Archive for the ‘Bone Marrow Stem Cells’ Category

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Most kids with peanut allergies do not outgrow them. But, with a little help, some might be able to better tolerate accidental exposures.

In January, the Food and Drug Administration approved Palforzia, a new drug designed to help kids who are allergic to peanuts react better, if they are accidentally exposed.

"Because there is no cure, allergic individuals must strictly avoid exposure to prevent severe and potentially life-threatening reactions," Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research said at the time in a news release. "When used in conjunction with peanut avoidance, Palforzia provides an FDA-approved treatment option to help reduce the risk of these allergic reactions."

Palforzia is not designed to be administered during an allergic reaction, instead it works as an allergy exposure therapy: children ages 4 through 17 receive daily doses of peanut powder under clinical supervision, and slowly up-dose it over time.

In clinical trials, the strategy worked well, but not perfectly. When peanut-allergic kids were fed 600 milligrams of peanut protein, 67.2% of Palforzia recipients who'd been using the medication for six months tolerated it, while only 4% of the control group did.

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The 11 most mind-blowing, awe-inspiring health discoveries and innovations of 2020 - Business Insider - Business Insider

First gene therapy to receivefull EU marketing authorization for eligible MLD patients

One-time treatment with Libmeldy has been shown to preserve motor and cognitive function

Achievement shared with research alliance partners Fondazione Telethon and Ospedale San Raffaele

BOSTON and LONDON and MILAN, Italy, Dec. 21, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, and its research alliance partners Fondazione Telethon and Ospedale San Raffaele, today announced that the European Commission (EC) granted full (standard) market authorization for Libmeldy (autologous CD34+ cells encoding the ARSA gene), a lentiviral vector-based gene therapy approved for the treatment of metachromatic leukodystrophy (MLD), characterized by biallelic mutations in theARSAgene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

MLD is a very rare, fatal genetic disorder caused by mutations in the ARSA gene which lead to neurological damage and developmental regression. In its most severe and common forms, young children rapidly lose the ability to walk, talk and interact with the world around them, and most pass away before adolescence. Libmeldy is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible young patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at which untreated patients show severe motor and cognitive impairments.

Todays EC approval of Libmeldy opens up tremendous new possibilities for eligible MLD children faced with this devastating disease where previously no approved treatment options existed, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Libmeldy is Orchards first product approval as a company, and I am extremely proud of the entire team who helped achieve this milestone. We are grateful for and humbled by the opportunity to bring this remarkable innovation to young eligible patients in the EU.

With Libmeldy, a patients own hematopoietic stem cells (HSCs) are selected, and functional copies of the ARSA gene are inserted into the genome of the HSCs using a self-inactivating (SIN) lentiviral vector before these genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the underlying disease with a single treatment.

The EC approval of Libmeldy comes more than a decade after the first patient was treated in clinical trials performed at our Institute, and ushers in a remarkable and long-awaited shift in the treatment landscape for eligible MLD patients, said Luigi Naldini, M.D, Ph.D., director of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. Our team at SR-Tiget has been instrumental in advancing the discovery and early-stage research of this potentially transformative therapy to clinical trials in support of its registration through more than 15 years of studies supported by Fondazione Telethon and Ospedale San Raffaele, and we are extremely proud of this achievement and what it means for patients and the field of HSC gene therapy.

MLD is a heart-breaking disease that causes immeasurable suffering and robs children of the chance of life, said Georgina Morton, chairperson of ArchAngel MLD Trust. As a community, we have been desperate for a treatment for young MLD patients, and we are incredibly excited to now have such a ground-breaking option approved in the EU.

The marketing authorization for Libmeldy is valid in all 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway. Orchard is currently undertaking EU launch preparations related to commercial drug manufacturing, treatment site qualification and market access.

Data Supporting the Clinical and Safety Profile of Libmeldy

The marketing authorization for Libmeldy is supported by clinical studies in both pre- and early- symptomatic, early-onset MLD patients performed at the SR-Tiget. Early-onset MLD encompasses the disease variants often referred to as late infantile (LI) and early juvenile (EJ). Clinical efficacy was based on the integrated data analysis from 29 patients with early-onset MLD who were treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.

Clinical safety was evaluated in 35 patients with MLD (the 29 patients from the integrated efficacy analysis as well as six additional patients treated with the cryopreserved formulation of Libmeldy). Safety data indicate that Libmeldy was generally well-tolerated. The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies (AAA) reported in five out of 35 patients. Antibody titers in all five patients were generally low and no negative effects were observed in post-treatment ARSA activity in the peripheral blood or bone marrow cellular subpopulations, nor in the ARSA activity within the cerebrospinal fluid. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For further details, please see the Summary of Product Characteristics (SmPC).

About MLD and Libmeldy

MLD is a rare and life-threatening inherited disease of the bodys metabolic system occurring in approximately one in every 100,000 live births. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50% and 44% at 10 years for juvenile patients.1

Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, is approved in the European Union for the treatment of MLD in eligible early-onset patients. In the U.S., OTL-200 is an investigational therapy which has not been approved by the U.S. Food and Drug Administration (FDA) for any use. Libmeldy was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.

About Orchard

Orchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters inLondonandU.S.headquarters inBoston. For more information, please visitwww.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About Orchard

Investors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

About Fondazione Telethon, Ospedale San Raffaele and the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget)

Based in Milan, Italy, the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Ospedale San Raffaele, a clinical-research-university hospital established in 1971 to provide international-level specialized care for the most complex and difficult health conditions, and Fondazione Telethon, an Italian biomedical charity born in 1990 and focused on rare genetic diseases. SR-Tiget was established in 1995 to perform research on gene transfer and cell transplantation and translate its results into clinical applications of gene and cell therapies for different genetic diseases. Over the years, the Institute hasgiven a pioneering contribution to the field with relevant discoveries in vector design, gene transfer strategies, stem cell biology, identity and mechanism of action of innate immune cells. SR-Tiget has also established the resources and framework for translating these advances into novel experimental therapies and has implemented several successful gene therapy clinical trials for inherited immunodeficiencies, blood and storage disorders, which have already treated >115 patients and have led through collaboration with industrial partners to the filing and approval of novel advanced gene therapy medicines.

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Forward-Looking Statements

This press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as anticipates, believes, expects, plans, intends, projects, and future or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, including its plans and expectations for the commercialization of Libmeldy, and the therapeutic potential of Libmeldy, including the potential implications of clinical data for eligible patients. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation:: the risk that prior results, such as signals of safety, activity or durability of effect, observed from clinical trials of Libmeldy will not continue or be repeated in our ongoing or planned clinical trials of Libmeldy, will be insufficient to support regulatory submissions or marketing approval in the US or to maintain marketing approval in the EU, or that long-term adverse safety findings may be discovered; the inability or risk of delays in Orchards ability to commercialize Libmeldy, including the risk that we may not secure adequate pricing or reimbursement to support continued development or commercialization of Libmeldy; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

1 Mahmood et al. Metachromatic Leukodystrophy: A Case of Triplets with the Late Infantile Variant and a Systematic Review of the Literature.Journal of Child Neurology2010, DOI:http://doi.org/10.1177/0883073809341669

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Orchard Therapeutics Receives EC Approval for Libmeldy for the Treatment of Early-Onset Metachromatic Leukodystrophy (MLD) - GlobeNewswire

The stock price of Creative Medical Technology Holdings Inc (OTCMKTS: CELZ) a company that engages in stem cell research and developing applications to treat male sexual dysfunction and related issues increased by 80.77% yesterday as it went from $0.0026 to $0.0047 per share. One of the biggest triggers for the stock price increase is an announcement about the company announcing the successful application of ImmCelz immunotherapy for treatment of stroke.

In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. And there were improvements in functional recovery were observed using the Rotarod test.

At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals that received bone marrow mesenchymal stem cells (73% of non-stroke control). And animals that received saline had a running time that was 50% of non-stroke controls.

KEY QUOTES:

The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research. Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially formregenerative memory cells.

Dr.Amit Patel, coinventor of ImmCelz

This data, which is covered by our previous filed patents, such as no. 15/987739,Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the$30 billion dollarmarket for stroke therapeutics. The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke.

Dr.Thomas Ichim, coinventor of the patent and Chief Scientific Officer of Creative Medical Technology

While stroke historically has been a major area of unmet medical need, the rise in stroke cases , as well as the fact that younger people are increasingly falling victim to stroke, strongly motivates us to accelerate our developmental programs and to continue to explore participation of Big Pharma in this space. We are eager to replicate the existing experiments start compiling the dossier needed to take ImmCelz into humans using the Investigational New Drug Application (IND) route through the FDA.

Timothy Warbington, President and CEO of Creative Medical Technology

Disclaimer: This content is intended for informational purposes. Before making any investment, you should do your own analysis.

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Creative Medical Technology Stock Price Increased 80.77%: Why It Happened - Pulse 2.0

Abstract

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5/Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

Reactive aldehydes, such as acetaldehyde and formaldehyde, are cytotoxic and carcinogenic because they damage DNA and interfere with transcription and replication. Whereas acetaldehyde is mostly produced by oxidative degradation of ingested alcohol, formaldehyde is an ordinary one-carbon (1C) metabolite that is generated from various in vivo biochemical reactions, including enzymatic demethylation of histones and nucleic acids (1, 2). These free aldehydes are swiftly oxidized to innocuous carboxylic acids by cellular dehydrogenases. Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde into acetate, but this enzyme is inactivated in ~50% of the population in East Asian countries because of a functional single-nucleotide polymorphism, rs671 [ALDH2*2, c.1510G>A, p.E504K; MAF (minor allele frequency) = 0.27 in Japanese]. Rs671 is known to cause alcohol flushing response after drinking (36). Apparently, alcohol flushing is not a disease; however, the rs671 defective (A) allele is protective against alcoholism and is also associated with an increased risk of various clinical conditions, including cardiovascular disorders (7, 8) and certain types of cancer (4, 912). In particular, the incidence of gastrointestinal cancers, represented by esophageal squamous cell carcinoma, is significantly higher in individuals with the rs671 defective allele when they regularly drink alcohol (1012). Despite a multitude of known genetic associations, no disease with a true digenic/oligogenic inheritance (1315), under complete penetrance, due to rs671 has been reported. With regard to the formaldehyde elimination, alcohol dehydrogenase 5 (also known as formaldehyde dehydrogenase or S-nitrosoglutathione reductase, ADH5/FDH/GSNOR) is the principal enzyme converting formaldehyde to formic acid in a glutathione-dependent manner (16). Because GSNOR is also a key enzyme for the modulation of cellular nitric oxide signaling, thereby regulating circulatory functions, ADH5 polymorphisms are known to be associated with an increased risk of cardiovascular disorders (16). Nevertheless, to date, no congenital disorders due to the loss of ADH5 function has been reported.

When the metabolic processes of aldehyde clearance become uncapable or the capacity overflows, various types of endogenous DNA damage increase. Aldehydes primarily produce DNA interstrand cross-links (ICL) and nonenzymatic DNA-protein cross-links (DPC) (17). These DNA lesions prevent replication fork progression; therefore, they are thought to be largely repaired by the following replication-coupled DNA repair mechanisms: (i) ICL repair pathway involves FANC proteins that are mutated in Fanconi anemia (FA), a rare inherited bone marrow failure syndrome (IBMFS) (18, 19). This pathway (otherwise known as FA pathway) is activated in S phase and eliminates ICL, by unhooking of covalently bridged Watson/Crick strands with structure-specific endonucleases, followed by sequential actions involving translesion synthesis (TLS), homologous recombination, and nucleotide excision repair (NER). (ii) DPC repair is similarly initiated by the stalling of DNA polymerases at replication forks, where metalloproteases, such as SPRTN, degrade DNA-bound proteins to remnant peptides before TLS and further excision of remaining lesions by NER. Mutations in the SPRTN gene also cause a rare disorder, Ruijs-Aalfs syndrome (RJALS), characterized by segmental progeria and early-onset hepatocellular carcinoma (20).

In this study, we report a number of families with a new form of IBMFS cases. On the basis of genome analysis of the patients, we identified disease-causing digenic mutations in the ALDH2 and ADH5 genes. Cellular and animal studies demonstrate that the simultaneous loss of ALDH2 and ADH5 activities leads to an increase of cellular formaldehyde sensitivity and multisystem abnormalities including hematopoietic failure. Our results suggest that the formaldehyde clearance is as important as the DNA repair system for normal development of both humans and mice.

We report 10 cases in eight unrelated families, presenting a previously unclassified trait, characterized by aplastic anemia (AA), mental retardation, and short stature and microcephaly (dwarfism), termed AMeD syndrome (AMeDS). Pedigrees of the families (Fig. 1A), summaries of clinical manifestations (Table 1), and hematological complications (Table 2) of the affected individuals are shown (see also detailed clinical episodes below). Each of the cases was initially diagnosed as AA, FA, refractory anemia (RA), Bloom syndrome (BS) or Dubowitz syndrome (DS), largely based on their facial appearance and hematological manifestations (18, 21, 22). All cases developed myelodysplasia during infancy to childhood, and of seven cases with detailed clinical records, four patients received bone marrow transplants (BMTs). The possibility of FA is often considered in the differential diagnosis of IBMFS. Notably, severe dwarfism (height and head circumference < 4.0 SD) and intellectual disabilities both typical in AMeDS cases are uncommon in FA; these additional symptoms rather resemble those of patients with transcription-coupled NER deficiency, Cockayne syndrome (CS) (23), and its related disorders [cerebro-oculo-facio-skeletal syndrome (COFS) and XFE progeroid syndrome (XFEPS)] (24, 25). Also in contrast to typical FA cases, neither polydactyly nor chromosome fragility was observed in any of the AMeDS cases. Dyskeratosis congenita (DC) was also excluded by normal telomere length tested in some of the cases. These families and cases were extracted from the Genome Instability Syndrome Diagnosis Project, a part of the Rare/Intractable Disease (nanbyo) Project of Japan, as well as from a collection of undiagnosed IBMFS children analyzed by the central review system of the Japanese Society of Pediatric Hematology and Oncology and the targeted sequencing system for IBMFS at Nagoya University Pediatrics Department.

(A) Pedigrees of AMeDS families 4 to 8. (B) Pathogenic variants identified in ADH5 and ALDH2. (C) Immunoblots of ADH5 and ALDH2 in primary fibroblasts from normal (1BR) and patients with AMeDS (N0608, N0611, and N0614). SMC3 is a loading control. (D) ADH5 transcript of normal (1BR) and AMeDS (N0608, N0611, and N0614) cells. The relative transcript levels analyzed by the CT method are shown for triplicate experiments. (E) Cell viability after continuous 30 M formaldehyde treatment. Results from triplicate experiments (means SD) are shown. **P < 0.01, two-tailed unpaired t test. (F) Immunoblots showing a reduced stability of ADH5 p.S75N identified in a healthy individual, NAG16714. Gene-edited hTERT-immortalized RPE1 (RPE1 hTERT) cells expressing the homozygous ADH5 p.S75N alleles (clones no. 10 and no. 52), and ADH5 cells are examined. (G) Stable expression of the p.S75N mRNA. (H) Cell viability after continuous 40 M formaldehyde treatment. Results from triplicate experiments (means SD) are shown. ***P < 0.001, two-tailed unpaired t test. (I) ADH5 p.S75N is unstable as with p.A278P. U2OS cells transfected with V5-tagged ADH5 WT (wild type), p.A278P, or p.S75N were harvested at the indicated times following cycloheximide (CHX) treatment. Cell lysates were immunoblotted with V5 and ACTB antibodies. (J) Quantification of ADH5-V5 levels in (I) by image analysis, normalized to ACTB levels. Means ( SD) from triplicate experiments are shown. *P < 0.05; one-way analysis of variance (ANOVA) with Tukeys multiple comparisons test.

NA, not analyzed. WBC, white blood cells; Neut, neutrophils; Mon, monocytes; Hb, hemoglobin; MCV, mean corpuscular volume; Ret, reticulocytes; Plt, platelets; HbF, fetal hemoglobin; PB, peripheral blood; BM, bone marrow; RCMD, refractory cytopenia with multilineage dysplasia; RAEB-1, refractory anemia with excess blasts-1.

N1254 (Family4), the first daughter of nonconsanguineous Japanese parents, was born at 39 weeks and 3 days with a birth weight of 2880 g (0.12 SD), after an uneventful antenatal period. She had neither obvious malformations nor abnormalities at birth. At 3 weeks of age, she had poor weight gain (Kaup index of 13) and presented with telecanthus and broad nasal tip. At 1 year of age, she was repeatedly admitted to the hospital because of prolonged fever and pancytopenia. Skin hyperpigmentation and displacement of the left third toe were pointed out. She was initially diagnosed with RA. At 2 years of age, she had severe growth retardation (height: 71 cm, 2.3 SD; weight: 6850 g, 2.7 SD), delayed motor and language development (spoke only two or three meaningful words), and was diagnosed with acute myeloid leukemia (AML; monosomy 7). She received a cord blood stem cell transplant from an unrelated donor. She had successful engraftment of neutrophils, but the thrombocyte levels did not return to normal. She had leukoencephalopathy and cerebral abscess and died at 2 years and 10 months of age. She had no episode of sunburn.

N1037 (Family4), a younger sister of N1254, was born at 41 weeks and 3 days with a birth weight of 2870 g (1.27 SD), after an uneventful antenatal period. She had neither obvious malformations nor abnormalities at birth. At 1 year of age, she was repeatedly admitted to the hospital because of prolonged fever and thrombocytopenia. At 5 years of age, she was initially diagnosed with possible BS based on her facial characteristics and hematological abnormalities. She presented with short stature, microcephaly, delayed motor and language developments (spoke only two or three meaningful words), analgia, hypohidrosis, hypothyroidism, and displacement of the left third toe. She died of interstitial pneumonia at 9 years and 8 months of age. She had no episode of sunburn.

N1267 (Family5), the second child of nonconsanguineous Japanese parents, was born at 40 weeks and 5 days with a birth weight of 2606 g (1.81 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. She was undergoing medical follow-up care because of low birth weight, failure to thrive, and short stature. She presented with pancytopenia at 7 years of age. She was initially diagnosed with DS. Bone marrow examination showed trilineage dysplasia with an abnormal karyotype: 46,XX,+1,der(1:21)(q10;q10) [7/20]; 46,idem,add(18)(p11.2) [13/20]. Regular bone marrow examination performed 1 year after the diagnosis revealed monosomy 7 clonal evolution. BMT from a human leukocyte antigen (HLA)matched sibling donor (sibling5-1) appeared to be successful; however, the disease relapsed 3 months after the transplant. She underwent her second BMT from an HLA-matched unrelated donor. She is alive and disease-free 5 years after the transplant.

N1269 (Family6), the second daughter of nonconsanguineous Japanese parents, was born at 39 weeks and 2 days with a birth weight of 2442 g (1.72 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. At 2 years of age, she presented with thrombocytopenia, short stature, and developmental delay. Following a transient elevation in platelet count, her thrombocytopenia and anemia subsequently progressed and she was diagnosed with myelodysplastic syndrome (MDS) with trilineage dysplasia at 3 years of age. Cytogenetic analysis revealed a complex karyotype with trisomy 8: 46,XX,der(5;17)(p10;q10),+8 [4/20]; 45,idem,add(7)(p11.2),-8,add(19)(p13) [14/20]; 46,XX,ins(1;?)(q12;?) [2/20]. BMT from an HLA-matched sibling donor was successful, and she is alive 6 years after the transplant.

N1270 (Family6), a younger brother of N1269, was born at 39 weeks and 0 days with a birth weight of 2366 g (2.14 SD), after an uneventful antenatal period. No physical abnormalities were noted at birth. At 3 months of age, he was admitted to the hospital because of poor weight gain and possible developmental abnormalities. He had bicytopenia (thrombocytopenia and anemia), hypothyroidism, skin hyperpigmentation, agenesis of corpus callosal, and recurrent epileptic seizures. Bone marrow examination showed MDS with a normal karyotype. His motor and intellectual disabilities were severe. He needed a gastrostomy tube for feeding at 1 year and 8 months of age. He died of infection at 2 years of age: height, 76.7 cm (4.5 SD); weight, 8.85 kg (3.0 SD); and head circumference, 40 cm (5.8 SD). Telecanthus, displacement of the right fourth toe, and low-set ears were pointed out. He had hypertrophic cardiomyopathy and frontal lobe atrophy.

N1275 (Family7), the first daughter of nonconsanguineous Japanese parents, was born at 41 weeks and 5 days with a birth weight of 2984 g (0.65 SD). She had initially presented with pancytopenia at 8 years of age. Bone marrow examination revealed hypoplastic MDS with the following abnormal karyotype: 46,XX,+1,der(1;22) (q10;q10) [2/20]; 47,idem,del(7)(q?),add(17)(p11.2),+mar1 [9/20]; 47,idem,add(17),del(20)(q1?),+mar1 [5/20]. She presented with FA-like physical anomalies, such as short stature, skin hyperpigmentation, and developmental delay. However, her chromosomal breakage test and FANCD2 ubiquitination were normal. BMT from a mismatched unrelated donor with reduced intensity conditioning was successful. She is alive 5 years after transplant.

N1329 (Family8), the second son of nonconsanguineous Japanese parents, was born at around 40 weeks with a birth weight of 3480 g (0.72 SD), after an uneventful antenatal period. He presented with short stature (2.52 SD) and had a delayed bone age at 6 years of age. He had Tanner stage 4 and an advanced bone age and was diagnosed with precocious puberty at 10 years of age. He had bicytopenia (anemia and leukopenia), and his bone marrow examination revealed MDS with an abnormal karyotype: 46,XY,+1,der(1;15)(q10;q10),add(17)(p11.2)x2 at 12 years of age. He was initially diagnosed with FA. At 15 years of age, he had short stature (height: 149.7 cm, 3.2 SD; weight: 31.35 kg, 2.7 SD), microcephaly (head circumference: 51.5 cm, 4.7 SD), and intellectual disability. He has no episode of sunburn.

We have implemented whole-exome sequencing (WES) for genetic screening of undiagnosed cases (standard WES procedure, see Materials and Methods). From the WES and follow-up studies, we identified biallelic mutations in the ADH5 gene in all of the AMeDS cases. By the WES analyses, we did not find any other potential causative genes shared among more than two of the cases under an autosomal recessive model of inheritance; we were not aware of any reported pathogenic variants of known disorders in any of the identified potential causative genes; no biallelic variants were detected in known FA-associated genes (table S1) (18). The patients were homozygous or compound heterozygous for the following ADH5 variant alleles: c.966delG, p.W322*; c.G832C, p.A278P; c.564+1G>A, 5 splice site (Fig. 1B and Table 1). Immunoblot analysis of AMeDS fibroblasts demonstrated a significant reduction of the ADH5 protein levels, indicating that the identified variants led to loss-of-function (LOF) changes causing a lack of gene expression or involving a severe protein destabilization (Fig. 1, C and D).

Previous animal studies demonstrated that combined inactivation of the endogenous aldehydes detoxification and the FA pathway leads to very severe attrition of hematopoietic stem and progenitor cells (HSPCs) and abnormal fetal development (2630). In these processes, ADH5 is the key enzyme in the protection against DNA damage induction, by eliminating endogenous formaldehyde (30). Consistent with this notion, ADH5-deficient AMeDS cells exhibited increased sensitivity to formaldehyde treatment (Fig. 1E), although the cells displayed normal ubiquitination of FANCD2 and resistance to ICL-inducing mitomycin C, indicating that the FA pathway is proficient in the AMeDS cases (fig. S1, A to C). From these results, we anticipated that the ADH5 deficiency was the primary cause of AMeDS.

In contrary, Adh5 null mice did not show any devastating phenotype that causes a survival disadvantage (31). To further evaluate the pathogenicity of the ADH5 deficiency in humans, we first searched for individuals with biallelic ADH5 rare variants in genotype-available databases. No homozygous ADH5 LOF variants were detected within ~140,000 individuals in gnomAD (v.2.1.1). Because all the AMeDS cases were of Japanese origin, we conducted an additional search of ~5600 Japanese individuals within ToMMo (Tohoku Medical Megabank; 2036 individuals), HGVD (Human Genetic Variation Database, Kyoto University; 300 individuals), BBJ (BioBank Japan, RIKEN Institute; 1006 individuals), and Nagahama Study (Nagahama Prospective Cohort for Comprehensive Human Bioscience, Kyoto University; 1321 individuals) datasets, as well as in-house genome databases. Furthermore, we genotyped the ADH5 pathogenic variant alleles (p.W322*, p.A278P, and c.564+1G>A) in ~26,000 Japanese individuals (Hospital-Based Epidemiologic Research Program at Aichi Cancer Center, Aichi Cancer Center). From these screenings, we identified a healthy individual (female, age 55, no preexisting conditions) with a homozygous mutation, c.G224A (p.S75N) in the ADH5 gene (NAG16714 in Nagahama Study; Table 1). As we could not obtain cellular materials from this individual, we generated hTERT-immortalized RPE1 (RPE1 hTERT) and U2OS cells with ADH5 and with the site-specific ADH5 p.S75N homozygous mutation using the CRISPR-Cas9based gene editing technique (without silent mutations, see Materials and Methods; table S2). Immunoblot analysis revealed severely decreased levels of the ADH5-p.S75N protein in the mutant cells (Fig. 1F and fig. S1D), although the ADH5 mRNA expression was unaffected (Fig. 1G). The ADH5-p.S75N mutant cells were as sensitive to formaldehyde as ADH5 cells (Fig. 1H and fig. S1E) due to destabilization of the ADH5 protein (Fig. 1, I and J). These initial results indicate that the loss of ADH5 expression or deficiency in formaldehyde detoxification is not associated with any obvious disease phenotype. These data suggest that the ADH5 monogenic deficiency is not sufficient to cause AMeDS.

We therefore considered a possibility of digenic/oligogenic inheritance. We focused on the ALDH2 gene and rs671 because ALDH2 retains a weak catabolic activity for formaldehyde (32) and for various endogenous active aldehyde species, such as 4-hydroxy-2-nonenal (4-HNE) that arises from membrane lipid peroxidation products (33), in addition to its primary function of detoxifying acetaldehyde. These active aldehydes generate ICL-DNA damage (17); consequently, they can put loads on the FA pathway and other DNA repair pathways, such as base excision repair and DPC repair. Therefore, the phenotypes of patients with AMeDS may result from the lack of enzymatic activity of ALDH2 in combination with the loss of ADH5 function for endogenous aldehydes.

Individuals harboring either one or two copies of the ALDH2 rs671 defective allele display a severe deficiency in acetaldehyde catabolic activity because the active enzyme complex requires the wild-type ALDH2 homotetramer (5, 34). By examining the ALDH2 rs671 genotype, we indeed found that all 10 patients with AMeDS carry at least one copy of the defective allele (G/A or A/A) (Table 1). Despite the high allele frequency in Japanese population, appearance of the rs671 defective allele in the AMeDS cases deviates substantially from the Hardy-Weinberg equilibrium (Pearsons 2 test; P = 0.0007), suggesting that this locus is strongly associated with the disease development. The healthy individual, NAG16714 with the homozygous ADH5 p.S75N defective variant, harbors the homozygous rs671 wild-type (G/G) alleles (Table 1). Furthermore, all three cases homozygous for the rs671 defective alleles (N1037, N1254, and N1270) manifested more severe phenotypes, including neurological abnormalities, prominent motor deterioration (confined to a wheelchair or bed), and early death (Tables 1 and 2). This suggests that the aldehyde detoxification activity determined by the rs671 genotype underlies the severity of AMeDS clinical features. Collectively, we conclude that the ALDH2 rs671 defective allele in combination with biallelic LOF mutations in the ADH5 gene is necessary and sufficient to cause a true digenic disorder, AMeDS, classified as IBMFS.

To determine potential substrates of the ADH5 and ALDH2 enzymes, we have measured growth inhibition profiles of ADH5- and/or ALDH2-deficient U2OS cells after treatments with various active aldehydes (fig. S2, A to C). Nine major endogenous aldehydesincluding ,-unsaturated aldehydes [4-hydroxyhexenal, (4-HHE), 4-HNE, 4-oxononenal, acrolein, and crotonaldehyde], the simplest aldehyde (formaldehyde), dialdehydes (glyoxal and methylglyoxal), and a saturated aldehyde (heptanal)whose chemical properties have been widely studied, were chosen for the proliferation assay.

While the treatments with ,-unsaturated aldehydes (4-HHE, 4-HNE, and acrolein) inhibited cell proliferation of ALDH2E504K U2OS cells, ADH5/ cells were not affected by the same treatment (fig. S2D); this may imply that these aldehydes are preferentially metabolized and detoxified by the ALDH2 enzyme. We found that formaldehyde and methylglyoxal treatments suppressed cell proliferation of ADH5/ALDH2E504K double-deficient U2OS cells compared to single-deficient ADH5/ or ALDH2E504K cells, indicating that these aldehydes are possible substrates of both ADH5 and ALDH2 enzymes (fig. S2D). The concentration of formaldehyde in human plasma is estimated to be ~100 M (35, 36), while that of methylglyoxal is much less than 1 M (37), which implies that near physiological levels of formaldehyde, but not methylglyoxal, can perturb cell proliferation. To further investigate the effects of formaldehyde treatment in ADH5/ALDH2E504K double-deficient U2OS cells more precisely, we analyzed replication inhibitory profiles by flow cytometry (Fig. 2A). While either LOF of ADH5 or ALDH2 modestly attenuated the progression of cell cycle compared to wild-type cells, digenic loss of ADH5 and ALDH2 led to the significant inhibition of DNA replication after formaldehyde treatment (Fig. 2, A and B).

(A) Formaldehyde treatment inhibits DNA replication in ADH5 and ALDH2 double-deficient cells. 5-ethynyl-2-deoxyuridine (EdU) incorporation in WT, ADH5, ALDH2E504K, or ADH5 ALDH2E504K double-mutant U2OS cells after formaldehyde treatment is measured by fluorescence-activated cell sorting (FACS) analysis. Cells were incubated with indicated concentration of formaldehyde or 10 mM hydroxyurea (HU) as a positive control for 8 hours followed by EdU incorporation for 1 hour. Then, cells were fixed with 70% ethanol and analyzed by FACS for Alexa Fluor 488labeled EdU and DNA stained with 7-aminoactinomycin D (7-AAD). Representative FACS images are shown. (B) Quantification of data in (A). Graph shows the percentage of EdU-positive cells. Means ( SD) from three independent experiments are shown. *P < 0.05, **P < 0.01, and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test. (C) Formaldehyde treatment induces DNA damage in cells from AMeDS-affected individuals. Immunoblots showing phospho-Ser139 histone H2AX (H2AX), a DNA damage marker, and PARP1, an apoptosis marker in normal (1BR) and AMeDS (N0608 and N0611) cells. KU70 is a loading control. (D) EdU incorporation in normal and AMeDS cells after formaldehyde treatment measured by FACS analysis. Cells were incubated with indicated concentration of formaldehyde for 22 hours followed by EdU incorporation for 2 hours. Then, cells were fixed with 70% ethanol and analyzed by FACS for Alexa Fluor 488labeled EdU and DNA stained with propidium iodide (PI). (E) Formaldehyde-induced DNA damage in AMeDS cells (N0611) is ameliorated with expression of either the wild-type ADH5 or ALDH2 cDNA. Green fluorescent protein as a mock control.

We next studied the cooperative actions of ADH5 and ALDH2 on the prevention of DNA damage induction. We assessed increased cellular DNA damage levels as a consequence of diminished formaldehyde processing activity in patients with AMeDS cells. We measured formaldehyde-induced DNA damage by immunoblotting of histone H2AX Ser139 phosphorylation (H2AX) as a DNA damage marker. AMeDS cells (N0608 and N0611) showed significant increase of H2AX levels after 200 M formaldehyde treatment, although normal cells were resistant to even such a high dose, indicating that unrepairable DNA damage are indeed increased in the AMeDS cells supposedly because of the lack of formaldehyde processing capacity (Fig. 2C). Similar to ADH5/ALDH2E504K double-deficient U2OS cells, significant inhibition of DNA replication after formaldehyde treatment was also confirmed in patient with AMeDS cells (Fig. 2D). Ectopic expression of either of the wild-type ADH5 or ALDH2 complementary DNA (cDNA) in the AMeDS cells completely eliminated the induction of formaldehyde-induced DNA damage, suggesting that both ADH5 and ALDH2 deficiencies underlie the decrease of formaldehyde detoxification capacity (Fig. 2E and fig. S2, E and F). Together, formaldehyde is metabolized by both ADH5 and ALDH2, and even naturally occurring concentration of formaldehyde may have a negative effect on cell proliferation and genome integrity in ADH5 and ALDH2 double-deficient cells.

We next investigated the effects of ADH5 and ALDH2 digenic deficiency on the progenitor cell capacity of HSPCs in humans. We performed colony-forming unit (CFU) assays of CD34+ umbilical cord bloodderived HSPCs, which were prepared from healthy Japanese donors (RIKEN BRC). The ALDH2 rs671 genotype was confirmed in each HSPC pool, and the ADH5 expression was eliminated by the CRISPR-Cas9based gene editing with specific single-guide RNAs (sgRNAs) (Fig. 3A and fig. S3, A and B). The loss of ADH5 did not induce unexpected DNA damage (determined by H2AX induction shown in fig. S3B), and it did not affect the proliferation of HSPCs regardless of the rs671 genotype during culture in hematopoietic maintenance medium (fig. S3C), suggesting that decrease in the formaldehyde detoxification capacity does not involve any growth disadvantage of HSPCs in ex vivo conditions. However, the differentiation and proliferation potential of HSPCs was severely compromised when ADH5 was deleted in HSPCs with the ALDH2 rs671 defective (G/A) but not with the wild-type (G/G) alleles (Fig. 3, B and C). In addition, these ADH5 and ALDH2 rs671 double-deficient HSPCs had reduced capacity to differentiate into common progenitor cells and/or their progeny cells (fig. S3D), suggesting that formaldehyde detoxification deficiency causes a wide range of hematopoietic abnormalities in humans.

(A) Schematic representation of CFU assay. CD34+ HSPCs are derived from umbilical cord blood of Japanese healthy donors. The numbers of HSPC pools with the designated ALDH2 rs671 alleles are shown. ADH5 was deleted in each HSPC pool by CRISPR-Cas9based gene editing. (B) CFU assay of gene-edited CD34+ HSPCs was performed using a methylcellulose medium. Representative images are shown. Scale bar, 3 mm. (C) Total number of colonies after 14-day CFU assay of gene-edited CD34+ HSPCs. The number of colonies was normalized to untreated control. Statistical analysis was performed using one-way ANOVA with Tukeys multiple comparisons test (***P < 0.001; ns, not significant). Lines represent median.

To investigate the consequences of the ADH5 and ALDH2 digenic deficiency for the development of multisystem abnormalities in AMeDS, we generated gene-edited mice with Adh5/ and Aldh2-E506K (equivalent to the human ALDH2-E504K and hereafter called Aldh2-KI) double mutation using the CRISPR-Cas9 technique. Adh5+/Aldh2+/KI female mice were interbred with Adh5+/Aldh2KI/KI male mice, and the offspring genotypes were measured. Adh5/Aldh2KI/KI mice were born at near Mendelian ratios (Fig. 4A). The weight and size of the Adh5/Aldh2KI/KI double-deficient neonates were indistinguishable from those of their littermates, indicating of no prenatal growth retardation, which is similar to human AMeDS cases (Fig. 4, B and C). Severe growth failure with poor weight gain was prominent in all of the Adh5/Aldh2KI/KI mice at 1 to 2 weeks after birth (Fig. 4, B and C); computed tomography (CT) and dissection analyses also revealed multisystem abnormalities, including small body size, extremely shrunken organs, diminished muscle and subcutaneous fat volumes, and kyphosis at 3 weeks after birth (fig. S4A), although all the animals received breast-feeding from their mothers without problem. Intriguingly, all the Adh5/Aldh2KI/KI mice displayed anemia and severe debility and eventually died, possibly due to cachexia or overall weakness, within 4 weeks after birth before weaning, although Adh5/Aldh2+/KI mice or mice with other genotypes did not show any survival disadvantage during this period (Fig. 4D). Notably, Adh5/ or Aldh2KI/KI animals did not show any obvious developmental defects, which is consistent with previous reports (31, 38).

(A) Observed and expected frequencies of mice at 2 weeks of age from intercrossed of Adh5+/Aldh2+/KI female mice with Adh5+/Aldh2KI/KI male mice. Chi-square test shows no significant difference between observed and expected (P = 0.17). (B) Postnatal growth defects of Adh5/Aldh2KI/KI mice. Representative pictures are shown. Blue arrows indicate Adh5/Aldh2KI/KI mice. Photo credit: Yasuyoshi Oka, Nagoya University. (C) Body weights of individual mice at 0 days, 2 weeks, or 6 weeks of age. **P < 0.01 and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test. (D) Kaplan-Meier curves with log-rank (Mantel-Cox) test show a significant decrease in survival of Adh5/Aldh2KI/KI compared to the mice with other genotypes (P < 0.0001). (E) Quantification of nucleated bone marrow cells in bilateral femurs and tibias from 3-week-old mice is shown (means SD; n = at least 5 animals). *P < 0.05 and ***P < 0.001; one-way ANOVA with Tukeys multiple comparisons test. (F and G) Quantification of hematopoietic subset: LKS (Linc-Kit+Sca-1+), HSC (Linc-Kit+Sca-1+CD150+CD48), MPP (Linc-Kit+Sca-1+CD150CD48), HPC1 (Linc-Kit+Sca-1+CD150CD48+), HPC2 (Linc-Kit+Sca-1+CD150+CD48+), CLP (Linc-KitlowSca-1lowCD127+CD135+), CMP (Linc-Kit+Sca-1CD34+CD16/32), MEP (Linc-Kit+Sca-1CD34CD16/32), and GMP (Linc-Kit+Sca-1CD34+CD16/32+) in individual mice at 3 weeks of age in (F) and at 8 to 9 months of age in (G). Means SD; n = at least 5 animals. *P < 0.05, **P < 0.01, and ***P < 0.001, one-way ANOVA with Tukeys multiple comparisons test.

Adh5/Aldh2+/KI mice also displayed smaller body weight compared to that of Adh5/ or Aldh2KI/KI animals from 2 to 6 weeks after birth (Fig. 4C). Similar but much milder manifestations compared to the Adh5/Aldh2KI/KI mice were also detected in the Adh5/Aldh2+/KI animals at 6 months (fig. S4B). Furthermore, we noticed that all middle-aged Adh5/Aldh2+/KI animals (8 to 9 months) displayed skin hyperpigmentation on the tails, indicative of FA-like features (fig. S4C). A previous report described a skin hyperpigmentation induced in Aldh2/ mice continuously administrated with ethanol (acetaldehyde precursor) (39). The Adh5/Aldh2+/KI male and female animals were fertile.

To study hematopoietic functions of the Adh5 and Aldh2 double-deficient mice in detail, we examined peripheral blood hematological parameters. Adh5/Aldh2KI/KI mice at the moribund stage (3 weeks of age) exhibited decreased red blood cells (RBCs), hemoglobin (HGB) levels, hematocrit (HCT) values, and increased levels of mean corpuscular volume (MCV), indicating macrocytic anemia, although age-matched Adh5/Aldh2+/KI mice did not present apparent hematopoietic defects at this point (fig. S4D). The Adh5/Aldh2+/KI mice eventually displayed similar abnormalities of erythrocytes at 8 to 9 months after birth (fig. S4E).

We further investigated the maintenance of HSPCs in the Adh5 and Aldh2 double-deficient mice. In Adh5/Aldh2KI/KI mice at the moribund stage (3 weeks of age), total number of nucleated bone marrow cells from tibiae and femora significantly decreased compared with that of other animals (Fig. 4E). Consistently, the number of multipotent self-renewing HSCs defined by Linc-Kit+Sca-1+ CD150+CD48 (CD150+ long-term HSCs) was significantly reduced in Adh5/Aldh2KI/KI mice (Fig. 4F and fig. S4I); similar trends were observed for immature hematopoietic progenitors, including Linc-Kit+Sca-1+CD150CD48 [CD150 multipotent progenitors (MPPs)] and Linc-Kit+Sca-1+CD150CD48+ [CD48+ restricted progenitors (HPC1)] cells. We found that the number of further differentiated progenitor cellsincluding Linc-KitlowSca-1low CD127+CD135+ [common lymphoid progenitors (CLPs)], Linc-Kit+ Sca-1CD34+CD16/32 [CD34+ common myeloid progenitors (CMPs)], and Linc-Kit+Sca-1CD34CD16/32 [bipotent megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs)]was also significantly diminished in Adh5/Aldh2KI/KI mice. In connection with the decrease of CLPs in Adh5/Aldh2KI/KI mice, the number of lymphocytes in peripheral blood and the weights of thymus and spleen were reduced without any significant alteration of lymphocyte distribution in these organs (fig. S4, F to H). Although Adh5/Aldh2+/KI mice did not show any anomaly of bone marrow cells at 3 weeks of age (Fig. 4F), the number of MPPs and CLPs was significantly decreased compared with that of Adh5 or Aldh2 single-deficient mice at 8 to 9 months of age (Fig. 4G). Collectively, hematopoietic abnormalities in the Adh5 and Aldh2 double-deficient animals are due to exhaustion of HSPCs. These findings demonstrate that the combined LOFs in the Adh5 and Aldh2 genes cause multisystem abnormalities potentially due to the lack of formaldehyde clearance capacity in the double-deficient animals, and the Aldh2-E506K allele defines the severities of manifestations, which clearly mimic the major clinical features of AMeDS in humans.

Digenic inheritance (DI) is the simplest genetic trait describing complex oligogenic disorders caused by the malfunctions of two or more genes (1315). In the past human genetics studies, thousands of monogenic disorders have been identified. However, to date, only tens of diseases with solid evidence for DI have been reported (1315). Moreover, even in well-documented DI disorders, such as retinitis pigmentosa and Bardet-Biedl syndrome, affected individuals often display heterogeneous clinical features because of incomplete penetrance, and unexplained pedigrees are frequently observed (40, 41). Our AMeDS cases all develop generally uniform clinical symptoms (AA, mental retardation, and dwarfism), and they are genetically characterized by true DI, i.e., mutations in two distinct genes are necessary and sufficient to cause a disease, with no exception. The ALDH2 rs671 defective allele is also involved in the severity of AMeDS clinical features; however, unlike other coinheriting genetic modifiers, it is essential for the disease development in addition with the ADH5 deficiency.

The accumulation of unrepaired endogenous DNA damage ultimately triggers cancer and aging through a failure in the essential functions of various cellular processes (4244). DNA lesions may induce mutations and chromosomal aberrations that cause genome instability and an increased risk of cancer. In parallel, major DNA lesions can also interfere with transcription and replication, resulting in the loss of accurate gene expression profiles, delay of cell cycle progression, and induction of cell death, which contribute to aging. The cellular defense against DNA damage involves serial mechanisms (two-tier protection): (tier 1) enzymatic detoxification processes of highly reactive genotoxic chemicals, such as reactive oxygen species (ROS) and active aldehydes, and (tier 2) DNA repair processes to eliminate various types of DNA damage and restore genetic information. In this regard, dysfunctions in either of these mechanisms may result in carcinogenesis and aging-related phenotypes. In particular, cancer predisposition and progeroid symptoms are naturally observed in a variety of human genetic disorders due to mutations in DNA repair genes (tier 2) (45). In contrast, there is only a small number of congenital diseases that are caused by abnormalities in the detoxification systems of chemical compounds that induce DNA damage (tier 1). Recent clinical reports have shown that a complete absence of the superoxide dismutase 1 (SOD1) enzyme, which is involved in the removal of ROS, causes an extreme oxygen sensitivity in patients cells and is associated with autosomal recessive progressive spastic tetraplegia and axial hypotonia (STAHP), characterized by severe and progressive psychomotor retardation in humans (46, 47). Note that mutations in the SOD1 gene usually cause autosomal dominant amyotrophic lateral sclerosis because of the toxic effects of protein aggregation rather than by the loss of enzymatic activity (48). The STAHP phenotype with the lack of SOD1 may be due to an overload of oxidative DNA damage in the single-strand break (SSB) repair pathway; this postulation is corroborated by a report that SSB repair deficiency by the XRCC1 gene mutation causes spinocerebellar ataxia (SCA) (49). Our AMeDS cases and the animal model further support the idea that malfunctions in the detoxification systems of active genotoxic compounds cause symptoms of cancer predisposition and accelerated aging.

Patients with AMeDS display many characteristic clinical features that overlap with other DNA repair deficiency disorders (table S3). Here, we propose that FA-like hematopoietic abnormalities observed in AMeDS may result from the overload of the FA pathway (ICL repair pathway) due to limitations of cellular detoxification properties against endogenous formaldehyde. During differentiation including hematopoiesis, various histone demethylases erase methyl marks on lysine residues of histones associated with gene regulation, leading to the release of active formaldehyde (50). Under a limited capacity of the FA pathway, the rs671 defective allele would significantly contribute to the increase of unrepaired formaldehyde-induced DNA lesions during hematopoiesis. This idea is consistent with previous reports that rs671 is a genetic modifier of the severity of BMF in Japanese FA cases (51), as well as in children with sporadic AA (52); this is also true for the FA pathwayproficient AMeDS cases, as rs671 genotype defines the severity of AMeDS clinical features. AMeDS cases display premalignant MDS or leukemia, indicative of cancer predisposition, although no solid tumor is present at the moment. Adulthood patients with FA commonly develop solid tumors including head and neck squamous cell carcinoma, in addition to MDS and leukemia (53). Because the ages of AMeDS cases with clinical records range from 2 to 16 years, follow-up studies are necessary to investigate the etiology of cancers. On the other hand, in canonical FA, severe dwarfism and neurological abnormalities, as well as psychomotor retardation, are uncommon. In this respect, AMeDS clinical features have substantial similarities to those of segmental progeroid disorders, RJALS and CS (and its severe forms, COFS and XFEPS). Since RJALS cells with mutations in the SPRTN gene display hypersensitivity to DPC-inducing chemicals, including formaldehyde (54), the phenotypes of AMeDS that overlap with RJALS could be explained from the overload of DPC repair pathway. From these perspectives, the severe phenotypes of AMeDS may be due to a combined failure of multiple DNA repair processes as represented by BRCA1 (FANCS) or XPF (FANCQ)deficient atypical FA cases, as well as by patients with ERCC1/XPF-deficient COFS/XFEPS (25, 5557), because BRCA1 and the ERCC1/XPF complex, respectively, contribute to DNA double-strand break repair and NER, together with the FA pathway. ADH5 and ALDH2 double deficiency would also induce various types of DNA damage apart from ICL and DPC, such as simple aldehyde base adducts, which can be repaired independently of the ICL and DPC repair pathways (5860). Consequently, in AMeDS cases, these synergistic effects may trigger the severe clinical features. Likewise, CS-like clinical features observed in AMeDS rather suggest an additional failure in TCR; further analyses will address this possibility. In conclusion, our data propose that the combined deficiency in formaldehyde metabolic processes, by harboring the prevalent polymorphism rs671 in ALDH2 together with biallelic mutations in ADH5, overburdens the multiple DNA repair pathways and leads to a true digenic disorder, AMeDS, which is similar both in the clinical features and molecular pathogenesis but distinct from other DNA repair deficiency disorders.

Affected individuals and normal control samples were obtained with local ethical approvals (the Ethics Committee for Human Genome Studies in Research Institute of Environmental Medicine, Nagoya University; the ethics committee of the Nagoya University Graduate School of Medicine). Written informed consent was obtained from the patients.

Next-generation sequencing (NGS) was performed in-house or by macrogen. Genomic DNA of the individuals was enriched by using the Agilent SureSelect Human All Exon Kit version 5/6 (Agilent, Santa Clara, CA, USA). The captured genomic fragments were sequenced on the Illumina HiSeq 2500 sequencer (Illumina, San Diego CA, USA) using paired-end (PE) flow cells to obtain 100 to 150base pair PE reads of 100 to 200 coverage.

The NGS data were analyzed by our standard exome pipeline. Briefly, low-quality reads were trimmed out by Trimmomatic (version 3.36) (61). The reads were then aligned to the human reference genome (GRC h37/hg19) with the Burrows-Wheeler Aligner (version 0.7.12-r1039) (https://arxiv.org/abs/1303.3997). Duplicate reads were removed using Biobambam2 (version 2.0.72) (doi: 10.1186/1751-0473-9-13). The aligned reads were locally realigned, and base quality scores were recalibrated using the IndelRealigner and BaseRecalibrator programs in Genome Analysis Toolkit (GATK; version 3.5) (62). Single-nucleotide variants were identified by the HaplotypeCaller program in GATK. All the variants were annotated with ANNOVAR (63) based on the GENCODE release 19 (GRCh37.p13). To further determine potentially pathogenic changes, commonly observed variants (MAF > 0.01) were excluded using public databases and functionally significant changes were extracted. According to an autosomal recessive inheritance model, genes that carried homozygous or compound heterozygous changes were determined. We considered 2 to 18 potential causative genes in each of the affected individuals (table S1), and we identified ADH5 as only pathogenic candidate gene shared among any subset of the affected individuals.

The following cell lines were used in this study: U2OS; RPE1 hTERT; HEK293 (human embryonic kidney293), immortalized normal human embryonic kidney cells; 1BR, normal human primary fibroblast; and FA20P, primary fibroblast from an FA-A individual. N0608, N0611, and N0614 were obtained from JCRB Cell Bank. All cells were maintained in Dulbeccos modified Eagles medium (DMEM) (Wako) supplemented with 10% fetal bovine serum (FBS; Invitrogen) and antibiotics, unless otherwise noted. Mycoplasma testing was performed routinely.

For plasmid-based genome editing experiments, a guide RNA (gRNA) coding sequence was cloned into the pX459 vector. The designated plasmid was transfected into U2OS cells using X-tremeGENE HP DNA Transfection Reagent (Merck). Cells were selected for 48 hours with puromycin (1 g/ml) in DMEM with 10% FBS. Single clones were isolated by limiting dilution. For ribonucleoprotein-based genome editing experiments, HiFi Cas9 Nuclease V3 (Integrated DNA Technologies) was mixed with crRNA (CRISPR RNA):tracrRNA (trans-activating CRISPR RNA) complex and single-stranded oligodeoxynucleotide (ssODN). The mixture was electroporated into U2OS or RPE1 hTERT cells using 4D-Nucleofector (Lonza). Cells were recovered by DMEM with 10% FBS and cultured on a 35-mm dish for 24 hours. Single-cell clones were isolated using a limiting dilution in 96-well plates. All gRNA and ssODN sequence information are listed in table S2.

Genomic DNA was extracted from gene-edited cells using the MightyAmp Genotyping Kit (Takara) according to the manufacturers instruction. Mutations and indel frequencies of gene-edited cells (CD34+ HSPCs, U2OS cells, RPE1 hTERT cells, and mice) were confirmed by Sanger sequencing and TIDE (tracking of indels by decomposition) analysis (64). Untreated cells were always used as a negative control for calculating indel frequencies with TIDE. All primer sequence information are listed in table S2.

Total RNA was isolated using an RNeasy mini kit (Qiagen), according to the manufacturers instructions, and cDNA was generated with SuperScript IV (Thermo Fisher Scientific), according to the manufacturers instructions. The quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed using LightCycler 96 System (Roche). For the detection of target genes, SYBR green (Qiagen) was used according to the manufacturers instructions. Expression of mRNAs was quantitated using the following set of primers: ADH5 (forward, 5-CCAGCACATTTTCTGAATACAC-3; reverse, 5-ACCAAAGACGGCACAAAC-3) and ACTB (forward, 5-TCACCCACACTGTGCCCATCTACGA-3; reverse, 5-CAGCGGAACCGCTCATTGCCAATGG-3). The LightCycler was programmed to run an initial heat-denaturing step at 95C for 15 min, 45 cycles at 94C for 15 s, an annealing step for 20 s at 58C, and an extension step for 10 s at 72C coupled with fluorescence measurements. Following amplification, melting curves of the PCR products were monitored from 65 to 97C to determine the specificity of amplification. Each sample was run in triplicate, and expression of target genes was normalized against ACTB.

Cells were lysed in EBC buffer [50 mM tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 0.5% NP-40, and 1 mM dithiothreitol (DTT)] or denaturing buffer [20 mM tris (pH 7.5), 50 mM NaCl, 1 mM EDTA, 0.5% NP-40, 0.5% SDS, 0.5% sodium deoxycholate, and 1 mM DTT] supplemented with protease inhibitor cocktail (Roche) and phosphatase inhibitor cocktail (Nacalai Tesque) and incubated on ice, cleared by centrifugation. Purified proteins were resolved by 6, 12.5, or 5 to 20% gradient SDSpolyacrylamide gel electrophoresis. Resolved protein samples were transferred to polyvinylidene difluoride membrane for immunodetection. Antibodies used for immunochemical experiments were as follows: rabbit monoclonal anti-ADH5 (ab174283, Abcam), rabbit polyclonal anti-ADH5 (HPA044578, Atlas Antibodies), mouse monoclonal anti-ALDH2 (MA5-17029, Invitrogen), rabbit polyclonal anti-SMC3 (A300-060A, Bethyl Laboratories), rabbit polyclonal anti-H2AX (no. 2577, Cell Signaling Technology), rabbit monoclonal anti-KU70 (no. 4588, Cell Signaling Technology), rabbit monoclonal anti-FANCD2 (ab108928, Abcam), rabbit polyclonal anti-FANCA (A301-980A, Bethyl Laboratories), mouse monoclonal antiACTB (sc-47778, Santa Cruz Biotechnology), rabbit polyclonal antiV5-tag (PM003, MBL), and mouse monoclonal anti-PARP1 (sc-8007, Santa Cruz Biotechnology).

U2OS cells were seeded in 96-well plates (10,000 cells per well) and treated with the following aldehydes for 8 hours: 4-HHE (Cayman Chemical), 4-hydroxynonenal (Cayman Chemical), 4-oxononenal (Cayman Chemical), acrolein (Wako), crotonaldehyde (Tokyo Chemical Industry), formaldehyde (Nacalai Tesque), glyoxal (Tokyo Chemical Industry), heptanal (Tokyo Chemical Industry), or methylglyoxal (Sigma-Aldrich). After incorporation of 5 M 5-ethynyl-2-deoxyuridine (EdU) for 1 hour, cells were fixed and permeabilized for 20 min in phosphate-buffered saline (PBS) containing 2% formaldehyde and 0.5% Triton X-100. After washing with PBS, cells were then incubated with coupling buffer with 10 M Alexa Fluor 488 azide (Invitrogen), 50 mM tris-HCl (pH 7.3), 4 mM CuSO4, 10 mM sodium ascorbate, and 4,6-diamidino-2-phenylindole (DAPI) for 60 min, followed by washing with PBST (PBS + 0.05% Tween 20). Fluorescent image acquisition and data processing were automated using CellInsight NXT (Thermo Fisher Scientific).

Cells were labeled with 5 M EdU for 1 hour (U2OS cells) or 2 hours (primary fibroblasts) followed by fixing in 70% ethanol overnight at 30C. Cells were incubated with coupling buffer with 10 M Alexa Fluor 488 azide (Invitrogen), 50 mM tris-HCl (pH 7.3), 4 mM CuSO4, and 10 mM sodium ascorbate for 60 min. DNA was stained with 7-aminoactinomycin D (7-AAD) or propidium iodide. Data were acquired on a Cytomics FC500 FACS analyzer (Beckman Coulter) or CytoFLEX S FACS analyzer (Beckman Coulter) and analyzed with FlowJo version 10.6.2.

For gene expression, HEK293 cells were transfected with the pLenti6.3 construct encoding gene of interest together with ViraPower Packaging Mix (Invitrogen) using Lipofectamine 2000 (Invitrogen). Viral particles were collected 48 hours after transfection and concentrated using PEG-it Virus Precipitation Solution (System Biosciences). For virus complementation experiments, viral particles produced by transfection of pLenti6.3 were used to infect cells. Selectin under blasticidin (5 g/ml) was carried out.

Cells were seeded in 96-well plates (500 to 1000 cells per well) and fixed and stained with 2% formaldehyde and DAPI at 4 days (U2OS and RPE1 hTERT cells) or 7 days (primary fibroblasts) after formaldehyde treatment. Cells were identified and quantified on the basis of DAPI signal using CellInsight NXT (Thermo Fisher Scientific).

The ALDH2 activity was analyzed using the colorimetric ALDH2 Activity Assay Kit (Abcam) according to the manufacturers instruction.

CD34+ HSPCs from normal cord blood were procured from RIKEN BioResource Center (RIKEN BRC). Frozen CD34+ HSPCs were thawed and cultured in StemSpan SFEM II medium supplemented with StemSpan CC110 cocktail (STEMCELL Technologies) for 48 hours before electroporation. CD34+ HSPCs were electroporated using 4D-Nucleofector (Lonza). The following conditions were used: 50,000 cells were pelleted and resuspended in Lonza P3 solution containing TrueCut Cas9 protein v2 (Thermo Fisher Scientific) complexed with synthetic chemically modified sgRNA (ADH5#1, 5-UCAGGGUAUAGGCAUCGGUG-3; ADH5#2, 5-CUGAUAGAUCAUUGCCACUG-3; Synthego) at a 1:3 molar ratio. This mixture was electroporated using the Lonza 4D-Nucleofector (program EH-100). Electroporated cells were recovered and transferred to culture in StemSpan SFEM II medium supplemented with StemSpan CC110 cocktail.

CD34+ HSPCs at 2 days after electroporation were resuspended in Iscoves MDM (modified Dulbeccos medium) and plated on methylcellulose-based media (MethoCult Optimum, STEMCELL Technologies) according to the manufacturers instruction. Cells were plated onto 35-mm petri dishes, in duplicate, and incubated for 14 days at 37C with 5% CO2 and 95% humidity. CFU-erythroid; burst-forming uniterythroid; CFU granulocyte and macrophage; and CFU granulocyte, erythroid, macrophage and megakaryocyte were classified and counted according to standard morphological criteria under microscopy in a blind fashion.

All the animal studies were conducted in compliance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. The experiments using genetically modified mice were approved by the Animal Care and Use Committee and the recombinant DNA experiment committee of Nagoya University and Osaka University.

C57BL/6JJcl mice were purchased from CLEA Japan. The animals were kept under conditions of 50% humidity and a 12-hour light/12-hour dark cycle. They were fed a standard pellet diet (MF, Oriental Yeast) and tap water ad libitum, unless otherwise noted.

The following reagents were purchased: HiFi Cas9 Nuclease V3, tracrRNA, crRNA, and ssODN (Integrated DNA Technologies). To design gRNA sequence, software tools (http://crispor.tefor.net/ and https://crispr.dbcls.jp/) predicting unique target sites throughout the mouse genome were used. Pronuclear-stage mouse embryos were prepared by thawing frozen embryos (CLEA Japan) and cultured in a KSOM (potassium simplex optimization medium) (ARK Resource). For electroporation, 100 to 150 embryos at 1 hour after thawing were placed into a chamber with 40 l of serum-free media (Opti-MEM, Thermo Fisher Scientific) containing HiFi Cas9 Nuclease V3 (100 ng/l), Adh5 gRNA (100 ng/l), Aldh2 gRNA (100 ng/l), and ssODN (300 ng/l). They were electroporated with a 5-mm gap electrode (CUY505P5, Nepa Gene) in a NEPA21 super electroporator (Nepa Gene). The poring pulses for the electroporation were voltage of 225 V, pulse width of 1 ms for mouse embryos, pulse interval of 50 ms, and number of pulses of 4. The first and second transfer pulses were voltage of 20 V, pulse width of 50 ms, pulse interval of 50 ms, and number of pulses of 5. Mouse embryos that developed to the two-cell stage after the electroporation were transferred into the oviducts of female surrogates anesthetized with sevoflurane or isoflurane (Mylan). All gRNA and ssODN sequence information are listed in table S2.

CT analysis was performed on anesthetized mice using a CosmoScan FX system (RIGAKU), with the following parameters: x-ray tube (90 kV), current (88 A), FOV (field of view) (60 mm), and voxel size (240 m). Data were analyzed and visualized by 3D Slicer version 4.10.2.

Peripheral blood from the animals was subjected to complete blood cell count analysis. RBC, platelet (Plt), white blood cell (WBC), HGB, HCT, MCV, mean corpuscular hemoglobin concentration, and lymphocyte were measured using an IDEXX ProCyte Dx (IDEXX Laboratories).

Bone marrow cells were flushed from femurs and tibias using a 26-gauge needle, and spleens and thymuses were dissociated by crushing followed by passing through a cell strainer in Ca2+- and Mg2+-free Hanks buffered salt solution (Gibco) supplemented with 1% heat-inactivated bovine serum (Gibco). RBCs were lysed by resuspending the cells in RBC lysis buffer (eBioscience) for 5 min at room temperature. Cells were filtered through a 70-m cell strainer to obtain a single-cell suspension. Number of cells was measured with a hemocytometer. Antibodies used for fluorescence-activated cell sorting (FACS) analysis were as follows: fluorescein isothiocyanate (FITC)conjugated lineage cocktail (no. 133302, BioLegend), CD41 (FITC, no. 133903, BioLegend), FcRI (FITC, no. 134305, BioLegend), CD117 (APC, no. 105811, BioLegend), Sca-1 (PE, no. 108107, BioLegend), CD48 (Brilliant Violet 421, no. 103428, BioLegend), CD150 (APC/Fire 750, no. 115940, BioLegend), CD135 (Brilliant Violet 421, no. 135313, BioLegend), CD127 (PE/Cy7, no. 135014, BioLegend), CD16/32 (Brilliant Violet 421, no. 135313, BioLegend), CD34 (APC/Fire 750, no. 135014, BioLegend), CD3 (Alexa Fluor 488, no. 100321, BioLegend), CD19 (APC, no. 152410, BioLegend), CD4 (PE, no. 130310, BioLegend), and CD8a (APC, no. 100712, BioLegend). Antibody staining was performed at 4C for 20 min. Dead cells were excluded by staining with 7-AAD (BioLegend). Data were acquired on a CytoFLEX S FACS analyzer (Beckman Coulter) and analyzed with FlowJo version 10.6.2.

Acknowledgments: We would like to thank the families and clinicians for their involvement and participation. We are grateful to A. Lehmann for helpful comments and discussions on the manuscript. We thank M. Nakashima for comments on the animal analyses. We are grateful to S. Hashimoto, M. Isono, and K. Horiba, as well as M. Toyama, Y. He, and K. Katoh for the technical assistance. We thank JCRB Cell Bank (Osaka, Japan) for primary fibroblasts from patients, RIKEN BioResource Center (Tukuba, Japan) for fresh CD34+ umbilical cord blood cells and NIH for the use of dbGaP repositories (project no. 19720). Funding: This work was supported by the Special Coordination Funds for Rare and Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, and JP18kk020501 to N.Ma. and JP19ek0109281, JP19ek0109229, and JP19ek0109301 to T.O.); Grants in Aid for Scientific Research KAKENHI from the Japan Society for the Promotion of Science (JP16K21084 and JP18H03372 to Y. Oka, JP17K07255 and JP17KT0125 to K.Hi., JP17H01539 to N.Ma., 26253041, 15H02524, 16H06277, 18H03045, and 19K19425 to K.M., and JP15H02654 and JP17H00783 to T.O.); Grants in Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture, and Technology of Japan, consisting of Priority Areas of Cancer (17015018), Innovative Areas (221S0001), and a Grant-in-Aid for the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour, and Welfare of Japan to K.M.; a medical research grant from Daiichi Sankyo Foundation of Life Science to Y. Oka; a grant from Daiko Foundation to T.O.; Science Research Grants from Uehara Memorial foundation to Y. Oka and T.O.; and medical research grants from Takeda Science Foundation to Y. Oka and T.O. Author contributions: Y. Oka and T.O. designed the study and the experiments. Y. Oka, Y.Oku., K.Hi., N.Mit., Y.H., N.Miy., Y.Kaw., K.T., M.N., N.Ma., F.M., K.M., and T.O. analyzed the genetics data. Y. Oka, Y.N., Y.Oku., K.Ha., H.T., M.S., Y.Kas., S.N., and T.O. performed molecular and cell biological experiments. Y. Oka, M.S., Y.Ko., M.Y., M.T., T.S., S.Ki., and T.M. performed animal studies. Y. Oka., M.H., H.M., Y.Oku., K.Hi., K.Ha., T.H., T.K., H.S., T.I., S.O., K.Y., Y.W., K.K., S.M., K.I., M.O., H.K., F.M., Y.T., S.K., and T.O. analyzed clinical manifestations of the affected individuals and healthy control cases. M.H., H.M., K.Ha., T.K., H.S., T.I., S.O., K.Y., Y.W., K.I., M.O., H.K., F.M., K.M., Y.T., and S.K. contributed the patients and control samples. Y. Oka and T.O. wrote the manuscript. M.H., Y.N., H.M., Y.Oku., and K.Hi. contributed equally to the study. All authors commented on the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome - Science Advances

PHOENIX, Dec. 16, 2020 /PRNewswire/ --Creative Medical Technology Holdings Inc., (OTC CELZ) announced today positive preclinical data supporting the utilization of its ImmCelz cell based immunotherapy for treatment of stroke. In an animal model of ischemia stroke, the middle cerebral artery ligation model, administration of ImmCelz resulted in 34% reduction in infarct volume, whereas control bone marrow mesenchymal stem cells reduced infarct volume by 21%. Additionally, improvements in functional recovery where observed using the Rotarod test. At 28 days after induction of stroke the animals receiving ImmCelz had superior running time (92% of non-stroke controls) compared to animals which received bone marrow mesenchymal stem cells (73% of non-stroke control). Animals that received saline had a running time that was 50% of non-stroke controls.

"The regenerative potential of immune cells that have been programmed by stem cells is a fascinating and novel area of research." Said Dr. Amit Patel, coinventor of ImmCelz, and board member of the Company. "Conceptual advantages of using reprogrammed T cells include higher migratory ability due to smaller size, as well as ability to replicate and potentially form "regenerative memory cells."

"This data, which is covered by our previous filed patents, such as no. 15/987739, Generation of autologous immune modulatory cells for treatment of neurological conditions, demonstrate that immune modulation via this stem cell based method may be a novel and superior way of addressing the $30 billion dollar market for stroke therapeutics1." Said Dr. Thomas Ichim, coinventor of the patent and Chief Scientific Officer of the Company. "The fact that this technology, which has priority back to 2017, is demonstrating such stunning results, motivates us to consider filing an Investigational New Drug Application for use in stroke."

Creative Medical Technology Holdings possesses numerous issued patents in the area of cellular therapy including patent no. 10,842,815 covering use of T regulatory cells for spinal disc regeneration, patent no. 9,598,673 covering stem cell therapy for disc regeneration, patent no. 10,792,310 covering regeneration of ovaries using endothelial progenitor cells and mesenchymal stem cells, patent no. 8,372,797 covering use of stem cells for erectile dysfunction, and patent no. 7,569,385 licensed from the University of California covering a novel stem cell type.

"While stroke historically has been a major area of unmet medical need, the rise in stroke cases , as well as the fact that younger people are increasingly falling victim to stroke, strongly motivates us to accelerate our developmental programs and to continue to explore participation of Big Pharma in this space." Said Timothy Warbington, President and CEO of the Company. "We are eager to replicate the existing experiments start compiling the dossier needed to take ImmCelz into humans using the Investigational New Drug Application (IND) route through the FDA."

About Creative Medical Technology Holdings

Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in stem cell technology in the fields of urology, neurology and orthopedics and trades on the OTC under the ticker symbol CELZ. For further information about the company, please visitwww.creativemedicaltechnology.com.

Forward Looking Statements

OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website atwww.sec.gov.

Timothy Warbington, CEOCEO@ CreativeMedicalHealth.com

Creativemedicaltechnology.comwww.StemSpine.comwww.Caverstem.comwww.Femcelz.com

1 Stroke Management Market Size Forecasts 2026 | Statistics Report (gminsights.com)

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Creative Medical Technology Holdings Announces Successful Application of ImmCelz Immunotherapy for Treatment of Stroke - KPVI News 6

Cancer researchers have created a new class of drugs to selectively target and destroy myeloid leukaemia cells with TET gene mutations.

Photomicrograph of bone marrow biopsy showing myeloblasts of acute myeloid leukemia (AML), a cancer of white blood cells.

Researchers have developed a novel class of targeted cancer drug that may be highly effective for the treatment of myeloid leukaemias. According to the team, their synthetic molecule, called TETi76, was able to selectively kill cells with TET2 gene mutations, one of the most common driver mutations in myeloid leukaemias.

Myeloid leukaemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells. These malignancies are normally treated with chemotherapy, either alone or in combination with targeted drugs; however, the significant side-effects associated with this treatment mean a more selective/targeted treatment is desirable.

In a new study published inBlood Cancer Discovery, researchers from the Cleveland Clinics Taussig Cancer Institute and Lerner Research Institute, both US, describe a new pharmacological strategy to preferentially target and eliminate leukaemia cells with TET2 mutations.

In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill the mutant cancer cells both in the early phases of disease what we call clonal haematopoiesis of indeterminate potential, or CHIP and in fully developed TET2 mutant myeloid leukaemia, said Dr Jaroslaw Maciejewski, a practicing haematologist and chair of the Cleveland Clinic Department of Translational Hematology & Oncology Research, who has been investigating the TET2 gene for the last decade.

TET genes encode DNA dioxygenase enzymes, which remove chemical groups from DNA molecules. Their activity ultimately changes what genes are expressed and can contribute to the development and spread of disease.

TET genes act as tumour suppressors, so loss-of-function mutations are common in haematological cancers, like leukaemias. While all members of the TET family are dioxygenases, TET2 is the most powerful. Genetic TET2 deficiency has been shown to skew differentiation of blood cells and clonal expansion of progenitor and stem cells. However, its related genes TET1 and TET3 provide residual enzymatic activity, sufficient to facilitate the survival of these progenitor cells harbouring cancerous mutations, thereby promoting the spread of the cancer, even when TET2 is inactive.

In their study, the research team designed TETi76 to replicate and amplify the effects of a natural molecule called 2-hydroxyglutarate (2HG), which inhibits the enzymatic activity of TET genes. They hoped to selectively eliminate TET2 mutant leukaemia cells centres by targeting their reliance on this residual DNA dioxygenase activity.

We took lessons from the natural biological capabilities of 2HG, explained Dr Babal Kant Jha, Maciejewskis collaborator from the Department of Translational Hematology & Oncology Research. We studied the molecule and rationally designed a novel small molecule, synthesised by our chemistry group headed by Dr James Phillips. Together, we generated TETi76 a similar, but more potent version capable of inhibiting not just TET2, but also the remaining disease-driving enzymatic activity of TET1 and TET3.

The researchers studied TETi76s effects in both preclinical disease and xenograft models (where human cancer cells are implanted into preclinical models). In both models, treatment with the novel TET inhibitor suppressed the clonal evolution of TET2 mutant cells.

While the team cautioned that additional studies would be critical to investigate the small molecules cancer-fighting capabilities in patients, Dr Jha said we are optimistic about our results, which show not just that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives survival advantage to normal stem and progenitor cells.

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Novel class of targeted cancer therapies could treat myeloid leukaemias - Drug Target Review

Victoria Gray (second from left) with children Jamarius Wash, Jadasia Wash and Jaden Wash. Now that the gene-editing treatment has eased Gray's pain, she has been able be more active in her kids' lives and looks forward to the future. "This is really a life-changer for me," she says. Victoria Gray hide caption

Victoria Gray (second from left) with children Jamarius Wash, Jadasia Wash and Jaden Wash. Now that the gene-editing treatment has eased Gray's pain, she has been able be more active in her kids' lives and looks forward to the future. "This is really a life-changer for me," she says.

The last thing a lot of people want to do these days is get on a plane. But even a pandemic would not stop Victoria Gray. She jumped at the chance to head to the airport this summer.

"It was one of those things I was waiting to get a chance to do," says Gray.

She had never flown before because she was born with sickle cell disease. She feared the altitude change might trigger one of the worst complications of the devastating genetic disease a sudden attack of excruciating pain.

But Gray is the first person in the United States to be successfully treated for a genetic disorder with the help of CRISPR, a revolutionary gene-editing technique that makes it much easier to make very precise changes in DNA.

About a year after getting the treatment, it was working so well that Gray felt comfortable flying for the first time. She went to Washington, D.C., to visit her husband, who has been away for months on deployment with the National Guard.

"It was exciting. I had a window. And I got to look out the window and see the clouds and everything," says Gray, 35, of Forest, Miss.

Gray wore a mask the whole time to protect herself against the coronavirus, kept her distance from other people at the airport, and arrived happily in Washington, D.C., even though she's afraid of heights.

"I didn't hyperventilate like I thought I would," Gray says, laughing as she recounts the adventure in an interview with NPR.

NPR has had exclusive access to follow Gray through her experience since she underwent the landmark treatment on July 2, 2019. Since the last time NPR checked in with Gray in June, she has continued to improve. Researchers have become increasingly confident that the approach is safe, working for her and will continue to work. Moreover, they are becoming far more encouraged that her case is far from a fluke.

At a recent meeting of the American Society for Hematology, researchers reported the latest results from the first 10 patients treated via the technique in a research study, including Gray, two other sickle cell patients and seven patients with a related blood disorder, beta thalassemia. The patients now have been followed for between three and 18 months.

All the patients appear to have responded well. The only side effects have been from the intense chemotherapy they've had to undergo before getting the billions of edited cells infused into their bodies.

The New England Journal of Medicine published online this month the first peer-reviewed research paper from the study, focusing on Gray and the first beta thalassemia patient who was treated.

"I'm very excited to see these results," says Jennifer Doudna of the University of California, Berkeley, who shared the Nobel Prize this year for her role in the development of CRISPR. "Patients appear to be cured of their disease, which is simply remarkable."

Another nine patients have also been treated, according to CRISPR Therapeutics in Cambridge, Mass., and Vertex Pharmaceuticals in Boston, two companies sponsoring the research. Those individuals haven't been followed long enough to report any results, officials say.

But the results from the first 10 patients "represent an important scientific and medical milestone," says Dr. David Altshuler, Vertex's chief scientific officer.

The treatment boosted levels of a protein in the study subjects' blood known as fetal hemoglobin. The scientists believe that protein is compensating for defective adult hemoglobin that their bodies produce because of a genetic defect they were born with. Hemoglobin is necessary for red blood cells to carry oxygen.

Analyses of samples of bone marrow cells from Gray six months after getting the treatment, then again six months later, showed the gene-edited cells had persisted the full year a promising indication that the approach has permanently altered her DNA and could last a lifetime.

"This gives us great confidence that this can be a one-time therapy that can be a cure for life," says Samarth Kulkarni, the CEO of CRISPR Therapeutics.

Gray and the two other sickle cell patients haven't had any complications from their disease since getting the treatment, including any pain attacks or hospitalizations. Gray has also been able to wean off the powerful pain medications she'd needed most of her life.

Prior to the treatment, Gray experienced an average of seven such episodes every year. Similarly, the beta thalassemia patients haven't needed the regular blood transfusions that had been required to keep them alive.

"It is a big deal because we we able to prove that we can edit human cells and we can infuse them safely into patients and it totally changed their life," says Dr. Haydar Frangoul at the Sarah Cannon Research Institute in Nashville. Frangoul is Gray's doctor and is helping run the study.

For the treatment, doctors remove stem cells from the patients' bone marrow and use CRISPR to edit a gene in the cells, activating the production of fetal hemoglobin. That protein is produced by fetuses in the womb but usually shuts off shortly after birth.

The patients then undergo a grueling round of chemotherapy to destroy most of their bone marrow to make room for the gene-edited cells, billions of which are then infused into their bodies.

"It is opening the door for us to show that this therapy can not only be used in sickle cell and thalassemia but potentially can be used in other disorders," Frangoul says.

Doctors have already started trying to use CRISPR to treat cancer and to restore vision to people blinded by a genetic disease. They hope to try it for many other diseases as well, including heart disease and AIDS.

The researchers stress that they will have to follow Gray and many other patients for a lot longer to be sure the treatment is safe and that it keeps working. But they are optimistic it will.

Gray hopes so too.

"It's amazing," she says. "It's better than I could have imagined. I feel like I can do what I want now."

The last year hasn't always been easy for Gray, though. Like millions of other Americans, she has been sheltering at home with three of her children, worrying about keeping them safe and helping them learn from home much of the time.

"I'm trying to do the things I need to do while watch them at the same time to make sure they're doing the things they need to do," Gray says. "It's been a tough task."

But she has been able do other things she never got to do before, such as watch her oldest son's football games and see her daughter cheerleading.

"This is really a life-changer for me," she says. "It's magnificent."

She's now looking forward to going back to school herself, learning to swim, traveling more when the pandemic finally ends, and watching her children grow up without them worrying about their mother dying.

"I want to see them graduate high school and be able to take them to move into dorms in college. And I want to be there for their weddings just everything that the normal people get to do in life. I want to be able to do those things with my kids," she says. "I can look forward now to having grandkids one day being a grandmama."

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1st Patients To Get CRISPR Gene-Editing Treatment Continue To Thrive - NPR

Bone Regeneration Material Market: Introduction

Bone-regeneration techniques, either with autografts or allografts, represent a challenge for reconstructive surgery. Biomaterials are temporary matrices for bone growth and provide a specific environment and architecture for tissue development. Depending on the specific intended application of the matrix, whether for structural support, drug-delivery capability, or both, certain material categories may be more or less well suited to the final structure.

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Key Drivers and Restraints of Global Bone Regeneration Material Market

Increase in prevalence of degenerative joint diseases boost the market. Worldwide estimates of degenerative joint diseases indicate that 9.6% men and 18.0% women above 60 years have symptomatic osteoarthritis. According to expert opinions presented in the EULAR committee report, radiographic evidence of knee osteoarthritis in men and women over 65 years of age is found in 30% of the population.

In the absence of disease modifying therapy, a large number of patients with osteoarthritis progress to advance joint destruction. Surgery with bone grafts and substitutes play a major role in the management of osteoarthritis to avoid advanced joint destruction. According to the American College of Rheumatology, advances in biomaterial and tissue engineering are expected to create new opportunities to integrate surgical approaches in osteoarthritis.

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Increase in the number of orthopedic surgeries also fuels the market. According to the American Academy of Orthopaedic Surgeons (AAOS), approximately 129,000 total knee arthroplasty (TKA) surgeries were performed in the U.S. in 1990, and the number has increased to over 600,000 in 2010. The AAOS has projected that 3 million TKA procedures would be performed by 2030 in the U.S. alone. Moreover, spinal surgeries are becoming increasingly popular, and approximately 432,000 spinal fusions are performed in the U.S. each year. Bone grafts and substitutes are extensively used for the surgeries mentioned above. This is likely to fuel the bone regeneration material market.

Bone graft and substitutes are a long-term solution to bone problem treatment; however, these are expensive. No two patients or their customized bone grafts and substitutes treatments are exactly alike. Hence, the number of appointments, procedures, and costs vary accordingly. Surgeons charge US$ 35,000 to US$ 40,000 for a complex posterolateral lumbar spine fusion bone graft surgery. Most surgeons refer patients to specialty surgeons, neurologists, or orthopedic physicians, which increases the cost of procedure. Asia is price-sensitive and displays inhibitions with respect to investing in bone graft and substitutes, which are often only affordable to the elite population; therefore offering a comparatively smaller market.

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Cell-based Segment to Expand Significantly

Based on product type, the global bone regeneration material market can be divided into ceramic-based, polymer-based, growth factor-based, cell-based and others

The ceramic-based segment dominated the global market in 2019. It is projected to sustain its position during the forecast period. Ceramic-based bone grafts are widely used to reduce the need for iliac crest bone grafting. Rise in geriatric population with oral health issues across the world has augmented the number of bone graft surgeries performed in the last few years.

However, the cell based segment is projected to expand at a notable CAGR during the forecast period. Bone tissue engineering (BTE) using bone marrow stem cells has been suggested as a promising technique for reconstructing bone defect in order to overcome the drawbacks of bone graft materials.

Orthopedic surgery segment to dominate global bone regeneration material market

Based on application, the global bone regeneration material market can be segregated into orthopedic surgery, bone trauma, dental surgery and others.

In terms of revenue, the orthopedic surgery segment accounted for a prominent share of the market in 2019 owing to a rise in the geriatric population and increase in cases of orthopedic diseases. According to WHO, between 2015 and 2050, the proportion of the world's population over 60 years would nearly double from 12% to 22%. The number of people aged 60 years and older is estimated to outnumber children younger than 5 years by 2020. As per MVZ Gelenk-Klinik data, more than 2400 orthopedic surgical procedures are performed per year at the Gelenk Klinik Orthopaedic Hospital.

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North America to dominate global bone regeneration material market

In terms of region, the global bone regeneration material market can be divided into: North America, Europe, Asia Pacific, Latin America, and Middle East & Africa

North America accounted for a significant share of the bone regeneration material market in 2019, followed by Europe. Usage of new and innovative products in both premium and value segments among various bone grafts substitutes is projected to boost the bone regeneration material market in several countries in Europe and North America in the next few years. According to the Centers for Disease Control and Prevention (CDC), the total number of inpatient surgeries carried out in the U.S. were 51.4 million in 2014; of these 719,000 were total knee replacements and 332,000 were total hip replacement.

The market in developing countries in Asia Pacific is estimated to expand at a significant CAGR during the forecast period. The market in Asia Pacific is driven by an increase in population and time taken to accept new technologies. Increase in the number of patients and geriatric population are major factors that are expected to propel the market in Japan during the forecast period. According to the Gerontological Society of America, Japan has the highest proportion of geriatric population in the world. Hence, demand for orthopedic surgeries is estimated to be higher in Japan than that in other countries in Asia Pacific.

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Key Manufacturers Operating in Market

The global bone regeneration material market was highly fragmented in 2019. Key manufacturers operating in the global market are:

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Continued here:
Bone Regeneration Material Market: Cell-based Segment to Expand Significantly - BioSpace

If youre like 95% of American adults, you had chickenpox as a kid. Before the United States started its widespread vaccination program in 1995, there were roughly four million cases of chickenpox every year. So, most people suffered through an infection with this highly contagious virus and its itchy, whole-body rash.

But unlike many childhood viruses, the varicella-zoster virus that causes chickenpox doesnt clear from the body when the illness ends. Instead it hangs around, taking up residence and lying dormant in the nerves, sometimes for decades, with the immune system holding it in check. In some people, it lives there harmlessly for the rest of their life. But in others, the virus can suddenly emerge and strike again, this time appearing as a different condition known as shingles.

Like chickenpox, shingles also causes a blistering rash, but this time it generally appears as a painful band around one side of your ribcage or on one side of your face. The first symptom for many people is pain or a burning sensation in the affected area. You may also have fever, a headache, and fatigue. Along with the rash and other temporary symptoms, shingles can also bring unpleasant, long-lasting, and sometimes permanent complications, such as skin infections, nerve pain in the area where the rash appeared, or even vision loss.

Experts dont fully understand this. One theory is that shingles occurs when your immune system loses its ability to keep the virus in check.

After you get chickenpox, your immune system is able to recognize the varicella-zoster virus thanks to specialized immune system cells, called B and T cells, that are able to remember the virus and quickly marshal an attack on it. Factors that weaken the immune system increase your risk of developing shingles. These include

While you may not be able to control certain factors that might trigger shingles, there are strategies you can use to prevent shingles. The most important is vaccination. Research shows that the shingles vaccine Shingrix is 90% effective in preventing an outbreak of shingles. Even if you do get shingles after being vaccinated, Shingrix greatly reduces your risk of developing persistent pain in the affected area, known as post-herpetic neuralgia.

In addition to getting vaccinated, its always a good idea to take steps to keep your body healthy, such as choosing healthy foods, staying active, and getting sufficient sleep. Its not clear if healthy lifestyle habits like these can prevent shingles, but even if they dont, theyre worthwhile because they will benefit your body in many other ways.

Link:
Shingles: What triggers this painful, burning rash? - Harvard Health Blog - Harvard Health

Global Orthopedic Regenerative Medicine Market Growth To Increase Manifold By 2027 A fundamental overview of the Orthopedic Regenerative Medicine Market niche is provided in the Orthopedic Regenerative Medicine Market report accompanying definitions, classifications, applications along with industry chain framework. The Orthopedic Regenerative Medicine market report provides a broad assessment of the required market dynamics and the latest trends. It also highlights regional markets, prominent market players, multiple market segments [products, applications, end users, and key regions] and subsectors that broadly consider numerous departments along with applications.

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Top Key Players Global Orthopedic Regenerative Medicine Market Competition: Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.

The market can be segmented into:By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Furthermore, the report acknowledges that in this growing and immediately intensifying market situation, the most recent advertising and marketing details are critical to determining the performance of the forecast period and making an essential choice for the profitability and growth of the Orthopedic Regenerative Medicine market. Do it. Additionally, the report covers various factors influencing the growth of the Orthopedic Regenerative Medicine market during the forecast period. Additionally, this particular analysis will also determine its impact on individual segments of the market.

To identify the growth opportunities in the Orthopedic Regenerative Medicine market, the report has been segmented into regions that are growing faster than the overall market. This region was focused on regions with slower growth rates than the global market. Each geographic segment of the Orthopedic Regenerative Medicine market has been independently investigated, with price, distribution and demand data specifically for North America (US, Canada and Mexico), Europe (Germany, France, UK, Russia and Italy), and Asia-region markets. . Pacific (China, Japan, Korea, India and Southeast Asia), South America (Brazil, Argentina, Colombia, etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa).

Research purpose:

Provides strategic profiling of key players in the market, comprehensively analyzes core competencies, and derives the competitive landscape of the market.

Provides insight into factors influencing market growth. Orthopedic Regenerative Medicine market analysis based on various factors such as price analysis, supply chain analysis, Porter Five Force analysis, etc.

It provides detailed analysis of the market structure with forecasts for various segments and sub-segments of the global Orthopedic Regenerative Medicine market.

Provides a country level analysis of the market in relation to its current market size and future outlook.

Provides country-level analysis of the market by application, product type and sub-segment.

Provides historical and forecast revenue for the market segment and sub-segments in relation to the four major regions and countries in North America, Europe, Asia and other countries.

Track and analyze competitive developments such as joint ventures, strategic alliances, new product development and research and development in the global Orthopedic Regenerative Medicine Market.

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The chapters covered in the research report are as follows:

Chapter 1, 2: Targets of the Global Orthopedic Regenerative Medicine Market, encompassing market introduction, product images, market summary, and development scope.

Chapter 3, Chapter 4: Global Market Competition, Sales Volume, and Market Profit by Manufacturer.

Chapters 5, 6, 7: Global Supply (Production), Consumption, Exports, Imports by Regions such as USA, Asia Pacific, China, India, Japan. From 2015 to 2024, we conduct regional market research based on regional sales rate and market share.

Chapters 8, 9, 10: Global Market Analysis by Application, Cost Analysis, Marketing Strategy Analysis, Distributor/Trader

Chapters 11, 12: Market Information and Research Conclusions, Appendix and Data Sources.

The market report also primarily identifies additional useful and useful information about the industry, including the Orthopedic Regenerative Medicine market development trends analysis, return on investment, and feasibility analysis. Additionally, SWOT analysis is distributed in the report to analyze the growth of key global market players in the Orthopedic Regenerative Medicine market industry.

In addition, the research report investigates:

Competitors and manufacturers in the global market

By product type, application and growth factor

Industry status and outlook for major applications / end users / usage areas

Thanks for reading this article. You can also get individual chapter sections, such as North America, Europe, or Asia, or regional versions of the report.

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Impact of Covid-19 On Orthopedic Regenerative Medicine Market Business Overview and Forecast to 2027 | Curasan, Inc., Carmell Therapeutics...

The allogeneic off-the-shelf CD22-directed T-cell product, UCART22, showed early signs of activity and no evidence of unexpected toxicities at 2 dose levels for adult patients with relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia, according to the results of a study presented during the 2020 ASH Annual Meeting.1

In the phase 1 BALLI-01 (NCT04150497) dose-escalation and dose-expansion study, 2 patients at the 1 x 105 cells/kg dose achieved a complete remission (CR) with incomplete hematologic recovery on day 28. One of these patients attained a minimal residual disease (MRD)positive CR at day 42 followed by subsequent inotuzumab ozogamicin (Besponsa) and then transplant.

One patient at dose level 2, 1 x 106 cells/kg, experienced a significant bone marrow blast reduction at day 28, followed by disease progression.

No patients experienced dose-limiting toxicities (DLTs), immune effector cellassociated neurotoxicity syndrome (ICANS), graft-versus-host disease (GVHD), adverse effects (AE) of special interest (AESI), a UCART22-related AE that was grade 3 or higher, or a serious AE (SAE).

UCART22 showed no unexpected toxicities at the doses of 1 x 105 cells/kg and 1 x 106 cells/kg with fludarabine and cyclophosphamide lymphodepletion, lead study author Nitin Jain, MD, an assistant professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a virtual presentation during the meeting. Host immune recovery was observed early, and the addition of alemtuzumab [Lemtrada] to fludarabine and cyclophosphamide lymphodepletion is currently being explored with the goal to achieve deeper and more sustained T-cell depletion and to promote expansion and persistence of UCART22.

Standard treatment for adult patients with B-cell ALL includes multiagent chemotherapy with or without allogeneic stem cell transplant. However, 30% to 60% of patients with newly diagnosed B-cell ALL who achieve a CR will relapse, and the expected 5-year survival rate for those with relapsed/refractory disease is approximately 10%.

Previously, UCART19, when paired with lymphodepletion using fludarabine, cyclophosphamide, and alemtuzumab, was found to show efficacy in this patient population.2

CD22 is an FDA-approved therapeutic target in B-cell ALL. UCART22 is an immediately available, standardized, manufactured agent with the ability to re-dose, and its CAR expression redirects T cells to tumor antigens, Jain explained.

Moreover, through its mechanism of action, TRAC becomes disrupted using Transcription activator-like effector nucleases (Talen) technology to eliminate TCR from cell surface and reduce the risk of GVHD. CD52 is also disrupted with the use of Talen to eliminate sensitivity to lymphodepletion with alemtuzumab. Finally, there is a CD20 mimotope for rituximab (Rituxan) as a safety switch, Jain added.

UCART22 has also demonstrated in vivo antitumor activity in immune-compromised mice that were engrafted with CD22-positive Burkitt lymphoma cells in a dose-dependent manner.

In the dose-escalation/dose-expansion BALLI-01 study, investigators are enrolling up to 30 patients in a modified Toxicity Probability Interval design. There are 3 cohorts, which have 2 to 4 patients on each cohort: 1 x 105 cells/kg (dose level 1), 1 x 106 cells/kg (dose level 2), and 5 x 106 cells/kg. The focus of the dose-escalation phase of the trial was to determine the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D) before heading into the dose-expansion portion of the trial.

To be eligible for enrollment, patients must have been between 18 and 70 years old, have acceptable organ function, an ECOG performance status of 0 or 1, at least 90% of B-cell ALL blast CD22 expression, and had previously received at least 1 standard chemotherapy regimen and at least 1 salvage regimen.

End points of the trial included safety and tolerability, MTD/R2PD, investigator-assessed response, immune reconstitution, and UCART22 expansion and persistence.

The lymphodepletion regimens were comprised of fludarabine (at 30 mg/m2 x 4 days) plus cyclophosphamide (1 g/m2 x 3 days); the study has since been amended to include the regimen of fludarabine (at 30 mg/m2 x 3 days), cyclophosphamide (500 g/m2 x 3 days), and alemtuzumab (20 mg/day x 3 days) and is currently enrolling patients.

Following screening, lymphodepletion, and UCART22 infusion, patients underwent an observation period for DLTs with a primary disease evaluation at 28 days; additional efficacy evaluations occurred at 56 days and 84 days. Patients were followed for 2 years and continued to be assessed for long-term follow-up.

As of July 1, 2020, 7 patients were screened, of which 1 patient failed and 6 were therefore enrolled on the study. One patient discontinued therapy before receiving UCART22 due to hypoxia from pneumonitis that was linked with lymphodepletion. Five patients were treated with UCART22 at dose level 1 (n = 3) and dose level 2 (n = 2).

The median age of participants was 24 years (range, 22-52), 3 of the 5 patients were male, and 3 had an ECOG performance status of 0. The median number of prior therapies was 3 (range, 2-6), and there were a median 35% bone marrow blasts (range, 10%-78%) prior to lymphodepletion.

Three patients had complex karyotype and 2 had diploid cytogenetics. One patient each had the following molecular abnormalities: CRLF2, CRLF2 and JAK2, CDKN2A loss, KRAS and PTPN11, and IKZF1. Only 1 patient had undergone haploidentical transplant. Four patients previously received prior CD19- or CD22-directed therapy, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and CD19-directed CAR T-cell therapy. At study entry, 3 patients had refractory disease and 2 patients had relapsed disease.

Grade 3 or higher treatment-emergent AEs (TEAEs), which were unrelated to study treatment, included hypokalemia, anemia, increased bilirubin, and acute hypoxic respiratory failure. Also not related to UCART22, 3 patients experienced 4 treatment-emergent SAEs: porta-hepatis hematoma, sepsis, bleeding, and sepsis in the context of disease progression. No treatment discontinuations due to a treatment-related TEAE were reported.

The patient who achieved a CR followed by transplant was a 22-year-old male who had undergone 2 prior treatments for B-cell ALL and received UCART22 at a dose of 1 x 105 cells/kg. He did not experience CRS, ICANS, GVHD, nor a SAE, and all TEAEs were grade 1.

Jain also noted that host T-cell constitution was observed in all patients within the DLT observation period. UCART22 was also not detectable through flow cytometry or molecular analysis, the latter of which was at dose level 1 only.

References:

1. Jain N, Roboz GJ, Konopleva M, et al. Preliminary results of BALLI-O1: a phase I study of UCART22 (allogeneic engineered T cells expressing anti-CD22 chimeric antigen receptor) in adult patients with relapsed/refractory anti-CD22+ B-cell acute lymphoblastic leukemia (NCT04150497). Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; Virtual. Abstract 163.

2. Benjamin R, Graham C, Yallop D, et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory b-cell acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):896. doi:10.1182/blood-2018-99-111356.

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Early Signs of Activity and Tolerability Found in Allogeneic Product UCART22 for Patients with Relapsed/Refractory CD22+ B-Cell ALL - Cancer Network

As interest in chimeric antigen receptor (CAR) T-cell therapy continues to grow with more promising data coming out and approvals from the FDA in various hematologic malignancies, the role of this cellular therapy has yet to be defined in multiple myeloma, but recent data have inspired hope for this therapy in the relapsed/refractory population.

The B-cell maturation antigen (BCMA)directed CAR T-cell therapy idecabtagene vicleucel (ide-cel; bb2121) has generated excitement in this population following the submission of a Biologics License Application (BLA) in March 2020, seeking approval of ide-cel in patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody, and a Priority Review designation granted in September 2020. Following delays in the review due to coronavirus disease 2019, the Prescription Drug User Fee Act action date has been set as March 27, 2021.

Deep and durable responses were observed with ide-cel as treatment of heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated results from the CRB-401 study presented by Yi Lin, MD, PhD, assistant professor of oncology and associate professor of medicine at Mayo Clinic, during the 2020 American Society of Hematology (ASH) Annual Meeting. The efficacy and safety findings were consistent with prior findings and supported a favorable clinical risk-benefit profile at target dose levels 150 x 106.1

The median overall survival with ide-cel was 34.2 months (95% CI, 19.2-not evaluable) among all patients in this triple-classexposed population, and half of the patients who had ongoing responses achieved a duration of response >2 years. The median progression-free survival (PFS) was 8.8 months (95% CI, 5.9-11.9). The objective response rate (ORR) overall was 75.8%, which included complete responses (CRs) in 38.7%.

These results from CRB-401 are comparable to the findings from the pivotal phase 2 KarMMa study (NCT03361748), which were presented earlier this year during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program and support the Biologics License Application. The median OS for this study was 19.4 months, and the median PFS was 8.8 months. The ORR was 73%, which included a CR rate of 33%, and the median duration of response was 10.7 months.2

Ide-cel is being explored in several ongoing studies as well, including the phase 2 KarMMa-2 (NCT-3601078), phase 3 KarMMa-3 (NCT03651128), and phase 1 KarMMa-4 (NCT04196491) clinical trials. These phase 2 and 3 studies are evaluating ide-cel in patients with triple-classexposed disease, and the phase 1 study will explore the use of this CAR T-cell therapy in patients with high-risk newly diagnosed multiple myeloma.

These data have also set the stage for other BCMA-directed CAR T-cell therapies in development for the treatment of patients with multiple myeloma.

In an interview with Targeted Oncology, Lin discussed the updated findings from the CRB-401 study of ide-cel as treatment of patients with relapsed/refractory multiple myeloma.

TARGETED ONCOLOGY: What historical data have we seen with BCMA-directed CAR T-cell therapy in patients with relapsed/refractory multiple myeloma?

Lin: With the CAR T approach in multiple myeloma, the very first case report was actually with CD19-targeted CAR T because there was already experience with that particular antigen in leukemia and lymphomas. There's some ongoing effort in terms of dual targeting with CD19 and BCMA, but BCMA very quickly emerged as an ideal candidate for the myeloma space. This is an antigen that is more uniformly expressed on plasma cells, including myeloma cells, and maybe a small subset of mature B cells, but otherwise BCMA is not expressed on healthy tissues.

There have been some single-center clinical trials with the BCMA-targeted CAR T approach prior to the CRB-401 study, both with National Cancer Institute and the University of Pennsylvania with slightly different constructs. With those early phase 1 studies, there was a little bit more toxicity seen, although there was certainly some response, but the response wasn't particularly durable. CRB-401 is the first in a series of now industry-sponsored multicenter studies, in which we are now seeing a much more encouraging durable response rate and also a more favorable side effect profile as well. At ASH this year, I presented the longer follow-up on the phase 1 CRB-401 study. There is a pivotal phase 2 KarMMa study using the same CAR T construct that had been presented at ASCO earlier this year.

TARGETED ONCOLOGY: Please describe the design of the trial and what was different about the study.

Lin: The CRB-401 study has 2 parts. The first part is the dose-escalation part, and the second part is the dose expansion. The dose escalation is basically testing the range of a fixed dose of 50 million all the way up to 800 million of ide-cel CAR T cells in a relatively small number of patients, basically looking for signs of severe side effects to identify a safe dose. The dose expansion cohort is where we take the more promising doses in terms of response, and also safety profile, and test them in more patients to get a better safety signal, which is then moved forward for phase 2 testing in the KarMMa study.

In the dose-expansion portion of CRB-401, we required that each patient must have had exposure to an anti-CD38 antibody. That was allowed in a dose escalation but not required for everybody. [To be included in the study,] the patient must have had become refractory to the most recent line of treatment before they came on the study. The other thing that was different was that in the dose-escalation cohort, all patients had their myeloma cells in the bone marrow reviewed centrally by immunohistochemistry staining, and they were required to have at least 50% of these cells having BCMA expression in a dose-expansion cohort, to better understand the clinical efficacy and safety profiles of this treatment. We also included some patients that had BCMA expression below that to even levels that were not detectable by immunohistochemistry.

TARGETED ONCOLOGY: What were the results from this study?

Lin: The study [included] a total of 62 patients. The results from the first 33 patients were already published in the New England Journal of Medicine last year, and this year at ASH, data were presented for outcomes of the entire 62-patient cohort, with a median follow-up of now 18.1 months. What we have seen so far is in this entire treated patient cohort these are patients with very high-risk features of myeloma, and close to a third of these patients had high-risk cytogenetics, 37% of these patients had extra modularity plasma effect, and almost half of these patients needed some type of systemic therapy while their CAR T cells are being made. These patients, on average, had 6 lines of prior therapy, and in close to 70% or higher, these patients are either triple-refractory or were refractory to the most recent line of therapy.

For this group of patients that was treated overall, the safety signal was very tolerable, which is not surprising with CAR T therapy because these patients also do get lymphodepletion chemotherapy as part of the treatment with CAR T. We do see that low blood count is the most common side effect, including the more severe low blood counts, but on average, the recovery of these blood counts can be seen well under the first 3 months after CAR T infusion. The other most common side effects that we need to watch for with CAR T are cytokine release syndrome (CRS) and neurotoxicity. What we have seen in this study is that, on average, about 76% of these patients had some type of CRS. However, those that had grade 3 or higher, that is only [seen] in 6.5% of the patients, so much lower, and that's also reflected in the relative lower use of tocilizumab and steroids, as well, to manage the side effects. About 35% of these patients had some type of neurologic side effect, but again, only 1 patient had a more severe form of neurotoxicity. Compared to what we have seen with the CAR T experience in the lymphoma/leukemia space, this is a very, very encouraging safety profile.

We have also now seen that the ORR is quite high. It's 75.8% with a CR and stringent CR rate of about 38.7%. Many of these patients that had bone marrow that were evaluable for minimal residual disease (MRD) response were MRD-negative. We are seeing, since we tested many doses, that there is a dose-related increase in response with increasing [the] dose, and we have also seen that the duration of response is 10.3 months. When we look at the dose that was tested as well in those expansions [in] the 150 to 450 range, what we have seen is that the duration of response is comparable, so not significantly decreased, for patients with high-risk features like those with extramedullary disease for older patients, as well as patients who needed to get bridging therapy during treatment. The median PFS is 8.8 months, and the median OS is 34.2 months.

So far, the response rate, duration of response, and PFS seem to be comparable to what we also now see in the KarMMa study, which has less follow-up, but we are seeing a very nice median OS for a treatment in which we're just giving a 1 dose infusion and no follow-up maintenance therapy.

TARGETED ONCOLOGY: In terms of CAR T-cell therapy, how do you see this strategy impacting this patient population in the future?

Lin: I think there's definitely a role for this in the practice. The BLA for ide-cel has been submitted to the FDA, so we're anticipating review sometime in early 2021. This is very exciting because this could very well be the first CAR T for multiple myeloma. I think this would definitely be a treatment option for these patients. Based on how KarMMa is designed, we anticipate that the FDA approval will be in the space of patients who [have] had at least 3 lines of prior therapy and have been exposed to the currently approved 3 main backbones of treatmenta PI, IMiD, and the CD38 antibody. The full detail is pending final FDA review and the label. However, in that space, certainly looking at the demographic of the patient that's been treated so far as CRB-401 and KarMMa, that's a wider group of patients. Based on the fact that this is a treatment that is a basically living active cells, I perceive that the earlier that patient could get this therapy in the earliest possible approved indication, there would likely be potentially more benefit for the patients.

TARGETED ONCOLOGY: Do you think there is hope for this treatment in other hematologic malignancies outside of lymphomas and leukemias as well?

Lin: That is actually a very interesting question because what we're seeing in terms of the severity of CRS and neurotoxicity is a reflection of our evolving learning about how to manage the toxicity, as well. There is a component to the CAR design, the disease, the nature of the disease, the kinetics of the CAR T actions, in the manifestation of these symptoms. What we are seeing now, with even the prior CAR and next-generation CAR coming on, we will likely see an ongoing improvement in terms of a reduction of severity of these symptoms and also in the ways that we could manage these symptoms.

The fact that myeloma would be the next disease that has an FDA-approved CAR T also relates to the fact that the BCMA antigen is more restricted on the cell type where the malignancy is involved, similar to CD19 for lymphoid malignancy. We are seeing that there are some challenges, for example with acute myeloid leukemia or myeloid neoplasms where a number of antigens could overlap with stem cells, which we wouldn't want to try to hurt. There are some novel CAR approaches to try to overcome that, and those are in very early phase testing, so we'll need to see how those results evolve.

References

1. Lin Y, Raje NS, Berdeja JG, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: updated results from phase 1 CRB-401 study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 131.

2. Munshi NC, Anderson Jr LD, Jagannath S, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results.J Clin Oncol. 2020;38(suppl):8503. doi:10.1200/JCO.2020.38.15_suppl.8503

See original here:
Updated Findings Show Continued Efficacy for CAR T-Cell Therapy in Heavily Pretreated Myeloma - Targeted Oncology

Joceline Colvert was diagnosed with relapsing remitting Multiple Sclerosis in her early 20s and says she spent the first eight years researching and managing her condition while trying to mention it as little as possible to others and completing her Sound Production degree.

I spent most of my late 20s and early 30s finding ways to manage relapses, the symptoms of which have included whole body numbness, loss of the use of both hands, right eye blindness, vertigo and double vision, she said. Thankfully these symptoms did resolve however left scarring on my nerves. This results in reduced vision in my formerly blind eye and hands that dont function very well with repetitive tasks.

This semi-denial worked for me until about 2010 when I started to become a bit limpy which I did my best to hide. After a couple of memorable falls and fractures I decided to face up to being slightly rickety and got a hiking pole that I used occasionally in public. Since then Ive needed to get used to being visibly disabled, and switch between two hiking poles for very short distances and a wheelchair everywhere else.

Joceline, who lives with her husband and her five beloved cats and dogs, says she is not eligible for Haematopoietic Stem Cell Transplantation (HSCT), on the NHS which is the first treatment I have ever got excited about and believe could work. It could be truly life-changing.

As a result she is trying to raise money to fund the treatment herself.

HSCT is a procedure that aims to reset the faulty immune system which, in my case, is attacking my nervous system from within, Joceline said. Stem cells will be taken from my bone marrow or blood before my immune system is wiped out with chemotherapy. My cells are then reintroduced into my blood, where they grow a new immune system which will hopefully no longer attack my nerves or have any memory of MS.

The aim of HSCT is to completely halt progression, putting MS into remission with no requirement for immunosuppressant drug therapy. The success rate for relapsing remitting MS is 80% - 90% which is absolutely phenomenal compared to the limited available drug treatments, which only aim to slow down disability.

HSCT is available on the NHS, however there is a very strict criteria for which I do not qualify. The expense of the treatment and the increased pressures on the public purse mean the NHS will only treat patients who have been diagnosed for fewer than 15 years.

I have been diagnosed for 18 years.

I had prepared myself for this possibility and, for the last year, have been researching treatment with The National Pirogov Medical Centre Russia (Moscow). Russia has been pioneering in their use of HSCT to treat MS and are world renowned for their expertise and care. Im excited to have a treatment date in March 2021 which fills me with hope for a future free from progression. I need your help to get there.

Joceline, who loves making stop-motion animation puppets and props and playing musical instruments, says the treatment will cost 40,800, and the flights 800.

She has launched a Go Fund Me page at https://gf.me/u/y538k2 which has already seen donations of more than 26,000.

I am incredibly grateful for any help you can give towards enabling me to access this life-changing treatment, she said.

After almost two decades of managing MS flare-ups and their consequences, its hard to put into words just what a future without them would mean to me.

Thank you for reading this and for any help you can put towards this goal.

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Haywards Heath woman's bid to fund stem cell treatment to combat MS - Mid Sussex Times

Autologous hematopoietic stem cell transplant (AHSCT) induces a reduction in relapse rate and physical disability in patients with relapsing-remitting multiple sclerosis (RRMS) who respond inadequately to other treatments, a small study suggests.

The study, Selective cognitive dysfunction and physical disability improvement after autologous hematopoietic stem cell transplantation in highly active multiple sclerosis, was published in the journal Nature Scientific Reports.

AHSCT is an experimental approach to treat multiple sclerosis (MS) that is meant to rebuild a patients immune system in order to stop attacks on the brain and spinal cord.

The procedure begins with collecting a patients own (meaning autologous) healthy hematopoietic stem cells immature cells that can develop into all types of blood cells from the bone marrow. These cells are put back into the patient after a fairly non-aggressive combination of chemotherapy is given to kill the patients immune cells.

A team of researchers at the Vilnius University, in Lithuania, evaluated the effectiveness and safety of the AHSCT procedure in 24 patients (18 female, mean age 37.8 years) with highly active RRMS (mean disease duration of 8.6 years) who failed to respond to conventional therapies.

The aim of the study was to assess cognitive dysfunction and physical disability after AHSCT, to explore the potential factors influencing disability regression after the transplant, and to estimate the safety of low-dose immunosuppressive therapy in highly active relapsing MS patients.

Researchers assessed participants disability and cognition through changes in several functional measures, including the expanded disability status scale (EDSS) and the Brief International Cognitive Assessment for MS, which includes three cognitive domains measured by the symbol digit modalities test, brief visuospatial memory test revised, and California verbal learning test second edition.

Of the 24 patients, 13 (54.2%) completed a 24-month follow-up and were included in the efficacy analysis of AHSCT. From those, two (15.4%) had one relapse during the first year after AHSCT and three patients (23.1%) had one relapse during the second year after AHSCT.

The annualized relapse rate (ARR) was 2.7 one year before AHSCT and 1.9 at two years before AHSCT. After the AHSCT procedure, ARR dropped to 0.2 in the first year and to 0.3 in the second year. This represented an 89% reduction in ARR, when comparing the values at two years after AHSCT with those at two years before AHSCT.

The researchers also noted a reduction in disability progression (as measured by EDSS scores), with 84.6% of patients improving their disability score after AHSCT at month six and 76.9% at one year. Additionally, 76.9% of patients showed stable disability scores two years after the transplant.

The findings of EDSS improvement in almost 85% of the patients suggest that disability may be often at least temporarily reversible in patients with highly active [relapsing] MS if they receive suitable and well-timed treatment, the researchers wrote.

Using appropriate statistical models, researchers found that the clinical variable that explained the disability regression at months 6 and 12 after AHSCT was the disability progression over 6 months before AHSCT.

Improvements in cognition after AHSCT also were observed. Specifically, the scores of information processing speed and verbal learning, measured by the symbol digit modalities test, were significantly higher at month 12 after AHSCT (56.8) when compared to month three (48.3).

The score of brief visuospatial memory test revised that assesses visuospatial memory was slightly lower at month three (25.6) than before AHSCT (27.8), however, the difference was not significant.

The score of the California verbal learning test, which assesses verbal learning, was significantly higher at month 12 (63.6) than before AHSCT (55.2).

No new or active lesions were found on MRI after AHSCT, suggesting that all patients remained without radiological disease activity.

Furthermore, regarding safety, the incidence and severity of adverse events (side effects) after AHSCT were in the expected range and all were resolved. There were no transplant-related deaths reported.

Researchers noted several limitations to the studys findings, including the low sample size and the fact that the patientss assessment and follow-ups were provided at the same center without a comparative group.

Nonetheless, the outcomes are highly promising, as compared to conventional MS treatment, the researchers wrote. Further research is needed to replicate these findings and to assess long-term outcomes and safety of AHSCT.

Diana holds a PhD in Biomedical Sciences, with specialization in genetics, from Universidade Nova de Lisboa, Portugal. Her work has been focused on enzyme function, human genetics and drug metabolism.

Total Posts: 1,053

Patrcia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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Stem Cell Transplant Reduces Relapses and Disability in RRMS... - Multiple Sclerosis News Today

Our goal with omidubicel is to revolutionize the field of bone marrow transplantation and bring a potentially curative cell therapy option to thousands of patients who are in need of a bone marrow transplant, but lack a suitable stem cell donor. These results bring us one step closer towards that goal, said Julian Adams, Ph.D., chief executive officer of Gamida Cell. Whats more, transplantation with omidubicel has been shown to result in more rapid neutrophil engraftment, a decrease in the amount of time patients spend in hospital, and a reduction in infections. These are very meaningful outcomes for patients and may also lessen the financial costs of certain aspects of the transplant.

Gamida Cell previously reported top-line data for omidubicel. In October, the company reported that the omidubicel phase 3 study achieved its secondary endpoints, analyzed in all randomized patients (intent-to-treat). In May, Gamida Cell reported that the study achieved its primary endpoint, demonstrating a highly statistically significant reduction in time to neutrophil engraftment, a key milestone in a patients recovery from a bone marrow transplant.

These pivotal data form the basis of a Biologics License Application (BLA) that Gamida Cell expects to initiate on a rolling basis before the end of this year. Gamida Cell is preparing to be launch ready in anticipation of potential FDA approval as early as the fourth quarter of 2021, subject to ongoing FDA discussions on manufacturing, quality and other matters.

The live event will be available here. More information about the Phase 3 study of omidubicel and the other updates included in this release can be found in the Pipeline Deep Dive presentation on the Gamida Cell website immediately following the event.

Details of Phase 3 Endpoints

As previously reported, Gamida Cell achieved positive topline results from its Phase 3 clinical study evaluating the safety and efficacy of omidubicel. The median time to neutrophil engraftment was 12 days for patients randomized to omidubicel compared to 22 days for the comparator group (p<0.001). Neutrophil engraftment is a measure of how quickly the stem cells a patient receives in a transplant are established and begin to make healthy new cells, and rapid neutrophil engraftment has been associated with fewer infections and shorter hospitalizations.

Today, Gamida Cell announced the details of achieving all three of the prespecified secondary endpoints of the study, analyzed in all randomized patients (intent-to-treat). These secondary endpoints were the proportion of patients who achieved platelet engraftment by day 42, the proportion of patients with grade 2 or grade 3 bacterial or invasive fungal infections in the first 100 days following transplant, and the number of days alive and out of the hospital in the first 100 days following transplant. All three secondary endpoints demonstrated statistical significance in an intent-to-treat analysis.

Additionally, Gamida Cell reported that the exploratory endpoints in the study demonstrated a reduction in the cumulative incidence of viral infections.

The international, multi-center, randomized Phase 3 study for omidubicel was designed to evaluate the safety and efficacy of omidubicel in patients with hematologic malignancies undergoing allogeneic bone marrow transplant compared to a comparator group of patients who received a standard umbilical cord blood transplant.

The company anticipates reporting the full data set in a peer-reviewed setting in the first half of 2021.

Commercial Readiness

The company discussed the market potential for omidubicel and launch plans. These included quantifying the market opportunity and keys aspects for a successful launch.

As it prepares for the potential commercial launch of omidubicel, the company also announced plans for the Gamida Cell Assist program, which has been designed to focus on patient access and support of every individual and their caregiver at each step of the transplant process. Once the program is launched, the Gamida Cell Assist case management team would provide a consistent, single point of contact for patients and health care professionals. This team would work with the transplant center to track each individual patients omidubicel therapy and provide real-time updates on the status of the therapy. Gamida Cell Assist is also designed to provide additional services, including coverage and reimbursement support, and patient and caregiver support, which may include financial, travel, and lodging assistance.

At Gamida Cell we are inspired to cure, with the goal of pioneering new standards of care for patients with blood cancers and serious blood diseases, said Michele Korfin, chief operating and chief commercial officer of Gamida Cell. The transplant process can be challenging and complex for the patient, caregivers and the entire transplant care team. As we prepare for commercialization, we have developed Gamida Cell Assist to serve as a comprehensive support program to focus on assuring a positive patient experience with omidubicel. We are committed to supporting patients and their caregivers during every step of their journey and enabling what matters most, a successful clinical outcome that makes a meaningful difference for patients.

Update on Natural Killer Cell Therapy GDA-201

In an oral presentation at the recent American Society of Hematology (ASH) 62nd Annual Meeting, it was shown that GDA-201 was well tolerated and no dose limiting toxicities were observed in the Phase 1 clinical study. GDA-201 demonstrated significant clinical activity in patients with non-Hodgkin lymphoma, with 13 complete responses and one partial response observed in 19 patients, for a response rate of 74 percent. Full details of the presentation can be found in the press release.

Phase 2 Study of Omidubicel in Patients with Severe Aplastic Anemia

In a poster presentation at ASH, it was shown that patients with severe aplastic anemia treated with omidubicel achieved sustained early engraftment. These data, which were presented on December 5 by Mohamed Samour, M.D., Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, are the first evidence that omidubicel can result in rapid engraftment and can achieve sustained hematopoiesis in patients who are at high risk for graft failure with conventional umbilical cord blood transplant.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant solution for patients with hematologic malignancies (blood cancers). In both Phase 1/2 and Phase 3 clinical studies (NCT01816230, NCT02730299), omidubicel demonstrated rapid and durable time to engraftment and was generally well tolerated.12 Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit http://www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the U.S. Food and Drug Administration or any other health authority.

About GDA-201

Gamida Cell applied the capabilities of its NAM-based cell expansion technology to develop GDA-201, an innate natural killer (NK) cell immunotherapy for the treatment of hematologic and solid tumors in combination with standard of care antibody therapies. GDA-201 addresses key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs of NK cells expanded in culture. GDA-201 is in Phase 1 development through an investigator-sponsored study in patients with refractory non-Hodgkin lymphoma and multiple myeloma.3 For more information on the clinical study of GDA-201, please visit http://www.clinicaltrials.gov.

GDA-201 is an investigational therapy, and its safety and efficacy has not been established by the U.S. Food and Drug Administration or any other health authority.

About the NAM Therapeutic Platform

Gamida Cells proprietary NAM-based cell expansion platform is designed to enhance the number and functionality of donor cells in culture, enabling the creation of potentially transformative therapies that move beyond what is possible with existing approaches. The NAM therapeutic platform leverages the unique properties of nicotinamide to enable the expansion of multiple cell types including stem cells and natural killer (NK) cells with appropriate growth factors to maintain the cells' original phenotype and potency. This can enable the administration of a therapeutic dose of cells with the potential to improve patient outcomes.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to timing of initiation and progress of and data reported from the clinical trials of Gamida Cells product candidates, anticipated regulatory filings, launch readiness and FDA approval, commercialization efforts and Gamida Cells expectations regarding its projected ongoing operating activities, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Gamida Cells clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on February 26, 2020, its Reports on Form 6-K filed with the SEC on May 18, 2020, August 11, 2020 and November 10, 2020, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

______________________1 Horwitz M.E., Wease S., Blackwell B., Valcarcel D. et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol. 2019 Feb 10;37(5):367-374.2 Gamida Cell press release, Gamida Cell Announces Positive Topline Data from Phase 3 Clinical Study of Omidubicel in Patients with High-Risk Hematologic Malignancies, issued May 12, 2020. Last accessed August 31, 2020.3 Clinicaltrials.gov identifier NCT03019666

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Gamida Cell Provides Pipeline Update, Including Detailed Results of Pivotal Phase 3 Clinical Study of Omidubicel, and Prepares to Start BLA Submission...

GROUNDBREAKING trial using stem cells on children with acquired brain injuries to begin in Madrid

Three children with an acquired brain injury (ABI) are set to take part in a pioneering stem cell trial that aims to improve their quality of life. Three neurologists at the Nio Jess Hospital in Madrid, the only public hospital in the country which has a dedicated unit for children with ABI, have had real success in using stem cell therapy in adults.

One of the children taking part in the trial in February 2021 is ten-year-old Bruno, who suffered inflammation in the brain when he was four-and-a-half years old that led to him being diagnosed with locked-in syndrome.

The children will begin by receiving an infusion of stem cells through n=bone marrow, which Brunos father hopes will change his boys life.

The doctors are very cautious, they believe that it will give him quality of life and we are going to notice it a lot, he said.

El Nio Jess is the only hospital doing something for acquired brain damage. We are pioneers.And the dream is that this trial becomes a drug, said Brunos mom Macarena

________________________________________________________________________

Thank you for taking the time to read this news article Groundbreaking Trial On Children With Brain Injuries In Madrid. For more UK daily news, Spanish daily news and Global news stories, visit the Euro Weekly News home page.

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Groundbreaking Trial On Children With Brain Injuries In Madrid - Euro Weekly News

- Lower rates of non-relapse transplant related mortality, sepsis, infections, and mucositis reported in patients receiving Iomab-B compared to patients on the control arm receiving salvage therapies

- Iomab-B enables high amounts of radiation to be delivered to the bone marrow to achieve targeted myeloablation

NEW YORK, Dec. 7, 2020 /PRNewswire/ -- Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company") today announced that safety data from its ongoing pivotal Phase 3 SIERRA trial of Iomab-B in patients with relapsed or refractory Acute Myeloid Leukemia (R/R AML) were presented at the 2020 American Society of Hematology (ASH) annual meeting. The oral presentation highlighted Iomab-B's targeting ability and corresponding safety data from 110 patients from the SIERRA trial for which detailed safety data was available. Iomab-B targets CD45, an antigen expressed on leukemia and lymphoma cancer cells and immune cells including bone marrow stem cells but not cells outside of the blood forming or hematopoietic system. This allows high amounts of radiation to be delivered to the bone marrow via Iomab-B while sparing healthy organs. As a result, statistically significant lower rates of sepsis were reported as well as lower rates of febrile neutropenia, mucositis and non-relapse transplant related mortality in patients receiving Iomab-B and bone marrow transplant (BMT) compared to patients that received salvage therapy and a BMT. In addition, patients that crossed over to receive Iomab-B and went to BMT after receiving salvage therapy but not achieving a complete response also had lower rates of sepsis, febrile neutropenia, mucositis and non-relapse transplant related mortality.

Dr. Mark Berger, Actinium's Chief Medical Officer, commented, "We are pleased that the engraftment and safety profile of Iomab-B remains positive and consistent with prior interim safety results at 75% of patient enrollment in SIERRA and also consistent with the large body of historical data from Iomab-B. Collectively, this data gives excitement as we approach the upcoming ad hoc interim analysis for SIERRA that will be completed by year-end and the ultimate potential of Iomab-B for patients with R/R AML and other blood cancers as a targeted conditioning regimen."

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Safety data presented in ASH oral presentation are highlighted in the table below:

ASH Oral Presentation: High Doses of Targeted Radiation with Anti-CD45 Iodine (131I) Apamistamab [Iomab-B] Do Not Correlate with Incidence of Mucositis, Febrile Neutropenia or Sepsis in the Prospective, Randomized Phase 3 Sierra Trial for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Adverse Event

Received Iomab-B/HCT (N=47)1% (N)

No CR Crossed over to Iomab-B/HCT (N=30)2 % (N)

Achieved CR and received Std HCT (N=9) % (N)

Sepsis

4.3 (2)

22.2 (6)

33.3 (3)

Febrile Neutropenia Gr 3-4

34.8 (16)

40.7 (11)

55.6 (5)

Mucositis Gr 3-4

10.9 (5)

18.5 (5)

33.3 (3)

Day +100 Non-Relapse Mortality3

2/45

(4.4%)

3/26

(11.5%)

2/9

(22.2%)

1 Adverse Event data available for 46 of 47 evaluable patients

2 Adverse Event data available for 27 of 30 evaluable patients

3 Iomab-B arm: 4 patients unevaluable. Conventional Care Arm: 4 patients unevaluable

Patient Group

No. of Patients

Radiation dose delivered to the Marrow. Median (range)

Radiation dose to GI tract. Median (range)

Iomab-B

47

14.9 Gy

(4.6-32)

2.8 Gy

(1.6-6.7)

Vijay Reddy, Vice President, Clinical Development and Head of BMT, "The targeted nature of Iomab-B makes it highly differentiated from current BMT conditioning regimens that are largely comprised of non-targeted cytotoxic chemotherapies. These data from SIERRA showing higher rates of sepsis, neutropenia and mucositis in patients receiving chemotherapy are consistent with the literature and unfortunately what we expected but hope to address with Iomab-B. Particularly, chemotherapy's effect on the GI tract and resulting mucositis, which we believe is leading to the higher rates of sepsis seen in the control arm. We are highly encouraged by the lower rates of adverse events and the universal engraftment reported from SIERRA and excited for the potential of targeted conditioning could have an BMT access, patient outcomes and quality of life."

About Iomab-B

Iomab-B (I-131 apamistamab) via the monoclonal antibody apamistamab, targets CD45, an antigen widely expressed on leukemia and lymphoma cancer cells, B cells and stem cells. Apamistamab is linked to the radioisotope iodine-131 (I-131) and once attached to its target cells emits energy that travels about 100 cell lengths, destroying a patient's cancer cells and ablating their bone marrow. By carrying iodine-131 directly to the bone marrow in a targeted manner, Actinium believes Iomab-B will avoid the side effects of radiation on most healthy tissues while effectively killing the patient's cancer and marrow cells.

Iomab-B is currently being studied in the pivotal Phase 3 SIERRA (Study of Iomab-B in Relapsed or Refractory AML) trial, a 150-patient, randomized controlled clinical trial in patients with relapsed or refractory Acute Myeloid Leukemia (AML) who are age 55 and above. The SIERRA trial is being conducted at preeminent transplant centers in the U.S. with the primary endpoint of durable Complete Remission (dCR) at six months and a secondary endpoint of overall survival at one year. Upon approval, Iomab-B is intended to prepare and condition patients for a bone marrow transplant, also referred to as a hematopoietic stem cell transplant, in a potentially safer and more efficacious manner than the non-targeted intensive chemotherapy conditioning that is the current standard of care in bone marrow transplant conditioning. A bone marrow transplant is often considered the only potential cure for patients with certain blood-borne cancers and blood disorders. Additional information on the Company's Phase 3 clinical trial in R/R can be found at http://www.sierratrial.com.

About Actinium Pharmaceuticals, Inc. (NYSE: ATNM)

Actinium Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing ARCs or Antibody Radiation-Conjugates, which combine the targeting ability of antibodies with the cell killing ability of radiation. Actinium's lead application for our ARCs is targeted conditioning, which is intended to selectively deplete a patient's disease or cancer cells and certain immune cells prior to a BMT or Bone Marrow Transplant, Gene Therapy or Adoptive Cell Therapy (ACT) such as CAR-T to enable engraftment of these transplanted cells with minimal toxicities. With our ARC approach, we seek to improve patient outcomes and access to these potentially curative treatments by eliminating or reducing the non-targeted chemotherapy that is used for conditioning in standard practice currently. Our lead product candidate, I-131 apamistamab (Iomab-B) is being studied in the ongoing pivotal Phase 3 Study of Iomab-B in Elderly Relapsed or Refractory Acute Myeloid Leukemia (SIERRA) trial for BMT conditioning. The SIERRA trial is over seventy-five percent enrolled and positive single-agent, feasibility and safety data has been highlighted at ASH, TCT, ASCO and SOHO annual meetings. More information on this Phase 3 clinical trial can be found at http://www.sierratrial.com. I-131 apamistamab will also be studied as a targeted conditioning agent in a Phase 1 study with a CD19 CAR T-cell therapy and in a Phase 1/2 anti-HIV stem cell gene therapy with UC Davis. In addition, we are developing a multi-disease, multi-target pipeline of clinical-stage ARCs targeting the antigens CD45 and CD33 for targeted conditioning and as a therapeutic either in combination with other therapeutic modalities or as a single agent for patients with a broad range of hematologic malignancies including acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Ongoing combination trials include our CD33 alpha ARC, Actimab-A, in combination with the salvage chemotherapy CLAG-M and the Bcl-2 targeted therapy venetoclax. Underpinning our clinical programs is our proprietary AWE (Antibody Warhead Enabling) technology platform. This is where our intellectual property portfolio of over 130 patents, know-how, collective research and expertise in the field are being leveraged to construct and study novel ARCs and ARC combinations to bolster our pipeline for strategic purposes. Our AWE technology platform is currently being utilized in a collaborative research partnership with Astellas Pharma, Inc. Website: http://www.actiniumpharma.com

Forward-Looking Statements for Actinium Pharmaceuticals, Inc.

This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time.

Contacts:

Investors:Clayton Robertson Actinium Pharmaceuticals, Inc. crobertson@actiniumpharma.com

Hans Vitzthum LifeSci Advisors, LLCHans@LifeSciAdvisors.com(617) 430-7578

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SOURCE Actinium Pharmaceuticals, Inc.

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Actinium Highlights Iomab-B Safety Data Presented at the 62nd American Society of Hematology Annual Meeting - Yahoo Finance

Flotetuzumab was found to demonstrate antileukemic activity in patients with primary induction failure (PIF) and early-relapse acute myeloid leukemia (ER-AML), and the treatment appears tolerable with infrequent neurologic adverse events, according to results from an updated analysis of an ongoing open-label phase 1/2 study (ClinicalTrials.gov Identifier: NCT02152956). The preliminary findings were presented by Ibrahim Aldoss, MD, of the Gehr Family Center for Leukemia Research at City of Hope in Duarte, California, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

CD123 is overexpressed on AML cells, including leukemia stem cells, as well as other hematological malignancies, said Dr Aldoss. Flotetuzumab is a humanized CD3 x CD123 bispecific T-cell engager that redirects T cells to kill tumor cells expressing CD123.

The open-label, single-arm, multicenter, phase 1/2 study previously identified the recommended phase 2 dosage of flotetuzumab as 500 ng/kg/d administered via continuous infusion in 28-day cycles following a step-up lead-in dose administered during cycle 1 in week 1 of treatment. The primary objective of the study was to assess safety and antileukemic activity of flotetuzumab in patients with PIF/ER-AML.

A total of 44 patients (PIF, n= 27; ER-AML, n=17) were included in the study. Median patient age was 63.5 years (range, 28.0-81.0), and most patient were men (70.5%). According to the European LeukemiaNet (ELN) 2017 risk stratification criteria, the majority of patients had nonfavorable risk (97.7%).

Evidence of antileukemic activity was documented in 59.1% of patients, with a median decrease of 81.0% in bone marrow blasts. Median time to first response was 1 cycle (range, 1-3).

The combined complete response rate (CR, <5% bone marrow blast) and CR with partial hematologic recovery (CRh) was 25.0% (PIF, 33.3%; ER-AML, 11.8%) and 31.8% when including CR with incomplete hematologic recovery (CRi). Among the 14 patients with CR/CRh/CRi, 8 patients subsequently underwent stem cell transplantation.

In addition, morphologic leukemia-free state was reported in 3 patients (PIF, n=1; ER-AML, n=2). Of the 10 patients with TP53 mutation, 5 were reported to have CRR/CRh/CRi, and 3 of those patients (60.0%) underwent stem cell transplantation.

For all patients who achieved CR/CRh/CRi, median duration of response was 8.13 months, and median overall survival was 10.7 months.

Cytokine release syndrome (CRS), the most frequently reported treatment-related adverse event, occurred in 100% of patients (n=44; all grade). One grade 3 CRS event occurred. Approximately half of CRS events (52%) occurred during step-up dosing in the first week of treatment, and the incidence of CRS progressively decreased over time.

Neurologic adverse events were reported as infrequent and of mild to moderate severity (all-grade headache, n=13; 29.5%). Neurologic treatment-related adverse events of grade 3 or more were confusional state (n=3) and dizziness (n=1).

Flotetuzumab demonstrated encouraging activity in patients with primary induction failure in early-relapse AML, a population with poor prognosis and high unmet medical need, Dr Aldoss concluded.

The study (ClinicalTrials.gov Identifier: NCT02152956) is currently enrolling patients.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Read more ofHematology Advisorscoverage of the ASH 2020 meeting by visiting theconference page.

Aldoss I, Uy G, Vey N, et al. Flotetuzumab as salvage therapy for primary induction failure and early relapse acute myeloid leukemia. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract 331.

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Antileukemic Activity Seen With Flotetuzumab in Primary Induction Failure, Early-Relapse AML - Hematology Advisor

Korean medical professionals have discovered a method to resolve postoperative complications of hematopoietic stem cell transplants (HSCT).

A team of researchers from Seoul National University Hospital (SNUH) said Monday that they had found a solution to prevent HSCT complications by effectively producing T lymphocytes progenitor-T cells (T cells hereafter) from HSCs.

The team said if a patient with a blood tumor receives T-cells with HSCT, it can reduce the fatal infection that may occur after transplantation.

This is because T-cells prevent various viral infections by attacking and destroying cancer cells. It is differentiated in the HSCT and developed through T-precursor cells in the thymus.

HSCT is a treatment transplanting healthy HSCs after removing cancer and HSCs from blood cancer patients. It is effective and important in curing various types of blood cancer, including bone marrow failure syndromes.

However, this method has a high risk of complications and can only be applied to some patients. Also, the lack of development of T-cells causes fatal complications, such as cytomegalovirus infections, even causing death.

The research team, led by Professor Shin Dong-yeop of the Department of Hematology-Oncology at the hospital, has successfully produced T cells from HSCs.

They extracted cord blood HSCs at high purity and created an artificial thymic organoid (ATO) culture using recombinant proteins and cytokines from humans. They focused on this idea, excluding the method which uses mice-derived proteins because it did not apply to humans.

As a result, they found that T cells increased more effectively by combining a low oxygen environment's physiological conditions. The phenomenon has been confirmed in multiple amounts by the leading antioxidant agent, ascorbic acid (vitamin C).

After 200 trials, we have found a method to cultivate progenitor T cells. This will improve therapeutic performance for patients who need transplants, and contribute to enhancing the T-cell therapy, which is developing at a fast rate, researchers said.

The results were published in Stem Cells, an international stem cell journal.

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SNUH finds way to produce T-cells to prevent HSCT complications - Korea Biomedical Review

NHS England is to grant immediate access to AstraZenecas cancer drug Calquence (acalabrutinib) for certain patients with chronic lymphocytic leukaemia (CLL) after NICE backed it in first draft recommendations.

NICE recommended regular NHS funding for Calquence in CLL who are considered high-risk due to 17p deletion or TP53 mutations.

It is also recommended for adults with CLL who have had at least one previous treatment and only if AbbVie and Janssens class rival Imbruvica (ibrutinib) is their only suitable treatment option.

NHS England is granting access via an interim funding arrangement with AstraZeneca, which will end 30 days after publication of positive final guidance, after which treatment will be funded by routine commissioning budgets.

However the guidance has rejected Calquence for a third group of patients with untreated, non-high risk CLL who are unsuitable for treatment with chemotherapy.

AZ said it will provide further data analyses for continued discussions with NICE about this group of patients.

Calquence was approved in CLL by the EMA last month as monotherapy or in combination with Roches Gazyvaro (obinutuzumab).

In CLL, too many blood stem cells in the bone marrow become abnormal white blood cells, and these have difficulty in fighting infections.

As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets. This could result in anaemia, infection, and bleeding.

B-cell receptor signalling through Brutons tyrosine kinase (BTK) is one of the essential growth pathways for CLL.

In B-cells, BTK signalling results in the activation of pathways necessary for growth: proliferation, trafficking, chemotaxis, and adhesion.

Calquence binds selectively to BTK, inhibiting its activity.

This is the second recommendation of a therapy for CLL in the space of a month in November it recommended AbbVie/Roches chemotherapy-free option of Venclyxto (venetoclax) and Gazyva.

NICEs decision allows for a 12-month fixed duration treatment option based on data from the phase 3 CLL14 trial.

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CLL patients in England to get AZ's Calquence after okay from NICE - - pharmaphorum

A new clinical trial offers the most compelling evidence to date that a donor stem cell transplant can improve survival rates for older patients with higher-risk myelodysplastic syndrome (MDS), Dana-Farber Cancer Institute investigators report at the virtual 62nd American Society of Hematology (ASH) Annual Meeting.

Despite being the only current cure for MDS and widely used for younger patients, transplant generally hasnt been offered to older patients because it has not been proven beneficial in that population. The new trial, conducted by the Blood and Marrow Transplant Clinical Trials Network, is likely to change that, according to study leaders. Involving 384 patients at 34 medical centers across the U.S., the trial found that transplantation of hematopoietic stem cells from compatible donors nearly doubled the survival rate of patients age 50-75.

Transplantation has been underutilized, historically, in this patient group, said study senior author Corey Cutler, MD, MPH, FRCPC, of Dana-Farber. Based on our findings all patients should at least be referred to a transplant center so that those who are eligible and have a suitable donor can undergo transplant and have better survival. It is important to refer these patients early so the transplant center can work on finding an optimal donor right from the get-go.

MDS encompasses a group of disorders in which blood-forming cells in the bone marrow become abnormal, resulting in the production of defective blood cells. In about one in three patients, MDS can progress to acute myeloid leukemia, a rapidly growing cancer of bone marrow cells.

Allogeneic hematopoietic stem cell transplantation replaces a patients abnormal blood-forming stem cells with healthy ones from a compatible donor. Because the procedure hadnt been proven to be helpful for older patients, it hasnt been covered by Medicare for people over age 65 unless done as part of an approved study. Medicare approved the design of the trial and is expected to consider the findings when determining future payment policies.

Participants in the new trial were referred to transplant centers, which searched for suitable stem cell donors. The 260 patients who were matched with a donor within 90 days were assigned to receive a stem cell transplant; the other 124 patients received standard supportive care.

Roughly three years after enrolling in the trial, 47.9% of those slated for transplant were alive, compared to 26.6% of those for whom no donor had been found at the 90-day mark. Survival without a recurrence of leukemia was also higher in those assigned to receive a transplant (35.8%) than in those who were not (20.6%). The researchers observed no significant differences among subgroups and no differences in quality of life between the two study arms.

Cutlerpresented findings on this study at the Whats on the Horizon: Practice-Changing Clinical Trials press briefing on Friday, Dec. 4 at 12:30 p.m. EST. Further details were presented during Session 732, Abstract 75, on Saturday, Dec. 5 at 10:30 a.m. EST.

Cutlers disclosures include a consulting or advisory role for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte.

Complete details on Dana-Farbers activities at ASH are available online at http://www.dana-farber.org/ash.

This press releasewas originally published on December 4, 2020, by Dana-Farber Cancer Institute. It is republished with permission.

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Donor Stem Cell Transplant Improves Survival in Older Patients with Myelodysplastic Syndrome - Cancer Health Treatment News

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CAPE TOWN - International cricketer JP Duminy has his sights set on raising R400 000 in conjunction with the South African Bone Marrow Registry (SABMR) the figure thats still needed this year for them to match donors with patients suffering from life-threatening blood disorders who cant afford it.

Alicia Venter, Head of Patient Services at the SABMR says for many who dont have medical aid, the costs associated with finding a donor are a barrier to getting the life-saving treatment they need.

These costs include the search for an unrelated donor match in cases where no suitably matched donors are found among family members, testing and verification, the procurement and transportation of stem cells (from anywhere in the world), as well as travel and accommodation of the donor should the collection centre be far from home. Costs related to bone marrow stem cell transplants from international donors are more than double that of local donors.

Our Patient Assistance Programme is available to patients who are unable to obtain adequate funds for the treatment or in cases where their medical aid doesnt cover donor searches, despite appeal, explains Venter.

The SABMRs Give a Little Save a Life campaign, which kicks off on 10 December is being steered by Duminy, who is a long-time ambassador for the registry.

The Covid-19 pandemic has resulted in all the SABMRs events being cancelled, which usually brings in the bulk of the funds annually for the Patient Assistance Programme.

Right now, there are two young South Africans awaiting bone marrow stem cell transplants, whose families cant afford the cost of finding a donor.

One is a 6-year-old boy from Gauteng who has been diagnosed with Acute Lymphocytic Leukaemia and the other a 19-year-old girl from the Free State who has Acute Myeloid Leukaemia.

Their only hope of survival is a stem cell transplant. By rallying together, we can raise the funds to make it a reality and give them the second chance they deserve. In my life, Ive experienced many exhilarating moments both on and off the field and wish the same for these two young patients and others who are in a similar position. If you have the means to give, even if its just R50, youll never regret it.

At any given time, there are more than 200 patients in SA that need a bone marrow transplant unfortunately, many of whom cant afford it. While its been a tough year with very little funding coming in, the SABMR managed to redirect funds from its own reserves toward the programme.

This has helped to cover some of the key costs associated with finding suitably matched unrelated donors for eight patients.

Kamiel Singh, Head of Sustainability at the SABMR says while this years Give a Little Save a Life campaign will be solely online, he hopes it will galvanise a new generation of social media-savvy fundraisers that will support the SABMRs efforts.

Social media enables people to engage with each other and healthcare in ways that were almost unimaginable a decade ago. By combining the power of social media and sporting heroes such as JP Duminy, we hope to raise enough funds to make a real difference to the lives of hundreds of patients suffering from blood disorders in the coming year, says Singh.

Donations toward the registrys Patient Assistance Programme can be made via:

https://www.backabuddy.co.za/sabmrgivealittle and http://www.sabmr.co.za where there are various payment options available.

The SABMRs Give a Little Save a Life campaign can be followed on the following social media platforms: Facebook Twitter and Instagram

@IOLSport

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JP Duminy goes to bat for the SA Bone Marrow Registry - IOL

DUARTE, Calif.--(BUSINESS WIRE)--City of Hope doctors participated in research presented at the American Society of Hematology (ASH) virtual meeting, Dec. 5 to 8, that are helping advance the treatment of blood cancers, including one study which demonstrated allogeneic stem cell transplants do have a survival benefit for older adults with myelodysplastic syndromes (MDS) compared with current standard of care.

The study is the largest and most definitive trial to demonstrate the benefits of an allogeneic stem cell transplantation for older adults with MDS, and is just one of numerous studies that City of Hope doctors help lead with the aim of finding more effective treatments of various blood cancers.

This years ASH conference truly showcases City of Hopes leadership in finding more effective treatments for blood cancers, said Stephen J. Forman, M.D., director of City of Hopes Hematologic Malignancies Research Institute. Whether its finding innovative treatments to make it possible for more older adults with cancer to receive stem cell transplants, or pursuing therapies that are more effective with fewer side effects, City of Hope doctors continue to lead innovative research in blood cancers and other hematological malignancies.

City of Hope doctors are leading novel clinical trials for patients with leukemia, lymphoma and other blood cancers.

Multicenter clinical trial led by City of Hope makes stem cell transplant possible for older adults with myelodysplastic syndromes

Allogeneic hematopoietic cell transplantation, or stem cell/bone marrow transplants, for blood cancers that have recurred or are difficult to treat can put the disease into long-term remission and provide a potential cure. The therapy establishes a new, disease-free blood and immune system by transplanting healthy blood stem cells from a donor into a cancer patient after destroying the patients unhealthy bone marrow.

City of Hope and other institutions started this therapy in 1976, primarily for younger patients with blood cancers. The therapy involves using high-dose chemotherapy and/or radiotherapy to make room for a person to receive new stem cells; serious side effects can also occur after transplant. Because of these and other considerations, for many years, older adults with blood cancers have not been considered for transplants.

City of Hope has been leading the way to make transplants possible for more older adults with various cancers.

A new study presented at ASH demonstrates transplants are now a possibility and beneficial for patients with myelodysplastic syndromes (MDS). Approximately 13,000 people in the United States each year are diagnosed with MDS, an umbrella term describing several blood disorders that begin in the bone marrow.

Co-led by City of Hopes Ryotaro Nakamura, M.D., director of City of Hopes Center for Stem Cell Transplantation, the study is the largest and first trial to demonstrate the benefits of an allogeneic stem cell transplantation for older adults with MDS as opposed to the standard of care currently provided to these patients. The multicenter trial for patients aged 50 to 75 with serious MDS compared how long transplant patients survived with those who didnt receive a transplant, as well as disease progression and quality of life. The transplant therapy used reduced-intensity conditioning, which delivers less chemotherapy and radiation before transplant and relies more on the anti-tumor effects of the therapy.

Between 2014 and 2018, the study enrolled 384 participants at 34 cancer centers nationwide. It included 260 patients who were able to find a donor for a transplant, as well as 124 patients who did not find a donor for a transplant.

After three years, nearly 48% of MDS patients who found a donor for transplant had survived compared with about 27% of those patients who didnt have a donor for transplant and received current hypomethylating therapy, a type of chemotherapy that is current standard of care for MDS. Leukemia-free survival which is relevant because myelodysplastic syndrome can develop into leukemia was also greater in transplant recipients after three years nearly 36% compared with about 21% for those who did not have a transplant.

There was a large and significant improvement in survival for patients who had a transplant, Nakamura said. The benefit margin in overall survival was over 20% (21.3%) for patients who had a transplant.

In addition, quality of life was the same for both transplant and nontransplant patients. There were no clinically significant differences when taking such measurements as physical and mental competency scores.

This is an extremely exciting study because it provides evidence that stem cell transplant is highly beneficial for older patients with serious MDS and will likely be practice-changing for this group, Nakamura said. Before, many doctors wouldnt even consider a transplant for this group of patients, but our study demonstrates that these patients should be evaluated for a transplant, which could potentially provide a cure for their disease.

The trial is part of Blood and Marrow Transplant Clinical Trials Network, which was established with support from the National Heart, Lung, and Blood Institute and National Cancer Institute, because of a critical need for multi-institutional clinical trials focused directly on improving survival for patients undergoing hematopoietic cell transplantation.

Updated results from a study of a potential new CAR T cell therapy, liso-cel, for relapsed/refractory chronic lymphocytic leukemia

Patients with relapsed or difficult-to-treat chronic lymphocytic leukemia/small lymphocytic leukemia continue to do well 24 months after receiving lisocabtagene maraleucel (liso-cel) chimeric antigen receptor (CAR) T cells, according to Tanya Siddiqi, M.D., director of City of Hopes Chronic Lymphocytic Leukemia (CLL) Program, which is part of the Toni Stephenson Lymphoma Center. She presented these findings during the 2020 ASH annual meeting virtual conference.

Overall, 23 and 22 patients were evaluated for safety and efficacy in this phase 1 trial, respectively. Their median age was 66 and they had received a median of four prior therapies; all patients had received prior ibrutinib, which is one of the standard of care drugs for CLL.

The overall response rate, or patients whose CLL diminished after liso-cel CAR T cell therapy, was 82%, and 45% of patients also had complete responses, or remissions.

After 15 months of treatment, 53% of patients maintained their responses to the therapy, and six patients continued to be in remission. After 18 months, 50% of patients maintained their response, and there were five remissions. All seven patients who completed the 24-month study maintained their response. Median progression-free survival, or the amount of time the cancer did not worsen during and after treatment, was 18 months.

As early as 30 days after receiving liso-cel, about 75% of 20 patients evaluated for the therapys efficacy had undetectable minimal residual disease (MRD, or no detectable traces of cancer) in the blood and 65% had undetectable MRD in the marrow.

These are remarkable results for a group of patients that prior to this CAR T treatment had no good treatment options if they had already progressed on novel targeted therapies like ibrutinib and venetoclax, Siddiqi said. Liso-cel is providing new hope for CLL patients, and the remissions are also long lasting with few serious side effects.

Because of its safety and effectiveness in clinical trials, liso-cel, which targets the CD19 protein on cancer cells, may soon receive approval from the Food and Drug Administration as a commercial therapy for relapsed or refractory B cell lymphoma. City of Hope is also taking part in the phase 2 trial of liso-cel in CLL patients.

Consolidation treatment with brentuximab vedotin/nivolumab after auto stem cell transplant for relapsed/refractory Hodgkin lymphoma patients leads to 18-month progression free-survival

Patients who have Hodgkin lymphoma that has not been cured by initial treatment will usually receive more chemotherapy and an autologous hematopoietic cell transplant. But even after a stem cell transplant, recurrence of the lymphoma is possible.

This multicenter phase 2 clinical trial, led by City of Hope, examined whether treating patients with brentuximab vedotin (BV), an antibody-based treatment that targets delivery of chemotherapy only to Hodgkin lymphoma cells, and nivolumab, which works by blocking the PD-1 immune checkpoint pathway that Hodgkin lymphoma hijacks to evade the immune system, was safe and effective as consolidation to prevent disease recurrence after transplant in patients with high-risk Hodgkin lymphoma.

Alex Herrera, M.D., assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, discussed 19-month progression-free survival for trial participants, as well as overall survival, safety and response rates during ASH.

Fifty-nine patients were enrolled in the trial. Patients received the consolidation treatment starting a median of 54 days after transplant, and received a median of eight cycles of the therapy. The 19-month progression-free survival in patients was 92%, and overall survival in patients was 98%. Only three patients relapsed after receiving BV and nivolumab consolidation after transplant, and one patient passed away due to PCP pneumonia unrelated to the study treatment.

The most common sides effects related to the treatment were peripheral neuropathy (51%), neutropenia (42%), fatigue (37%) and diarrhea (29%).

Using brentuximab vedotin and nivolumab after transplant is a promising approach for preventing relapse of Hodgkin lymphoma after transplant that merits further study, Herrera said.

City of Hope doctors published research on innovative approaches against graft-versus-host-disease

Historically, a bone marrow/stem cell transplant is more likely to be effective if patients have a donor who is a 100% match, or as close to that as possible. Finding that perfect match is more difficult for African Americans, Latinos, Asian Americans and other ethnic groups as bone marrow donor registries are still trying to increase the number of non-white donors.

Transplant doctors are also looking for ways to make the transplant more effective if a perfect match cant be found; donors who are not a 100% or close match are referred to as mismatched unrelated. One major barrier to these transplants being effective is a condition known as graft-versus-host-disease (GVHD). The condition, which is more common in transplants involving mismatched donors, is caused by donated cells that recognize the recipient's cells as foreign and attack them, damaging the skin, eyes, lungs, liver and digestive tract.

In order to help prevent GVHD, therapies can be given to patients after transplant. A prospective clinical trial at City of Hope examined whether using cyclophosphamide after an infusion of stem cells could prevent GVHD.

Thirty-eight patients were enrolled in the trial, which is the first to examine the use of cyclophosphamide in transplants with a mismatched unrelated donor.

With a median follow-up period of 18 months, 87% of patients had survived, and the majority did not relapse or develop severe GVHD.

During the first 100 days post-transplant, acute GVHD incidence was around 50%; most cases were mild to moderate while severe GVHD was only 15%. A year after transplant, 52% of patients had some form of chronic GVHD, but only 3% had moderate or severe chronic GVHD.

The trial also examined toxicities, infections and immune system recovery after the transplant.

Our study showed that patients who received a transplant from a mismatched unrelated donor using post-transplant cyclophosphamide had a comparable outcome to what we see in matched donor transplants with few cases of serious GVHD cases, said Monzr Al Malki, M.D., associate clinical professor of City of Hopes Department of Hematology & Hematopoietic Cell Transplantation and director of unrelated donor BMT and haploidentical transplant programs. Our data support further development of this therapy in transplant patients who would otherwise have no suitable donors and limited treatment options.

City of Hopes Anthony Stein, M.D., also led a pilot trial that examined whether a new treatment approach may reduce the rate of GVHD in patients with acute myelogenous leukemia (AML) who have received an allogeneic hematopoietic cell transplant. Although a transplant can put AML into remission, GVHD remains the main serious complication after transplant, impacting a patients quality of life and increasing health care costs.

Eighteen patients between the ages of 18 and 60 enrolled in the trial. Each patient received a novel conditioning regimen of total marrow and lymphoid irradiation, which targets a patients marrow and lymph nodes while reducing radiation to other parts of the body, and cyclophosphamide, a therapy that suppresses the immune system. Tacrolimus was also provided to patients.

Radiation was delivered twice daily on the fourth day before transplant and on the day of transplant without chemotherapy. Cyclophosphamide was given to patients on the third and fourth day after transplant.

There were mild to moderate toxicities. Acute GVHD developed in two patients and only one patient developed the most serious GVHD. Five patients developed mild chronic GVHD. Nearly 60% of patients had not developed GVHD or the condition had not worsened after a year.

After a year, all patients had survived, and 83% had not relapsed. After two years, nearly 86% of patients had survived, and the relapse number remained the same.

The therapeutic approach did not interfere with the transplant process as all patients engrafted, or the donors cells started to produce bone marrow and immune cells.

This is welcome news for AML patients who receive an allogeneic transplant and are concerned about developing GVHD, said Stein, associate director of City of Hope's Gehr Family Center for Leukemia Research. Our study demonstrated that using this new combination of therapies is safe and feasible and does not interfere with the engraftment process.

In addition, after a year, patients in this trial were no longer taking immunosuppressive therapy and had an improved quality of life, Stein said. He added that because many of the patients didnt have GVHD, health care costs after a year were also lower than if patients required treatment for the condition.

City of Hope now plans to start a larger phase 2 trial using this treatment approach.

Bispecific antibodies continue to show promise against blood cancers

Mosunetuzumab is a promising new immunotherapy for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) that recently received breakthrough therapy designation from the Food and Drug Administration. The designation is intended to expedite the development and review of drugs for serious or life-threatening diseases.

Elizabeth Budde, M.D., Ph.D., assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, is leading clinical trials that are showing how well mosunetuzumab works against NHL. At this years ASH, one trial discussed is how the therapy is working for patients with follicular lymphoma.

Mosunetuzumab is a bispecific antibody targeting both CD3 (a protein found on the surface on T cells) and CD20 on the surface of B cells. The therapy redirects T cells to engage and eliminate malignant B cells.

Sixty-two patients, ranging in age from 27 to 85 years old, were enrolled in the trial for follicular lymphoma. They received intravenous doses of mosunetuzumab.

Sixty-eight percent of the patients responded to the therapy, and 50% had a complete response, or went into remission. Consistent complete response rates occurred even in patients with double refractory disease and patients who received prior CAR T cell therapy. Median duration of response was approximately 20 months, and media progression free survival was nearly one year.

Side effects were reported in 60 patients with serious adverse effects in 22 patients. The most frequently reported serious side effects were hypophosphatemia, an electrolyte disorder, and neutropenia, a condition caused by low numbers of white blood cells. Fourteen patients experienced cytokine release syndrome, but none required extensive treatment for it.

Neurological side effects included headache, insomnia and dizziness.

Patients in this trial had high response rates and their disease remained in control for a year, Budde said. This is remarkable because many patients were no longer responding to other therapies.

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hopes translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope has been ranked among the nations Best Hospitals in cancer by U.S. News & World Report for 14 consecutive years. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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City of Hope Doctors Present Innovative Therapies to Better Treat Blood Cancers at American Society of Hematology Virtual Conference - Business Wire

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced clinical data from its ongoing multicenter Phase 1 clinical trial of JSP191, a first-in-class anti-CD117 monoclonal antibody, in patients with severe combined immune deficiency (SCID). The trial is evaluating JSP191 as a conditioning agent to enable stem cell transplantation in patients with SCID who are either transplant-naive or who received a prior stem cell transplant with a poor outcome.

Data from the first transplant-nave SCID patient in the Phase 1 trial, a 6-month-old infant, showed that a single dose of JSP191 administered prior to stem cell transplant was effective in establishing sustained donor chimerism followed by development of B, T and NK immune cells. No treatment-related adverse events were reported. The data were presented by primary investigator Rajni Agrawal-Hashmi, M.D., of Stanford University, at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition.

We have previously shown that JSP191 can be successfully used as a single conditioning agent in SCID patients who had failed a previous transplant, said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. This new data presented at ASH 2020 showing success in an infant with SCID undergoing a first transplant provides proof of concept of the safety and efficacy of the use of JSP191 as an alternative to genotoxic chemotherapies currently used to deplete stem cells prior to transplant.

Hematopoietic cell transplantation offers the only curative therapy for SCID, a severe genetic immune disorder that leaves patients without a functioning immune system. With this approach, standard-of-care chemotherapeutic conditioning regimens are given prior to transplant to reduce the number of blood stem cells in the bone marrow to make space for donor blood stem cells to engraft and cure the patient. JSP191 is designed to replace the need for chemotherapeutic conditioning agents, which are DNA-damaging and highly toxic.

Dr. Heller added, With our Phase 1 trials in SCID and hematologic disorders underway, we are planning to expand the development of JSP191 into additional indications, such as gene therapies, autoimmune diseases, Fanconis anemia and other rare disorders that can be cured by stem cell transplant.

The open-label, multicenter Phase 1 study is evaluating the safety, tolerability and efficacy of JSP191 as a conditioning agent in patients with SCID undergoing first or repeat hematopoietic cell transplantation. Up to three different doses of JSP191 are being assessed for dose-limiting toxicities. The trial is currently open for enrollment at Stanford University, the University of California, San Francisco, Memorial Sloan Kettering Cancer Center, the University of California, Los Angeles, and Cincinnati Childrens Hospital. Additional clinical trial sites in the United States will initiate enrollment in the coming weeks.

About SCID

Severe combined immune deficiency (SCID) is a group of rare disorders caused by mutations in genes involved in the development and function of infection-fighting immune cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections. The condition is fatal, usually within the first year or two of life, unless infants receive immune-restoring treatments, such as transplants of blood-forming stem cells, gene therapy or enzyme therapy.

About JSP191

JSP191 (formerly AMG 191) is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow. JSP191 binds to human CD117, a receptor for stem cell factor (SCF) that is expressed on the surface of hematopoietic stem and progenitor cells. The interaction of SCF and CD117 is required for stem cells to survive. JSP191 blocks SCF from binding to CD117 and disrupts critical survival signals, causing the stem cells to undergo cell death and creating an empty space in the bone marrow for donor or gene-corrected transplanted stem cells to engraft.

Preclinical studies have shown that JSP191 as a single agent safely depletes normal and diseased hematopoietic stem cells, including in animal models of SCID, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Treatment with JSP191 creates the space needed for transplanted normal donor or gene-corrected hematopoietic stem cells to successfully engraft in the host bone marrow. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients.

JSP191 is currently being evaluated as a sole conditioning agent in a Phase 1/2 dose-escalation and expansion trial to achieve donor stem cell engraftment in patients undergoing hematopoietic cell transplant for severe combined immunodeficiency (SCID), which is potentially curable only by this type of treatment. JSP191 is also being evaluated in a Phase 1 study in patients with MDS or acute myeloid leukemia (AML) who are receiving hematopoietic cell transplant. For more information about the design of these clinical trials, visit http://www.clinicaltrials.gov (NCT02963064 and NCT04429191). Additional studies are planned to advance JSP191 as a conditioning agent for patients with other rare and ultra-rare monogenic disorders and autoimmune diseases.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The companys lead compound, JSP191, is in clinical development as a conditioning antibody that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplant. This first-in-class conditioning antibody is designed to enable safer and more effective curative hematopoietic cell transplants and gene therapies. For more information, please visit us at jaspertherapeutics.com.

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Jasper Therapeutics Announces Data from First Transplant-naive Patient in Phase 1 Clinical Trial of JSP191 as Conditioning Agent in Patients with SCID...

A FORMER hairdresser from Bournemouth is appealing for people to help raise money to have life-saving surgery in Mexico to get rid of her Multiple Sclerosis once and for all.

Having been admitted to Royal Bournemouth Hospital for a suspected stroke or brain tumour in March 2017, at the age of 47, Kirsten Hannibal was found to have multiple lesions on her brain and was diagnosed with CIS which later progressed to MS.

During lockdown, Kirsten has researched into different ways to stop Multiple Sclerosis dead in its tracks, one of them being Hematopoietic Stem Cell Transplantation.

Although the procedure, which involves the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, is not widely accessible in the UK, it is available in Mexico, considered a world class hub for HSCT.

However she must raise over 40,000 to cover flights to Mexico as well as the cost of the procedure.

Vicky Dixon has set up a crowdfunding page to raise money for Kirstens medical procedure.

In a statement written on her crowdfunding page, she said: Our family are joining forces to raise the money needed to send our Kirsten to Mexico for Hematopoietic Stem Cell Transplantation treatment that is not universally available on the NHS, but will hopefully give Kirsten a chance of a future; a life free of pain, disability and heart breaking challenges.

We hope that Kirsten can follow the footsteps of other British MS sufferers and go to Mexico, a world class centre for HSCT, and cheaper than the UK, at the cost of 43,500.

The first large, randomised control trial, and several meta-analyses of HSCT, have confirmed that HSCT is a very effective therapy. This is now tipping the scales for HSCT becoming a mainstream treatment for MS in Britain.

However, the treatment has to take place before the MS becomes too advanced, and as it will be years before HSCT might be offered more widely, Kirsten would by then be swallowed up by the MS and not a suitable candidate for treatment.

Kirsten is on the brink of becoming too disabled for this treatment, hence the urgency of our appeal.

Sadly, the 46-year-old is now travelling a path similar to one her family have walked before.

In 1984 her mother at the age of 32 was diagnosed with lymphoblastic leukaemia and the Echo covered the story.

Her mother underwent aggressive chemotherapy and was the receiver of a ground-breaking treatment with a bone marrow transplant.

She was the first patient to receive this treatment in the south and, whilst the treatment was deemed a success, sadly her mother died.

Lynda Smiths legacy lives on because her bravery in allowing this treatment to take place is now the lifeline to many children and adults alike who survive leukaemia.

The treatment Kirsten is looking to have is similar to her mothers treatment, except it would be her own bone marrow that would be harvested. She will then be given chemotherapy and then the day Kirsten longs for, freedom from the disease.

The new birthday she dreams of is a stem cell birthday celebrated when the bone marrow is put back into her body giving her the chance of stopping Multiple Sclerosis.

So far, Kirstens fundraising appeal has raised 4,535, just over 10 per cent of her target.

To donate, visit https://www.gofundme.com/f/multiple-sclerosis-and-an-urgent-bid-for-freedom?utm_source=customer&utm_medium=email&utm_campaign=p_cp+sharesheet.

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Bid to fund stem cell treatment in Mexico for woman with MS - Bournemouth Echo