girl Born with Pale Purple Spots on Skin Winds Up Being Diagnosed with Two Different Types of ... - SurvivorNet

According to Market.us, the Mesenchymal Stem Cells Market Size is expected to achieve a value of around USD 10 billion by the year 2033. This indicates a noteworthy escalation from its 2023 valuation of USD 3 billion. Such substantial growth is forecasted to occur at a Compound Annual Growth Rate (CAGR) of 12.6% during the projection period spanning from 2024 to 2033.

The Mesenchymal Stem Cells Market is undergoing significant transformations, influenced heavily by its interconnectedness with various end-use industries. These industries are pivotal in shaping the Mesenchymal Stem Cells Markets dynamics, as they drive demand and set stringent quality standards. The alignment between the market offerings and the industries evolving needs ensures a consistent demand, fostering a scenario ripe for sustained growth in the Mesenchymal Stem Cells sector. This interdependence necessitates that market players remain agile, innovative, and responsive to the shifting requirements and emerging trends within these pivotal sectors.

Regulatory frameworks set by governments worldwide are integral to the Mesenchymal Stem Cells Markets structure, influencing its operational, environmental, and compliance standards. These regulations ensure the markets adherence to safety, quality, and sustainability norms, which are increasingly becoming stringent. The adherence to these standards in the Mesenchymal Stem Cells Market is not just about legal compliance but also about building trust with consumers and maintaining a competitive edge. The markets resilience is thus tied to its ability to navigate the complex regulatory landscape, adapt to new laws, and uphold the highest standards of operational excellence.

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In this market research, Market.us uncovered key insights that offer actionable takeaways and provide a clear direction for future market strategies. Mesenchymal Stem Cells market findings reveal critical trends and developments that shape the market landscape. These insights equip businesses with valuable information to make informed decisions and stay ahead of the competition. By understanding consumer preferences, market dynamics, and emerging opportunities, companies can optimize their product offerings, refine their marketing strategies, and capitalize on growth prospects. Mesenchymal Stem Cells research highlights the importance of staying agile and adaptable in response to evolving market conditions. With these key takeaways, businesses can confidently navigate the market landscape, mitigate risks, and drive sustainable growth in the long term.

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In market research, its essential to identify and understand various market segments to tailor strategies effectively. By delineating the key market segments within the Mesenchymal Stem Cells market, businesses can refine their approach to cater to specific customer groups. This segmentation allows for more targeted marketing efforts, product development, and customer relationship management. Through thorough analysis, industries can identify common characteristics, needs, preferences, and behaviors within each segment. Mesenchymal Stem Cells insights enable companies to craft tailored messaging, promotions, and offerings that resonate with the unique needs of each segment. Moreover, understanding Mesenchymal Stem Cells market segments facilitates resource allocation, helping businesses allocate their resources efficiently and maximize their return on investment. Overall, identifying and targeting key market segments is crucial for businesses seeking to effectively engage with their target audience and achieve sustainable growth.

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When researching the Mesenchymal Stem Cells industry, its crucial to understand and leverage factors that drive growth. These may include technological advancements, increasing consumer demand, and supportive government policies. By recognizing and capitalizing on these forces, Mesenchymal Stem Cells industry can position themselves strategically to capitalize on growth opportunities. However, its also important to address market restraints such as regulatory challenges, economic downturns, and shifting consumer preferences. By identifying these obstacles early on, businesses can develop strategies to mitigate their impact and navigate through challenges effectively.

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In assessing the competitive landscape of the Mesenchymal Stem Cells market, it is essential to analyze key players strengths, weaknesses, and strategies. Leading companies in the healthcare sector typically have robust distribution networks, strong brand recognition, and diversified product portfolios, which are their primary strengths. However, they may also face challenges such as fluctuating market demand, regulatory constraints, and competitive pricing pressures. Strategies employed by Mesenchymal Stem Cells industry players often include product innovation, strategic partnerships, mergers and acquisitions, and market expansion initiatives. By continuously leveraging their strengths and addressing weaknesses, these companies strive to maintain or enhance their market position while adapting to evolving industry dynamics. A comprehensive understanding of the competitive landscape enables stakeholders to make informed decisions and develop effective strategies to capitalize on Mesenchymal Stem Cells market opportunities.

Recent developments in the Mesenchymal Stem Cells market, including mergers, acquisitions, and product launches, are shaping the industry landscape. These events reflect strategic maneuvers by companies to gain competitive advantage and expand their market presence. Mergers and acquisitions often lead to market consolidation and portfolio diversification, while new product launches drive innovation and address evolving consumer demands. Staying informed about Mesenchymal Stem Cells developments is crucial for understanding market dynamics and identifying opportunities for growth and investment.

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Mesenchymal Stem Cells Market Will Increase USD 10 Billion By 2033 - PharmiWeb.com

Health & Wellness

May 2, 2024

Hormone therapy is a treatment that uses medications containing hormones like estrogen or progesterone to replace those the body stops producing during menopause. It can be a powerful tool for managing menopausal symptoms.

"While hormone therapy can significantly improve quality of life and overall health for many women, its not a one-size-fits-all solution," says Dr. Taryn Smith, a Mayo Clinic internist and womens health specialist.

She emphasizes the importance of a personalized medicine approach to hormone therapy, allowing healthcare providers to consider your health and potential risks.

Having discussions around menopause is important because it's often not a topic that is openly discussed or acknowledged, despite its significance and importance, she says. Menopause is a natural biological process, marking the time that a woman ends her menstrual cycle. It's diagnosed after a woman goes 12 months without a menstrual period.

"Many women dont know how to navigate menopause and the symptoms that come along with it, such as hot flashes and night sweats. Hormone therapy is used to manage many of these symptoms," says Dr. Smith. "But it's not for everybody."

Watch: Dr. Taryn Smith talks about hormone replacement therapy

Journalists: Broadcast-quality sound bites with Dr. Smith are available in the downloads at the bottom of the posts. Name super/CG: Taryn Smith, M.D./Internal Medicine/Mayo Clinic

Menopause symptoms and hormone therapy Hormone therapy is used to manage symptoms of menopause, such as hot flashes, night sweats, trouble sleeping, and irritability.

"For the average healthy woman, these options are very safe. But if there are any concerns about these risk factors, its best to consult your physician or your womens health specialist," she says.

Treatment options Hormone therapy is a prescribed medication that can come in different forms, including patches, gels, sprays and oral medications.

Those options may include "A patch you wear on the skin, almost like a bandage in the lower groin or over the buttocks. We have gels that you can rub into the inner thigh and sprays that can be sprayed on the forearm. We also have some oral options. With all the options available, typically, we can find a good option that meets the average woman's needs," says Dr. Smith.

Expected outcomes After starting hormone therapy, women can expect relief from symptoms. In many cases, hot flashes can be completely resolved, improving the womans quality of life.

"Often, we're able to completely resolve hot flashes. But if we cannot completely resolve them, we hope to get significant relief at least and help a woman restore her quality of life," she says.

Safety concerns While there are safety concerns associated with hormone therapy, such as potential risks of breast cancer, stroke, or heart disease, it is generally safe for the average woman who is close to the menopause transition and younger than 60.

"For the average healthy woman, these options are very safe. But if there are any concerns about these risk factors, it's best to consult your physician or your women's health specialist," says Dr Smith.

For those who are unable to take hormone therapy or choose not to, there are FDA-approved nonhormonal treatments for menopause symptoms. Talk with your healthcare team to find out what is the best option.

Go here to see the original:
Hormone therapy: Four things a Mayo Clinic women's health specialist wants you to know - Mayo Clinic

Hormone therapys benefits to treat menopausal symptoms outweigh the risks for women under 60. And its safer than previously thought, according to a new study published in JAMA, the journal of the American Medical Association. But the use of menopausal hormone therapy is not recommended to prevent heart disease, stroke, dementia or other chronic illnesses. It doesnt reduce those risks.

The study says roughly 55 million women in the U.S. and 1.1 billion worldwide are postmenopausal. A national coalition of researchers launched the Womens Health Initiative, which is the biggest study of womens health in the country, enrolling 161,808 postmenopausal women ages 50 to 79, to inform clinical practices around aspects of health impacting older women. Recruitment for the study began in 1993 and each participant was followed for up to 20 years.

For years, it was believed that hormone replacement therapy lowered the risk of heart disease, stroke, dementia, chronic disease and even death. But as United Press International reported, one of the Womens Health Initiatives clinical trials slammed the brakes on hormone replacement therapy in 2002, however, reporting that women taking combination (estrogen and progestin) hormone therapy had an increased risk for breast cancer, heart disease, stroke and blood clots.

But they continued to study the issue, as the popularity of hormone replacement therapy dropped and many doctors stopped prescribing it. The article said that a more nuanced picture of hormone therapys risks and benefits has emerged as the research continued.

The article said that research over time has continued to show that hormone therapy doesnt solve age-related risks like heart disease or hip replacements, which other early studies suggested. But its not as risky as believed for younger women bothered by symptoms as they approach menopause. And in menopause, hormone replacement therapy can offer relief from those symptoms. .

Per NPR, Most significantly, there are now different types of hormones delivered at lower doses that are shown to be safer.

Women should know that hormone therapy is safe and beneficial, Dr. Lauren Streicher, a clinical professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine, told NPR.

The same studys findings do not support routinely recommending women take calcium plus vitamin D supplements to prevent fractures, but these supplements are appropriate to fill nutritional gaps for women who dont get enough of those nutrients through their diet, the researchers said.

They also noted that a low-fat dietary pattern with increased intake of fruits, vegetables and grains did not prevent breast or colorectal cancer, but was associated with lower rates of death from breast cancer in long-term follow-up, offering an option for women seeking to reduce this risk, Dr. JoAnn Manson, chief of Preventive Medicine at Brigham and Womens Hospital and first author of the new report in JAMA, said in a news release. Women also have more options for treatment now, including estrogen in lower doses and delivered through the skin as a patch or gel, which may further reduce risks; non-hormonal treatments are also available.

The Mayo Clinic News Network talked with Dr. Taryn Smith, one of Mayos internists and womens health specialists, about the value of a personalized approach to medicine when it comes to hormone replacement therapy. Smith offered four things women should know:

More here:
For women under 60, no reason to fear hormone replacement therapy - Deseret News

Back in 2003, preliminary

But the findings of the study were later debunked, and other researchers discovered that the original study looked at women who were 65 and up who already had a greater risk of heart attack, stroke, blood clots, and more, which ended up skewing the data. The study also didnt factor in how old the women were when they started hormone therapy, which further muddled the results.

Now, a longitudinal follow-up to the Womens Health Intitiative (WHI) study is out in JAMAand the findings suggest that women in menopause are just fine to take hormone therapy.

The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause with bothersome menopausal symptoms, lead study author JoAnn E. Manson, M.D., chief of the division of preventive medicine at Brigham and Womens Hospital and the Michael and Lee Bell Professor of Womens Health at Harvard Medical School, said in a press release. Many women are good candidates for treatment and, in shared decision making with their clinicians, should be able to receive appropriate and personalized healthcare for their needs.

Dr. Mason also noted that women have more options for treatment now, including receiving estrogen in lower doses and delivered through the skin as a patch or gel which may further reduce risks.

But the study findings stop short of saying that hormone therapy will help with health issues associated with menopause, like bone loss, dementia, and heart disease, although other studies have found it may be helpful. Thats caused several doctors who treat women in menopause to be frustrated. Heres what you need to know.

The new study looked at long-term follow-up data of up to 20 years from the Womens Health Initiative. It found that women below the age of 60 had lower rates of adverse events and a more favorable benefit-to-risk ratio of hormone therapy than women in later menopause. Meaning, they got more out of doing hormone therapy than not taking it.

The study results found that women in early menopause had less moderate-to-severe hot flashes, night sweats, and other symptoms of menopause when they were on hormone therapy. However, they concluded that hormone therapy should not be used to prevent heart disease, stroke, dementia, or other chronic diseases.

The study also looked at calcium and vitamin D supplements, concluding that these should not be recommended to prevent fractures in all postmenopausal women. However, researchers also found that calcium and vitamin D supplements may be helpful to fill in nutritional gaps for women who dont get enough in their diet.

The researchers also concluded that a low-fat diet with more fruits, vegetables, and grains didnt reduce the risk of being diagnosed with breast or colorectal cancer, but it was linked with a lower risk of dying from breast cancer.

Hormone therapy and hormone replacement therapy are terms that are usually used interchangeably. Both terms are used to describe a medical treatment that may help relieve the symptoms of menopause and perimenopause (the period before menopause), according to the American College of Obstetricians and Gynecologists (ACOG). This can also be referred to as menopausal hormone therapy.

The Menopause Society uses the term hormone therapy to acknowledge that were not trying to replace pre-menopause levels of hormones, says Lauren Streicher, M.D., a clinical professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine. But hormone replacement therapy is a term that most women are familiar with. Doctors will often use the term menopausal hormone therapy when discussing this topic, though, Dr. Streicher says.

You could make an argument that hormone therapy applies to treatments like estrogen vaginal cream for vaginal dryness that has no systemic benefits, but theyre usually used interchangeably, says G. Thomas Ruiz, M.D., lead ob/gyn at MemorialCare Orange Coast Medical Center in Fountain Valley, CA.

There are mixed emotions about this study. This is really not astonishingly new information, says Mary Jane Minkin, M.D., a clinical professor of obstetrics and gynecology and reproductive sciences at Yale School of Medicine and founder of Madame Ovary. We know from previous studies that hormone therapy is quite safe in women proximate to menopause and that indeed it is the most effective intervention for women suffering from many menopausal symptoms.

But, despite its benefits, many women are scared of the idea of taking hormone therapy given the findings of the original Womens Health Initiative study. This study can help with reassuring women that hormone replacement therapy is, in fact, beneficial, says womens health expert Jessica Shepherd, M.D., an ob/gyn in Texas and author of the upcoming book on menopause, Generation M. However, there needs to be a more demonstrative approach to show the benefits and how to use hormone replacement therapy preventatively.

But some doctors are frustrated with these findings. Saying that this study should never be used as a reason to deny hormone therapy? Guess what? Thats exactly what the effects of the original study were, Dr. Ruiz says.

Dr. Streicher calls the study infuriating, adding, theyre taking data that was poorly designed and flawed in the first place and are commenting on it.

Dr. Streicher also says the conclusion that hormone therapy shouldnt be used to lower the risk of heart disease and breast cancer is tricky, given that other studies have found hormone therapy can be a helpful tool for lowering risk. Dr. Minkin agrees.

The one major anxiety of American women is breast cancer, she says. Even in the initial WHI studies, the group of women who were taking estrogen alone never showed any increased risk of breast cancer on estrogen alone; indeed they showed a reduced risk of breast cancer. And followup long-term studies on estrogen plus progestin showed no increases in mortality from estrogen and progestin. So, we have very good documentation of safety.

For prevention, we do know that estrogen therapy is protective against developing osteoporosis, Dr. Minkin says. We also know that for very young women, particularly those under the age of 45 who were not studied in the WHI studythat looked exclusively at women over 50that estrogen therapy is vital to help protect those very young women against heart disease and dementia, she says. But that data is not addressed in this particular study because the Womens Health Initiative study only looked at women over the age of 50, Dr. Minkin says.

What to do if youre interested in hormone therapy for menopause

There is still a lot of misinformation tied to the original Womens Health Initiative study, and some doctors are not up to speed on current data surrounding the benefits of hormone therapy, Dr. Ruiz says.

Thats why he and other ob/gyns recommend seeing a specialist if youre interested in taking hormone therapy for menopause. See someone who knows what they are talking about and understands the data, Dr. Streicher says. They should be able to help you find the right treatment based on your personal circumstances and goals.

Its up to patients and their healthcare providers to determine if HRT is right for them. Dr. Manson tells Prevention that the follow-up WHI study was designed to provide clarification to healthcare providers on the use of hormone therapy in menopausal women. Ive heard from women across the country saying that theyre having trouble finding someone who will still prescribe hormone therapy, she says. Were saying very clearly from the WHI investigators who know the trials extremely well that these findings should not be used as a reason to deny hormone therapy to women seeking treatment of bothersome menopausal symptoms.

Korin Miller is a freelance writer specializing in general wellness, sexual health and relationships, and lifestyle trends, with work appearing in Mens Health, Womens Health, Self, Glamour, and more. She has a masters degree from American University, lives by the beach, and hopes to own a teacup pig and taco truck one day.

Read more:
Study: Hormone Replacement Therapy Helps Menopause Symptoms - Prevention Magazine

Nothing will have you Googling HRT therapy faster than your first hot flash.Hormone Replacement Therapy, or HRT, can be a lifesaver for many women navigating the challenges of menopause. It helps ease those sneaky hot flashes, stabilizes wild mood swings, and can even mitigate some of the physical changes that come with the change. Yet with all the options available, deciding on the right path can feel daunting. While HRT offers various treatment methods, each comes with its own set of risks and benefits.

One of the biggest concerns surrounding HRT is the potential for side effects and health risks. These can range from minor irritations to more severe complications, depending on the delivery method and individual health factors. The risks of taking hormone therapy differ for each individual, says Cincinnati, OH OB/GYN Somi Javaid, MD. Factors like the type, dose, duration of use, route of administration, and timing of initiation all play a role in determining safety and effectiveness.

Hormone therapy can be delivered systemically, affecting the entire body, or locally, targeting specific areas. According to Dr. Javaid, systemic therapy is usually aimed at addressing broader menopausal symptoms, while local therapy targets specific issues like vaginal dryness. Systemic therapy can be delivered orally or via transdermal patches, gels, sprays, or pellets, she explains.

Oral tablets are the simplest method, but Dr. Javaid warns about higher risks like blood clots and vascular events associated with this form of delivery. Transdermal patches, on the other hand, provide a consistent hormone release and are generally considered safer due to a reduced risk of clotting issues, she notes.

Hormone gels and sprays are another option you can apply directly to the skin. These allow for more precise dosing says Dr. Javaid, but cautions, They require careful application to avoid unintentional transference to others.

Implants or pellets, which are inserted under the skin, offer a steady hormone release over several months. However, Duxbury, MA plastic surgeon Christine DiEdwardo, MD points out that Dosage adjustments with pellets can be challenging since once a pellet is placed, it cannot be easily removed.

Each HRT delivery method has its pluses and minuses.Willowbrook, IL dermatologistJessie Cheung, MDnotes the convenience and flexibility of some: The advantage of oral and topical therapies is that you can quickly adjust the dosing, as most are taken daily and patches are applied every few days. However, this flexibility can come at a cost. The disadvantage with pellets is that most pellet procedures are done every three to six months. So dosing cant be adjusted easily. There also some soreness for a few days after, Dr. Cheung explains.

Pellets can be convenient due to their long-lasting nature, but they do require a minor surgical procedure for insertion. For many patients, the convenience of pellets outweighs the inconvenience of a 5-minute, in-office procedure, says Dr. Cheung.

However, Lauren Streicher, MD,clinical professorofobstetricsandgynecologyatNorthwestern Universitys Feinberg SchoolofMedicine says the cons of pellets are many. Pellets are not FDA approved and not recommended by most academic menopause experts, she explains. Every single professional society, including ACOG and The Menopause society has a very clear statement saying that pellets are unregulated, result in dangerously high levels of hormones and are associated with bleeding, uterine pre-cancer, cancer increased rates of hysterectomy and other side effects.

Conversely, creams offer quick adjustments in dosage but can be messy and require daily application. Creams can transfer to clothing or be passed to others and theres variable absorption, adds Dr. DiEdwardo.

The pros of transdermalestrogenin the form of patches, creams, gels and sprays: since they are not metabolized by the liver and unlike oral estrogen, do not increase the risk of blood clots or gallbladder disease, notes Dr. Streicher.Dr. Javaid adds that one thing to consider with patches is they might not be ideal for individuals who have adverse reactions to adhesives or those who dont want others to know theyre using HRT.

The best form of HRT is one that the patient is comfortable with and compliant in using, Dr. Cheung says. The choice is influenced by several factors, including health history, lifestyle and specific symptoms. Dr. Javaid advises considering your health history and any medications youre currently taking. The risks of taking hormone therapy differ for each individual, depending on type, dose, duration of use, route of administration and timing of initiation, she adds.

Patients should also consider their daily routines and personal preferences. Dr. Cheung mentions that some patients grow weary of applying creams twice a day, while others find pellet insertion procedures uncomfortable.

Discuss your options with your healthcare provider to determine which method aligns best with your needs and lifestyle, says Dr. Javaid.

There have been shown to be benefits of HRT, however there are also potential risks and contraindications to hormone therapy. Therefore factors that are evaluated prior to HRT include underlying medial history and risk of certain diseases, like cancer, heart disease, stroke, and blood clots, age at the start of hormone therapy, type and route of administration, dosage and how long you are on the medication, notes Dr. DiEdwardo. A thorough medical and family history, discussion of symptoms, physical exam and extensive testing are part of the evaluation prior to initiating HRT.

Read this article:
Pellets, Patches, Sprays and Creams: All the Ways to Get Hormone Replacement Therapy - NewBeauty Magazine

AI-enabled protein design company Profluent has leveraged artificial intelligence to design an open-source gene editor called OpenCRISPR-1, demonstrating the technology can be used to create molecules with the power to edit human DNA.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology, developed more than a decade ago, allows scientists to modify DNA sequences within living organisms precisely.

Potential applications range from treatments for genetic disorders to researching disease mechanisms.

The molecules it designs are fully synthetic and do not exist in nature, in contrast to previous technologies in gene editing, such as CRISPR-Cas9.

The company is open-sourcing OpenCRISPR-1 for free ethical research and commercial use and published the science behind the protein's development in a preprint publication.

"Attempting to edit human DNA with an AI-designed biological system was a scientific moonshot, Ali Madani, Profluent cofounder and CEO, said in a statement. "Our success points to a future where AI precisely designs what is needed to create a range of bespoke cures for disease."

WHY THIS MATTERS

AI was at the heart of this achievement, with the company training large language models (LLMs) on massive scale sequence and biological context.

The Profluent team developed a database of 5.1 million Cas9-like proteins, and the AI model was trained on this database to create potential proteins for CRISPR use.

This enabled the LLM to create novel gene editors from scratch as it learned through examples found in nature.

After narrowing down the results, they identified OpenCRISPR-1, a protein performing similarly to Cas9 but with far less impact on off-target sites. This makes it more precise and causes minimal damage to DNA.

The goal of open-sourcing OpenCRISPR-1 is to encourage the use of AI for ethical research and commercial use, particularly in developing medicines leveraging CRISPR.

"We believe by doing so, we can help accelerate the pace of discovery and innovation in the field," Madani said. "Our vision is to move biology from being constrained by what can be achieved in nature to being able to use AI to design new medicines precisely according to our needs."

He added that the company intends to partner with cutting-edge research institutions and drug developers working across the drug development lifecycle to enable CRISPR medicines to become available to a greater number of patients and for a greater number of disorders.

THE LARGER TREND

Gene editing technologies, including SHERLOCK and DETECTR, are transforming digital diagnostics, enabling rapid detection of infectious diseases such as COVID-19.

Companies including Atomwise, Deep Genomics and Valo are incorporating gene editing into drug discovery processes, revolutionizing treatment development.

Beyond gene editing, AI is powering everything from bone marrow analysis software to drug discovery and platforms to help pair patients with the right cancer-treatment drugs.

Originally posted here:
Profluent releases AI-enabled OpenCRISPR-1 to edit the human genome - Mobihealth News