NEWARK, Calif., Nov. 04, 2022 (GLOBE NEWSWIRE) -- CymaBay Therapeutics, Inc. (NASDAQ: CBAY), a biopharmaceutical company focused on developing and providing access to innovative therapies for patients with liver and other chronic diseases, today announced encouraging seladelpar data in patients with primary biliary cholangitis (PBC) that are being presented at The Liver Meeting® of the American Association for the Study of Liver Diseases (AASLD), in Washington, DC (November 4th – 8th).

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CymaBay Therapeutics Presents Additional Analyses from Clinical Studies of Seladelpar for Patients with Primary Biliary Cholangitis at The Liver...

IPS Cell Therapy Comments Off on CymaBay Therapeutics Presents Additional Analyses from Clinical Studies of Seladelpar for Patients with Primary Biliary Cholangitis at The Liver… | November 6th, 2022

Late-breaking abstract one of nine abstracts selected by SITC Communications Committee to be showcased at the SITC 2022 Press Conference

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Immutep Announces Abstract Highlighting Eftilagimod Alpha Selected for SITC 2022 Annual Meeting Press Conference

IPS Cell Therapy Comments Off on Immutep Announces Abstract Highlighting Eftilagimod Alpha Selected for SITC 2022 Annual Meeting Press Conference | November 6th, 2022

Six-month outcomes are expected in second quarter of 2023 Six-month outcomes are expected in second quarter of 2023

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Osteal Therapeutics, Inc. Completes Enrollment in APEX Phase 2 Clinical Trial of VT-X7 for Periprosthetic Joint Infection

IPS Cell Therapy Comments Off on Osteal Therapeutics, Inc. Completes Enrollment in APEX Phase 2 Clinical Trial of VT-X7 for Periprosthetic Joint Infection | November 6th, 2022

MADRID, Spain and BOSTON, Nov. 04, 2022 (GLOBE NEWSWIRE) -- Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that its management will give an update on corporate progress at several international events in November.

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ORYZON to Give Updates on Corporate Progress in November

IPS Cell Therapy Comments Off on ORYZON to Give Updates on Corporate Progress in November | November 6th, 2022

CRANBURY, N.J., Nov. 04, 2022 (GLOBE NEWSWIRE) -- PMV Pharmaceuticals, Inc. (Nasdaq: PMVP), a precision oncology company pioneering the discovery and development of small molecule, tumor-agnostic therapies targeting p53, today announced the appointment of Carol Gallagher, Pharm.D., to its Board of Directors. Dr. Gallagher brings more than 30 years of biotech leadership and expertise in drug development and commercialization. She replaces Thilo Schroeder, Ph.D., who is stepping down from the Board. The Board changes are effective immediately.

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PMV Pharmaceuticals Appoints Industry Veteran Dr. Carol Gallagher to Board of Directors

IPS Cell Therapy Comments Off on PMV Pharmaceuticals Appoints Industry Veteran Dr. Carol Gallagher to Board of Directors | November 6th, 2022

ALG-055009, a THR-? agonist drug candidate in development as a treatment for NASH, demonstrated dose-dependent reductions in several atherogenic lipids and a favorable pharmacokinetic profile in subjects with hyperlipidemia

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Aligos Therapeutics Presents Clinical Data for its NASH Program and Nonclinical Data for its Chronic Hepatitis B Portfolio at AASLD’s The Liver...

IPS Cell Therapy Comments Off on Aligos Therapeutics Presents Clinical Data for its NASH Program and Nonclinical Data for its Chronic Hepatitis B Portfolio at AASLD’s The Liver… | November 6th, 2022

Data demonstrated treatment with TERN-501 resulted in time- and dose-dependent increases in sex hormone binding globulin (SHBG), a key marker linked to NASH histologic efficacy

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Terns Pharmaceuticals Highlights Results from Phase 1 Clinical Trial of TERN-501 at AASLD The Liver Meeting® 2022

IPS Cell Therapy Comments Off on Terns Pharmaceuticals Highlights Results from Phase 1 Clinical Trial of TERN-501 at AASLD The Liver Meeting® 2022 | November 6th, 2022

Media Advisory

Wednesday, August 31, 2022

At the National Institutes of Health, a surgical team successfully implanted a patch of tissue made from patient cells with the goal of treating advanced dry age-related macular degeneration (AMD), also known as geographic atrophy. Dry AMD is a leading cause of vision loss among older Americans and currently has no treatment.

The patient received the therapy as part of a clinical trial that is the first in the United States to use replacement tissues from patient-derived induced pluripotent stem (iPS) cells. The surgery was performed by Amir H. Kashani, M.D., Ph.D., associate professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine with assistance by Shilpa Kodati, M.D., staff clinician, NEI. The procedure was performed at the NIH Clinical Center in Bethesda, Maryland, under a phase 1/2a clinical trial to determine the therapys safety.

This iPS cell derived therapy was developed by the Ocular and Stem Cell Translational Research Section team led by Kapil Bharti, Ph.D., senior investigator at the National Eye Institute (NEI), part of NIH, in collaboration with FUJIFILM Cellular Dynamics Inc., and Opsis Therapeutics, based in Madison, Wisconsin. Safety and efficacy of this cell therapy was tested by the NEI preclinical team. Clinical-grade manufacturing of this cell therapy was performed at the Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, NIH.

This surgery is the culmination of 10 years of research and development at the NEI. In the NIH lab, the patients blood cells were converted to iPS cells, which can become almost any type of cell in the body. In this case, they were programmed to become retinal pigment epithelial (RPE) cells, the type of cell that degenerates in the advanced forms of dry AMD. RPE cells nourish and support light-sensing photoreceptors in the retina. In AMD, the loss of RPE leads to the loss of photoreceptors, which causes vision loss. This work was supported by the NIH Common Fund and NEI Intramural funding.

Kapil Bharti, Ph.D., senior investigator, Ocular and Stem Cell Translational Research Section, NEI

Brian Brooks, M.D., Ph.D., chief, Ophthalmic Genetics and Visual Function Branch, NEI

To schedule interviews with Drs. Bharti and Brooks, contact NEI at neinews@nei.nih.gov

NIH launches first U.S. clinical trial of patient-derived stem cell therapy to replace and repair dying cells in retina (News release)

NIH researchers rescue photoreceptors, prevent blindness in animal models of retinal degeneration (News release)

Autologous Transplantation of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Geographic Atrophy Associated with Age-Related Macular Degeneration (Clinical trial information)

About the NEI: NEI leads the federal governments efforts to eliminate vision loss and improve quality of life through vision researchdriving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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First U.S. patient receives autologous stem cell therapy to treat dry ...

IPS Cell Therapy Comments Off on First U.S. patient receives autologous stem cell therapy to treat dry … | October 29th, 2022

BORDEAUX, France, Oct. 11, 2022 /PRNewswire/ --TreeFrog Therapeutics,a biotechnology company developing stem cell-derived therapies in regenerative medicine and immuno-oncology based on the biomimetic C-Stemtechnology platform, and Invetech, a global leader in the development and production ofautomated manufacturing solutionsfor cell and advanced therapies, today announced the delivery of a GMP-grade cell encapsulation device using the C-Stemtechnology. The machine will be transferred in 2023 to a contract development and manufacturing organization (CDMO) to produce TreeFrog's cell therapy candidate for Parkinson's disease, with the aim of a first-in-human trial in 2024.Over 2023, Invetech will deliver three additional GMP encapsulation devices to support TreeFrog's in-house and partnered cell therapy programs in regenerative medicine and immuno-oncology.

TreeFrogs C-Stem technology generates alginate capsules seeded with induced pluripotent stem cells (iPSCs) at very high speed. Engineered to mimic the in vivo stem cell niche, the capsules allow iPSCs to grow exponentially in 3D, and to differentiate into ready-to-transplant functional microtissues.

Blending microfluidics and stem cell biology, TreeFrog's C-Stemtechnology generates alginate capsules seeded with induced pluripotent stem cells (iPSCs) at very high speed. Engineered to mimic the in vivo stem cell niche, the capsules allow iPSCs to grow exponentially in 3D, and to differentiate into ready-to-transplant functional microtissues. And because alginate is both porous and highly resistant, encapsulated iPSCs can be expanded and differentiated in large-scale bioreactors without suffering from impeller-induced shear stress.

"TreeFrog Therapeutics introduces a breakthrough technology for cell therapy, which impacts scale, quality, as well as the efficacy and safety potential of cellular products. Automating this disruptive technology and turning it into a robust GMP-grade instrument is a tremendous achievement for our team. This deliverable is the result of a very fruitful and demanding collaboration with TreeFrog's engineers in biophysics and bioproduction over the past four years. We're now eager to learn how the neural microtissues produced with C-Stemwill perform in the clinic." Anthony Annibale, Global VP Commercial at Invetech.

Started in 2019, the collaboration between TreeFrog and Invetech led to the delivery of a prototype in October 2020. With this research-grade machine, TreeFrog demonstrated the scalability of C-Stem, moving within six months from milliliter-scale to 10-liter bioreactors. In June 2021, the company announced the production of two single-batches of 15 billion iPSCs in 10L bioreactors with an unprecedented 275-fold amplification per week, striking reproducibility and best-in-class cell quality. The new GMP-grade device delivered by Invetech features the same technical specifications. The machine generates over 1,000 capsules per second, allowing to seed bioreactors from 200mL to 10L. However, the device was entirely redesigned to fit bioproduction standards.

"With the GMP device, our main challenge was to minimize the learning curve for operators, so as to facilitate tech transfer. Invetech and our team did an outstanding job in terms of automation and industrial design to make the device both robust and easy to use. As an inventor, I am so proud of the journey of the C-Stemtechnology. Many elements have been changed and improved on the way, and now comes the time to put the platform in the hands of real-world users to make real products." Kevin Alessandri, Ph.D., co-founder and chief technology officer, TreeFrog Therapeutics

"In October 2020, we announced that we were planning for the delivery of a GMP encapsulation device by the end of 2022. Exactly two years after, we're right on time. I guess this machine testifies to the outstanding execution capacity of TreeFrog and Invetech. But more importantly, this machine constitutes a key milestone. Our platform can now be used to manufacture clinical-grade cell therapy products. Our plan is to accelerate the translation of our in-house and partnered programs to the clinic, with a focus on immuno-oncology and regenerative medicine applications." Frederic Desdouits, Ph.D., chief executive officer, TreeFrog Therapeutics

About Invetech

Invetech helps cell and gene therapy developers to visualize, strategize and manage the future. With proven processes, expert insights and full-spectrum services, we swiftly accelerate life-changing therapies from the clinic to commercial-scale manufacturing. Through our ready-to-run, preconfigured systems, our custom and configurable technology platforms and automated production systems, we assure predictable, reproducible products of the highest quality and efficacy. Our integrated approach brings together biological scientists, engineers, designers and program managers to deliver successful, cost-effective market offerings to more people, more quickly. Working in close collaboration with early-stage and mature life sciences companies, we are committed to advancing the next generation of vital, emerging therapies to revolutionize healthcare and precision medicine.invetechgroup.com

About TreeFrog Therapeutics

TreeFrog Therapeutics is a French-based biotech company aiming to unlock access to cell therapies for millions of patients. Bringing together over 100 biophysicists, cell biologists and bioproduction engineers, TreeFrog Therapeutics raised $82M over the past 3 years to advance a pipeline of stem cell-based therapies in immuno-oncology and regenerative medicine. In 2022, the company opened technological hubs in Boston, USA, and Kobe, Japan, with the aim of driving the adoption of the C-Stemplatform and establish strategic alliances with leading academic, biotech and industry players in the field of cell therapy.www.treefrog.fr

Media ContactsPierre-Emmanuel GaultierTreeFrog Therapeutics+ 33 6 45 77 42 58pierre@treefrog.fr

Marisa ReinosoInvetech+1 858 437 1061marisa.reinoso@invetechgroup.com

TreeFrog Therapeutics is a French-based biotech company aiming to unlock access to cell therapies for millions of patients. Bringing together over 100 biophysicists, cell biologists and bioproduction engineers, TreeFrog Therapeutics raised $82M over the past 3 years to advance a pipeline of stem cell-based therapies in immuno-oncology and regenerative medicine.

Invetech logo (PRNewsFoto/Invetech)

Cision

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SOURCE Invetech; Treefrog Therapeutics

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BREAKTHROUGH TECHNOLOGY FOR IPS-DERIVED CELL THERAPIES TURNED INTO GMP PLATFORM BY TREEFROG THERAPEUTICS & INVETECH - Yahoo Finance

IPS Cell Therapy Comments Off on BREAKTHROUGH TECHNOLOGY FOR IPS-DERIVED CELL THERAPIES TURNED INTO GMP PLATFORM BY TREEFROG THERAPEUTICS & INVETECH – Yahoo Finance | October 13th, 2022

AMSBIO has published an interview with Professor Marius Wernig from Stanford University, Pathology Stem Cell Institute that discusses what could be the worlds first widely applicable curative treatment for Epidermolysis Bullosa (EB).

This rare genetic disease causes chronic and incredibly painful skin wounds that often lead to an aggressive form of skin cancer and eventual death.

While various cell-therapy approaches have been attempted, Professor Wernig and collaborators identified the need for induced pluripotent stem cells (iPSCs), and how they could become used to treat EB in a more efficient, applicable, and commercially viable manner.

In the past, the only way Professor Wernigs research group could grow iPSCs cells with a normal karyotype over longer periods of time was on mouse feeder cells with serum. This combination of mouse cell co-culture and undefined bovine serum set was not a suitable methodology as it was almost impossible to perform in compliance with FDA safety standards.

Professor Wernig describes how StemFit Basic03 clinical grade stem cell culture medium, available from AMSBIO has allowed his research group to safely expand their cells using an FDA compliant protocol. While there are still hurdles to climb before a cure for EB is fully realised, using StemFit Basic03 has solved the challenge of reproducibly growing clinical grade iPSCs.

Read the full interview.

Completely free of animal- and human-derived components StemFit Basic03 provides highly stable and reproducible culture condition for Induced Pluripotent Stem and Embryonic Stem cells under feeder-free conditions during the reprogramming, expansion, and differentiation phases of stem cell culture. StemFit Basic03 combines high colony forming efficiency with lower than standard media volume consumption to offer cost effective colony expansion when compared to leading competitors.

More information online

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iPS-Cell Based Cell Therapies for Genetic Skin Disease

IPS Cell Therapy Comments Off on iPS-Cell Based Cell Therapies for Genetic Skin Disease | October 5th, 2022

JCR Pharmaceuticals Co., Ltd. and Sysmex Corporation announced that they have established a joint venture(hereafter the "joint venture") for carrying out research and development, manufacture and sales of cell-based regenerative medicine products including hematopoietic stem cells and other stem cells. In recent years, the significant potential of regenerative medicine and cell therapy have been established in particular in areas that have traditionally been difficult to address with conventional chemically synthesized low molecular weight drugs1 or biopharmaceuticals2, such as the restoration of tissues and functions lost as a result of aging, illness, autoimmune diseases, or cancer. In particular, research and development on the therapeutic application of stem cells including hematopoietic stem cells, mesenchymal stem cells, and iPS cells have generated significant attention. Since its inception, JCR has been engaged in the research, development, manufacturing and sales of pharmaceutical products using regenerative medicine, genetic engineering, and gene therapy technologies to advance therapies in the rare disease field. This is exemplified in the field of regenerative medicine, by the approval of TEMCELL HS Inj.3, the first allogeneic regenerativemedicine in Japan (Non-proprietary name: Human (allogeneic) bone marrow-derived mesenchymal stem cells) in February 2016 for the treatment of acute graft-versus-host disease (acute GVHD)4, a serious complication that develops after hematopoietic stem cell transplantation. In recent years, JCR has further streamlined and integrated its expertise around the establishment of groundbreaking medicines for the advancement of highly innovative medicines that could not be developed without such groundbreaking technologies. In the joint venture, the two companies aim to realize the social implementation of regenerative medicine and cell therapy by integrating JCR's expertise in developing, manufacturing and marketing regenerative medicine products, with Sysmex's expertise in quality control testing technology and knowledge of workflows efficiency using robotics technology, including IoT. AlliedCel Corporation, which is the corporate name of the joint venture following prior discussions regarding the alliance both companies, was established on October 3, 2022. The joint venture will advance programs of the potential for technology development and commercialization, including the project currently being promoted by both companies using hematopoietic stem cell proliferation technology. The name AlliedCel stands for the joint venture's aspiration to integrate knowledge and expertise from a broad set of collaborators and stakeholders including business partners, patients and their families, with the united goal of unleashing the power of cells in supporting patients in their needfor life-changing therapies. Through the research and development of regenerative medicineproducts using diverse cells such as stem cells, AlliedCel aims to provide appropriate treatmentoptions to patients and improve their prognosis.

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Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy - Marketscreener.com

IPS Cell Therapy Comments Off on Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy – Marketscreener.com | October 5th, 2022

MeiraGTx

Multiple Poster Presentations Highlight Versatility and Novelty of MeiraGTxs Technology Platforms for Gene and Cell Therapy

LONDONandNEW YORK, Oct. 04, 2022 (GLOBE NEWSWIRE) -- MeiraGTx Holdings plc(Nasdaq: MGTX), a vertically integrated, clinical stage gene therapy company, today announced the Company will exhibit 15 poster presentations at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress, which will be held from October 11-14, 2022, in Edinburgh, Scotland.

The posters will include data from MeiraGTxs novel gene regulation platform, including the first data demonstrating the potential to regulate CAR-T, as well as data from the Companys promoter platforms and several new, optimized pre-clinical programs addressing severe unmet needs for indications such as amyotrophic lateral sclerosis (ALS) and Wilsons disease. In addition, the Company will have presentations on its proprietary viral vector manufacturing technology and potency assay development.

Were pleased to present data illustrating the depth and versatility of MeiraGTxs scientific platforms, said Alexandria Forbes, Ph.D., president and chief executive officer of MeiraGTx. The 15 published abstracts at this years ESGCT Congress reflect the extraordinary productivity of our research efforts in developing new technologies and applying them to the design of optimized genetic medicines, as well as innovation in manufacturing and process development technology. I am particularly excited for us to present our riboswitch gene regulation technology applied to cell therapy for the first time, in this case the regulation of CAR-Ts, which is a huge area of scientific and clinical interest, continued Dr. Forbes. We look forward to presenting these data highlighting our innovative platform technologies and broad R&D capabilities.

Abstract Title (P101): AI-driven promoter optimization at MeiraGTxSession Title: Advances in viral and non-viral vector designDate: October 12, 2022

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Abstract Title (P124): Promoter Engineering Platform at MeiraGTxSession Title: Advances in viral and non-viral vector designDate: October 13, 2022

Abstract Title (P243): UPF1 delivered by novel expression-enhanced promoters protects cultured neurons in a genetic ALS modelSession Title: CNS and sensoryDate: October 12, 2022

Abstract Title (P254): Optimization and scale-up of AAV2-AQP1 production using a novel transient transfection agentSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P264): Designing and screening formulations to improve manufacturability and distribution of AAV gene therapiesSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P270): Use of anion exchange chromatography to provide high empty AAV capsid removal and product yieldsSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P320): Multivariate analysis for increased understanding of MeiraGTx upstream processSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P362): Development of AAV-UPF1 gene therapy to rescue ALS pathophysiology using microfluidic platformsSession Title: Disease models (iPS derived and organoids)Date: October 13, 2022

Abstract Title (P399): Titratable and reversible control of CAR-T cell receptor and activity by riboswitch via oral small moleculeSession Title: Engineered T and NK CARs and beyondDate: October 12, 2022

Abstract Title (P436): Novel riboswitches regulate AAV-delivered transgene expression in mammals via oral small molecule inducersSession Title: Gene and epigenetic editingDate: October 13, 2022

Abstract Title (P553): Development of optimized ATP7B gene therapy vectors for the treatment of Wilsons Disease with increased potencySession Title: Metabolic diseasesDate: October 12, 2022

Abstract Title (P554): A CNS-targeted gene therapy for the treatment of obesitySession Title: Metabolic diseasesDate: October 13, 2022

Abstract Title (561): Riboswitch-controlled delivery of therapeutic hormones for gene therapySession Title: Metabolic diseasesDate: October 12, 2022

Abstract Title (P622): Riboswitch-controlled delivery of therapeutic antibodies for gene therapySession Title: OtherDate: October 13, 2022

Abstract Title (P630): Improving AAV in vitro transducibility for cell-based potency assay developmentSession Title: OtherDate: October 13, 2022

About MeiraGTxMeiraGTx (Nasdaq: MGTX) is a vertically integrated, clinical stage gene therapy company with six programs in clinical development and a broad pipeline of preclinical and research programs. MeiraGTx has core capabilities in viral vector design and optimization and gene therapy manufacturing, and a transformative gene regulation platform technology which allows tight, dose responsive control of gene expression by oral small molecules with dynamic range that can exceed 5000-fold. Led by an experienced management team, MeiraGTx has taken a portfolio approach by licensing, acquiring, and developing technologies that give depth across both product candidates and indications. MeiraGTxs initial focus is on three distinct areas of unmet medical need: ocular, including inherited retinal diseases and large degenerative ocular diseases, neurodegenerative diseases, and severe forms of xerostomia. Though initially focusing on the eye, central nervous system, and salivary gland, MeiraGTx plans to expand its focus to develop additional gene therapy treatments for patients suffering from a range of serious diseases.

For more information, please visit http://www.meiragtx.com.

Forward Looking StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding our product candidate development and our pre-clinical data and reporting of such data and the timing of results of data, including in light of the COVID-19 pandemic, as well as statements that include the words expect, will, intend, plan, believe, project, forecast, estimate, may, could, should, would, continue, anticipate and similar statements of a future or forward-looking nature. These forward-looking statements are based on managements current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, our incurrence of significant losses; any inability to achieve or maintain profitability, raise additional capital, repay our debt obligations, identify additional and develop existing product candidates, successfully execute strategic priorities, bring product candidates to market, expansion of our manufacturing facilities and processes, successfully enroll patients in and complete clinical trials, accurately predict growth assumptions, recognize benefits of any orphan drug designations, retain key personnel or attract qualified employees, or incur expected levels of operating expenses; the impact of the COVID-19 pandemic on the status, enrollment, timing and results of our clinical trials and on our business, results of operations and financial condition; failure of early data to predict eventual outcomes; failure to obtain FDA or other regulatory approval for product candidates within expected time frames or at all; the novel nature and impact of negative public opinion of gene therapy; failure to comply with ongoing regulatory obligations; contamination or shortage of raw materials or other manufacturing issues; changes in healthcare laws; risks associated with our international operations; significant competition in the pharmaceutical and biotechnology industries; dependence on third parties; risks related to intellectual property; changes in tax policy or treatment; our ability to utilize our loss and tax credit carryforwards; litigation risks; and the other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, as such factors may be updated from time to time in our other filings with the SEC, which are accessible on the SECs website at http://www.sec.gov. These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent managements estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, unless required by law, we disclaim any obligation to do so, even if subsequent events cause our views to change. Thus, one should not assume that our silence over time means that actual events are bearing out as expressed or implied in such forward-looking statements. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.

Contacts

Investors:MeiraGTxInvestors@meiragtx.com

Media:Jason Braco, Ph.D.LifeSci Communicationsjbraco@lifescicomms.com

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MeiraGTx Announces the Upcoming Presentation of 15 Abstracts at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress - Yahoo...

IPS Cell Therapy Comments Off on MeiraGTx Announces the Upcoming Presentation of 15 Abstracts at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress – Yahoo… | October 5th, 2022

The global stem cell market size is expected to reach USD 19.13 Billion in 2028 at a CAGR of 8.4% during the forecast period, according to the latest report by Reports and Data.

The globalstem cell marketsize is expected to reach USD 19.13 Billion in 2028 at a CAGR of 8.4% during the forecast period, according to the latest report by Reports and Data. Growing adoption of stem cell therapies to treat chronic and rare diseases, rising number of clinical trials for regenerative medicine globally, and rapid progress in stem cell research are key factors expected to drive market revenue growth over the forecast period. In addition, increasing investment by major pharmaceutical and biotechnology companies, advancements in regenerative medicine, and development of advanced gene editing and tissue engineering techniques are also expected to contribute to revenue growth of the market going ahead.

Stem cells are unspecialized cells that have the ability to develop into different types of cells such as liver cells, muscle cells, and brain cells, among others. Stem cells have remarkable ability of self-renewal in undifferentiated state and can differentiate into various cell types with specific functions under appropriate triggers. Stem cells have played a major role in regenerative medicine, with increasing focus on stem cells of human origin such as adult stem cells, somatic stem cells, and embryonic stem cells. These cells can be used to regenerate human cells, organs, and tissues and have the capability to restore normal function after disease or debilitating injury. During embryonic development, stem cells can form cells of all three germ layers mesoderm, endoderm, and ectoderm. They play a crucial role in repair system of body and normal turnover of regenerative organs such as skin and blood, and this has boosted their importance in medical therapies for the treatment of various degenerative illnesses.

Get a sample of the report @https://www.reportsanddata.com/sample-enquiry-form/2981

Increasing investment to accelerate stem cell research, rapid adoption of stem cell therapies for the treatment of chronic and neurodegenerative disorders, and the increasing number of clinical trials across the globe are some key factors expected to drive market growth Our Expert Review

Recent advancements in stem cell biology and research have enhanced the application scope of stem cell therapy in treating diseases wherein currently available medical therapies have failed to cure, prevent progression, or alleviate symptoms. This is also a key factor expected to contribute to revenue growth of the market over the forecast period. However, ethical issues and political controversies, concerns related to immunity, and stringent regulatory policies associated with stem cell research are some key factors expected to restrain market growth to a certain extent over the forecast period.

Some Key Highlights from the Report:

Asia Pacific is expected to lead the market growth over the coming years owing to rapid advancements in the healthcare sector in APAC countries such as India, China, and Japan. North America is anticipated to register the highest market growth over the forecast period attributed to the increasing availability of robust healthcare and clinical settings, legalization of medical marijuana, favorable reimbursement scenario, presence of key market players, and rapid technological advancements in the region.

The growing popularity of over-the-counter medications driving market growth

Growing incidence of acute and chronic diseases and lesser access to advanced medical facilities owing to low disposable income levels are driving the demand for over-the-counter medications. Availability of generic and low-cost alternatives to medical therapies are some other factors playing a major role in driving demand for over-the-counter medications.

Restriction on product launches and R&D activities to hamper the market growth

The imposition of strict government regulations and shortage of funds has put a halt on product launches and R&D activities and is expected to restrain market growth over the forecast period. In addition, the launch of expensive drugs and therapies and increasing regulations regarding safety and approvals are also hampering the market growth.

Competitive Landscape:

The global market comprises various market players operating at regional and global levels. These key players are adopting various strategies such as R&D investments, license agreements, partnerships, mergers and acquisitions, collaborations, and joint ventures to gain a robust footing in the market.

Top Companies Profiled in the Report:

Celgene Corporation, Virgin Health Bank, ReNeuron Group plc, Biovault Family, Mesoblast Ltd, Precious Cells International Ltd, Caladrius, Opexa Therapeutics, Inc., Neuralstem, Inc., and Pluristem.

Stem Cells Market Segmentation:

Product Outlook (Revenue, USD Billion; 2018-2028)

Technology Outlook (Revenue, USD Billion; 2018-2028)

Therapy Outlook (Revenue, USD Billion; 2018-2028)

Application Outlook (Revenue, USD Billion; 2018-2028)

Regional Outlook:

Frequently asked questions addressed in the report:

Thank you for reading our report. For more details please connect with us and our team will ensure the report is customized to meet all the needs of clients. The report also offers a comprehensive regional analysis and specific countries can be included in the report according to the requirements.

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Stem Cells Market Size Expected to Reach USD 19.31 Billion by 2028: Increasing Number of Clinical Trials Across the Globe - Digital Journal

IPS Cell Therapy Comments Off on Stem Cells Market Size Expected to Reach USD 19.31 Billion by 2028: Increasing Number of Clinical Trials Across the Globe – Digital Journal | September 27th, 2022

Specially treated stem cells derived from a single individual have been successfully implanted into that same individuals eyes in a first-of-its-kind clinical trial testing ways to treat advanced dry age-related macular degeneration (AMD).

The therapy, currently in its first phase of testing to ensure that its safe for humans, involves harvesting and processing a persons blood cells and using them to replace the persons retinal cells that had succumbed to AMD, a leading cause of vision loss globally.

The procedure was performed by researchers from the National Eye Institute (NEI), a branch of the National Institutes of Health in Bethesda, Maryland, and from the Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore. The NIH researchers have been working on the new treatment for a decade.

The scientists, who previously demonstrated the safety and effectiveness of the therapy in rats and pigs, took blood cells from the patient and, in the laboratory, converted them into patient-derived induced pluripotent stem (iPS) cells. These immature, undifferentiated cells have no assigned function in the body, which means they can assume many forms. The researchers programmed these particular iPS cells to become retinal pigment epithelial (RPE) cells, the type that die in AMD and lead to late-stage dry AMD.

In healthy eyes, RPE cells supply oxygen to photoreceptors, the light-sensing cells in the retina at the back of the eyeball. The death of RPE cells virtually dooms the photoreceptors, resulting in vision loss. The idea behind the new therapy is to replace dying RPE cells with patient-derived induced iPS ones, strengthening the health of the remaining photoreceptors.

Before being transplanted, the iPS-derived cells were grown in sheets one cell thick on a biodegradable scaffold designed to promote their integration into the retina. The researchers positioned the resulting patch between atrophied host RPE cells and the photoreceptors using a specially created surgical tool.

The patient received the transplanted cells during the summer and will be followed for a year as researchers monitor overall eye health, including retina stability, and whether any inflammation or bleeding develop, says Kapil Bharti, PhD, a senior investigator at the NEI and for the clinical trial.

Safety data are critical for any new drug, says Gareth Lema, MD, PhD, a vitreoretinal surgeon at New York Eye & Ear Infirmary, a division of the Mount Sinai Health System. Stem cells have added complexity in that they are living tissue, Dr. Lema says. Precise differentiation is necessary for them to fulfill their intended therapeutic effect and not cause harm."

This therapy also requires a surgical procedure to implant the cells, Lema says, adding that its an exquisitely elegant surgery, but introduces further risk of harm. For those reasons, he says, Patients must know that ocular stem cell therapies should only be attempted within the regulated environment of a nationally registered clinical trial.

The rules of a clinical trial dont generally allow specifics to be discussed this early in the process, says Dr. Bharti. Announcing that we were able to successfully transplant the cells now hopefully allows us to recruit more patients, since we can take up to 12 in this phase, he says. We also hope that it will give some optimism to patients with dry AMD and to researchers studying it.

It took seven months to develop the implanted cells, says Bharti, and although the federal Food and Drug Administration (FDA) approved the clinical trial in 2019, the onset of the COVID-19 pandemic delayed the start by two years, he says.

Macular degeneration comprises several stages of disease within the macula, the critical portion of the retina responsible for straight-ahead vision. Aging causes retinal cells to deteriorate, generating debris, or drusen, within the macula, setting the stage for early (aka dry) AMD. Geographic atrophy represents a more advanced stage. If the disease progresses to the relatively rare wet AMD, so named for the leaking of blood into the macula, central vision can be snuffed out.

Risk of AMD increases with age, particularly among people who are white, have a history of smoking, or have a family history of the disease.

Treatment to slow wet AMDs progression includes eye injections with anti-VEGF (or VEGF-A for vascular endothelial growth factor antagonists), a medication that halts the growth of unstable, leaky blood vessels in the eye. Some people may undergo photodynamic therapy, which combines injections and laser treatments.

Currently, there is no cure for dry AMD; it cant be reversed. Nor are there treatments to reliably stop its onset or progression for everyone at every stage of the disease. (Research has confirmed that a specialized blend of vitamins and minerals, available over the counter as AREDS, or Age-Related Eye Disease Studies supplements, reduces the risk of AMDs progression from intermediate to advanced stages.)

There are other, ongoing clinical trials for the treatment of dry AMD. Regenerative Patch Technologies, in Menlo Park, California, for example, is a little further along in testing a different stem cell treatment. Patients have been followed for three years, and 27 percent have shown vision improvement, says Jane Lebkowski, PhD, the companys president. There are a number of AMD clinical trials ongoing in the U.S., and patients should ask their ophthalmologists about trials that might be appropriate.

ClinicalTrials.gov, the NIHs clinical trials database, lists close to 300 AMD clinical trials at various stages in the United States.

Ferhina Ali, MD, MPH, a retinal specialist at the Westchester Medical Center in Valhalla, New York, who isnt involved in the trial, describes the newest stem cell therapy as elegant and pioneering. These are early stages but there is tremendous potential as a first-in-kind surgically implanted stem cell therapy and as a way to achieve vision gains in dry macular degeneration, Dr. Ali says.

Bharti says that in laboratory animals the implanted cells behaved as retinal cells should maintaining the retinas integrity. Over the next few years, he and his colleagues will determine whether they function effectively in humans.

Does that mean, however, that the same AMD disease process that destroyed the original retinal cells could destroy the transplanted ones? It takes 40 to 60 years to damage human cells, Bharti says, and if we get that long with the transplanted cells, well take it.

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Implanting a Patient's Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD - Everyday Health

IPS Cell Therapy Comments Off on Implanting a Patient’s Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD – Everyday Health | September 19th, 2022

In the present study, we derived two particularly noteworthy results. First, nearly half of the institutions that responded to the study were either currently providing UCB to private banks during the study period or had done so in the past. Second, some institutions were found to provide UCB not only to private banks but also to companies, research institutions, and medical treatment facilities.

During the present study, the APHSCT, along with related ministerial ordinances and guidelines, stipulated how public banks preserve and manage UCB. However, during the study period, these laws and regulations did not require the institutions that handled childbirth to keep records, except when providing UCB to public banks. Consequently, no one knew how many institutions handling childbirth supplied UCB to private banks or the status of UCB distribution. The present study determined that 34.4% of institutions handling childbirth currently provide UCB to private banks, while 16.1% of institutions did so in the past. Our study reported for the first time that these percentages far outstrip those for UCB supply to public banks (6.1% and 8.0%, respectively). These low percentages may be related to the low number of institutions handling childbirth in Japan partnered with public banks (96 institutions as of January 18, 2021) [14,15,16,17,18,19].

However, from the standpoint of appropriate collection, safe preservation, and effective usage of UCB, public and private banks should be regulated according to more uniform standards. More than one-fourth of institutions that provide or have provided UCB to private banks did not provide explanations about UCB collection to UCB donors, while nearly 20% of institutions did not obtain consent. Donors of UCB choose to have their UCB preserved and are also users of UCB who entrust their UCB to private banks, a state of affairs that may lead to the opinion that it is not that important for institutions handling childbirth to provide explanations or obtain consent. However, an MHLW survey reported that private banks do not provide sufficient explanations to users in advance [20]. This state of affairs may be related to the absence of regulations in private banks in Japan.

Even before we demonstrated problems with private banks in Japan in the present study with empirical data, these problems were already known anecdotally, which led many academic associations to issue warnings. In 2002, the Japan Society for Hematopoietic Cell Transplantation issued a statement declaring that private banks were almost completely ineffective, except in cases such as patients with refractory blood diseases within ones own family and that regulations were necessary to ensure proper technical guidelines and safety [21]. In addition, the Japan Association of Obstetricians and Gynecologists declared in 2002 that sufficient understanding was necessary regarding the status and background of private storage of UCB and that careful steps were required to ensure that private banks do not simply use UCB for profit [22].

However, as we analyzed the results of the present study, a relevant concern came to pass. In 2017, physicians who administered UCB to patients without notifying government authorities were found guilty of violating the Act on the Safety of Regenerative Medicine, with the vendor who sold the UCB charged as an accomplice [23, 24]. The UCB sold by the vendor leaked from a private bank that had gone bankrupt in 2009. However, the charge in this case was providing regenerative medicine to patients without reporting it to the MHLW; there was no law targeting the sale of the leaked UCB itself, which was, therefore, beyond the scope of legal penalty [25].

Spurred by the case described above, the MHLW conducted a survey of private UCB banks in Japan [20]. Of the seven vendors whose activities could be confirmed at the time of the survey, six responded; one of these vendors only distributed UCB without preserving it. The UCB held by the remaining five vendors constituted a supply for a total of 45,800 people; roughly 2,100 peoples worth of UCB had not been disposed after the vendors contracts with the donors had ended. One vendor provided UCB to a third party (roughly 160 times). The three vendors involved in the above case later went out of business [26].

Taking the case seriously, the MHLW revised the APHSCT to generally prohibit the collection, preparation, storage, testing, and delivery of UCB for transplantation as a business by entities other than public banks. The revision also stipulated that UCB for transplantation may not be delivered by anyone for commercial purposes. However, these prohibitions do not apply when a public bank delivers UCB, when UCB is used in the treatment of a blood relative to the donor, or when approval is granted by the MHLW. Violations of these prohibitions are subject to criminal penalties. Consequently, the two private banks that obtained approval from the MHLW were permitted to continue their activities.

However, regardless of legal permission, there is still the question of whether private UCB banks, which handle UCB for profit, are ethically permissible. For example, the 2004 European Commissions Group on Ethics in Science and New Technologies stated that while they did not completely disavow for-profit biobank activities, these activities engender ethical criticism. The group also stated that the human body in principle is not an object of commercial value and recommended that private biobank activities operate under strict conditions such as appropriate management by regulatory authorities [27]. Meanwhile, a non-Japanese study has reported that the possibility of UCB being used 20years later by the person who requested its preservation or by their family is an incredibly low 0.040.0005% [28]. The extent to which this information is explained to potential private bank users is unknown. In fact, the previously cited survey by the MHLW indicated that the role of public UCB banks and the actual utility of the UCB stored in the private banks were not sufficiently explained to users [20]. Future research must thoroughly examine the status of UCB private banks following revision of the law and compare the results of this examination to the findings of the present study.

A small number of institutions handling childbirth surveyed in the present study responded that they currently provide or used to provide UCB to medical treatment facilities (2.6%), research institutions (5.9%), companies (2.2%), or foreign medical treatment facilities, research institutions, or companies (0.3%). Some institutions handling childbirth also either currently store or used to store UCB themselves for treatment or research (2.3% and 3.2%, respectively). This aspect of the status of UCB distribution has never been demonstrated in a previous study.

Since the revision of the APHSCT, the delivery of UCB for transplantation has been strictly prohibited except in the cases of provision to a public bank, provision to a private bank approved by the MHLW, and use for treatment by a blood relative. Thus, it is currently considered illegal for institutions handling childbirth to deliver UCB to other facilities domestically or internationally or to store UCB themselves for treatment purposes. However, the revised law still does not apply to the handling of UCB for research purposes, that is, basic studies and the development of treatments. In addition, while there are laws and local ordinances that call for the incineration or burial of UCB according to specific methods, these regulations generallydo not cover the delivery of UCB for research purposes.

At a glance, there would seem to be no problem with an institution that handles childbirth providing UCB to a third party or storing UCB itself for research purposes. However, the results of the present study, which found that a certain number of institutions handling childbirth do not provide explanations or obtain consent when UCB is harvested from private bank users, and the results of the above-cited MHLW survey, which found that private banks also fail to provide users with sufficient explanations, cast doubt amidst the absence of relevant laws and regulations as to how much has been suitably explained to UCB donors when they consent to be third-party UCB donors.

We did not determine what sort of explanations institutions handing childbirth give when they deliver UCB to other institutions or store it themselves for research purposes, nor did we determine methods for obtaining consent, as we felt these fell outside the aim of the present study. Future studies must answer these questions and evaluate if there truly is no problem with the current state of affairs in Japan in the absence of rules regarding the harvest or delivery of UCB for research purposes by institutions handling childbirth.

The present study had several limitations. First, the response rate was only 36.7%, which is not at all high. However, the percentages of institutions handling childbirth by type that responded to our survey are roughly consistent with those of Japanese medical treatment facilities overall [29], implying that our results are representative to some extent. Of course, we cannot rule out the effect of non-responder bias. However, the present study can be considered sufficiently significant because this is the first study to determine the status of UCB delivery by Japanese institutions handling childbirth to private banks, other companies, research institutions, and medical treatment facilities. The 3,277 facilities included in this study represent 99.9% of childbirth facilities in Japan. The total number of facilities in Japan is approximately 3,280. Of which 1,084 facilities responded that they handled childbirth. A simple calculation from the actual number of births in 2016 (976,978 births), a year before this study was conducted [30], allowed us to estimate that the facilities included in our study handled a total of 322,879 births. The number of UCBs managed by these facilities can be considered significant. In addition, by determining the status of UCB delivery prior to revision of the APHSCT, we have made it possible to determine the effects of APHSCT via comparisons with post-revision survey results.

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Current status of umbilical cord blood storage and provision to private biobanks by institutions handling childbirth in Japan - BMC Medical Ethics -...

IPS Cell Therapy Comments Off on Current status of umbilical cord blood storage and provision to private biobanks by institutions handling childbirth in Japan – BMC Medical Ethics -… | September 19th, 2022

DUBLIN--(BUSINESS WIRE)--The "Induced Pluripotent Stem Cells Market - Growth, Trends, Covid-19 Impact, and Forecasts (2022 - 2027)" report has been added to ResearchAndMarkets.com's offering.

The Induced Pluripotent Stem Cells Market is projected to register a CAGR of 8.4% during the forecast period (2022 to 2027).

Companies Mentioned

Key Market Trends

The Drug Development Segment is Expected to Hold a Major Market Share in the Induced Pluripotent Stem Cells Market.

By application, the drug development segment holds the major segment in the induced pluripotent stem cell market. Various research studies focusing on drug development studies with induced pluripotent stem cells have been on the rise in recent years.

For instance, an article titled "Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening" published in the International Journal of Molecular Science in October 2020 discussed the broad use of iPSC derived cardiomyocytes for drug development in terms of adverse drug reactions, mechanisms of cardiotoxicity, and the need for efficient drug screening protocols.

Another article published in the Journal of Cells in December 2021 titled "Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective" focused on methods to reprogram somatic cells into human induced pluripotent stem cells and the solutions to overcome the immaturity of the human induced pluripotent stem cells derived cardiomyocytes to mimic the structure and physiological properties of adult human cardiomyocytes to accurately model disease and test drug safety. Thus, this increase in the research of induced pluripotent stem cells for drug development and drug modeling is likely to propel the segment's growth over the study period.

Furthermore, as per an article titled "Advancements in Disease Modeling and Drug Discovery Using iPSC-Derived Hepatocyte-like Cells" published in the Multi-Disciplinary Publishing Institute journal of Cells in March 2022, preserved differentiation and physiological function, amenability to genetic manipulation via tools such as CRISPR/Cas9, and availability for high-throughput screening, make induced pluripotent stem cell systems increasingly attractive for both mechanistic studies of disease and the identification of novel therapeutics.

North America is Expected to Hold a Significant Share in the Market and Expected to do Same in the Forecast Period

The rise in the adoption of highly advanced technologies and systems in drug development, toxicity testing, and disease modeling coupled with the growing acceptance of stem cell therapies in the region are some of the major factors driving the market growth in North America.

The United States Food and Drug Administration in March 2022 discussed the development of strategies to improve cell therapy product characterization. The agency focused on the development of improved methods for testing stem cell products to ensure the safety and efficacy of such treatments when used as therapies.

Likewise, in March 2020, the Food and Drug Administration announced that ImStem drug IMS001, which uses AgeX's pluripotent stem cell technology, would be available for the treatment of multiple sclerosis. Similarly, REPROCELL introduced a customized iPSC generation service in December 2020, as well as a new B2C website to promote the "Personal iPS" service. This service prepares and stores an individual's iPSCs for future injury or disease regeneration treatment.

Thus, the increasing necessity for induced pluripotent stem cells coupled with increasing investment in the health care department is known to propel the growth of the market in this region.

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS

4.1 Market Overview

4.2 Market Drivers

4.2.1 Increase in Research and Development Activities in Stem Cells Therapies

4.2.2 Surge in Adoption of Personalized Medicine

4.3 Market Restraints

4.3.1 Lack of Awareness Regarding Stem Cell Therapies

4.3.2 High Cost of Treatment

4.4 Porter's Five Force Analysis

5 MARKET SEGMENTATION

5.1 By Derived Cell Type

5.2 Application

5.3 End User

5.4 Geography

6 COMPETITIVE LANDSCAPE

6.1 Company Profiles

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/ylzwhr

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Global Induced Pluripotent Stem Cells Market (2022 to 2027) - Growth, Trends, Covid-19 Impact and Forecasts - ResearchAndMarkets.com - Business Wire

IPS Cell Therapy Comments Off on Global Induced Pluripotent Stem Cells Market (2022 to 2027) – Growth, Trends, Covid-19 Impact and Forecasts – ResearchAndMarkets.com – Business Wire | September 11th, 2022

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Correlation between PSC differentiation potential and level of CHD7 expression

The potential to differentiate is a critical feature of PSCs used for cell transplantation therapy. Therefore, establishing an assay to evaluate differentiation potential is essential for the maintenance culture of PSCs. EB formation in EB assays is used as a minimum requirement to demonstrate differentiation potential, although EB formation assays may not necessarily guarantee the ability to differentiate into the designated target cells without bias. We used ESC H9 cells in the majority of experiments shown in this study as a representative PSC cell line to minimize the concern of clonal variance in PSC clones that is typically observed among iPSC clones generated from somatic cells with various genetic and epigenetic profiles and with versatile reprogramming methods. H9 cells cultured on VTN-Ncoated dishes with Es8 (Thermo Fisher) medium formed a considerable number of EBs; however, the number of EBs was reduced considerably after the cells were transferred to RFF2 medium and cultured for 15days (3days/passage5). The cells showed an ability to form a comparable number of EBs again when transferred to Es8 and cultured for 24days (3days/passage8 passages), consistent with our previous report using ESC KhES-1 and iPSC PFX#91. The expression level of CHD7 determined by flow cytometry and the copy number of CHD7 measured by ddPCR was higher in cells cultured with Es8 than in cells cultured with RFF2 (Fig.1A). We noted that the cell number scored at day 3 was approximately 3 times higher in cells cultured with Es8 than with RFF2. There was a positive relationship between cell growth rate, CHD7 expression level, and differentiation potential when H9 cells were cultured on VTN-Ncoated dishes and passaged in a single-cell suspension.

The differentiation potential of cells in culture can be altered by culture medium. (A) H9 cells cultured with Essential 8 (Es8) medium on vitronectin-N (VTN)coated dishes were transferred to RFF2 medium, cultured for 15days (3days/passage5 passages), transferred again to Es8 medium, cultured 24days (3days/passage8 passages), and then transferred again to RFF2 medium. Photos of cells in designated culture conditions, with the cell number scored at day 3 after seeding 1.0105 cells (left panels); flow cytometric analysis of CHD7, CHD7 copy numbers from 5ng total RNA at day 3 (middle panels); and photographs of EBs formed by day 14 from cells in each culture condition and numbers of EBs formed (right panels). The results are representative of three independent experiments. (B) H9 cells were cultured either with Es8 or RFF2 on VTN-Ncoated dishes. The loci of copy number variants (CNVs) detected when cells were cultured with Es8 medium (left panels) or RFF2 medium (right panels) are shown. CHD7 expression was determined by flow cytometry (mean values are shown), and CHD7 copy numbers were determined by digital droplet PCR in cells cultured with Es8 or RFF2 medium.

We next explored the mechanisms through which cells had altered CHD7 expression levels and the ability to form EBs by simply changing the culture medium. There were at least two possible explanations for this mechanism. First, cells in culture might exhibit alterations in both CHD7 expression and the resultant differentiation potential because of signals initiated and mediated by certain factors in the medium. Alternatively, CHD7 expression levels might be genetically and epigenetically predetermined in individual cells and might not be regulated or changed by signals triggered by factors in the culture medium. In the latter case, CHD7 expression levels in cultured cells might change if different dominant cell populations were selected based on a growth advantage in a new culture medium. To evaluate these possible mechanisms, cells in the culture were marked by their CNVs so that changes in the dominant cell population could be detected by comparing CNV profiles. H9 cells cultured with Es8 medium were transferred to RFF2 medium and then were placed back in Es8 medium, and the CNV profiles of H9 cells were examined and compared. Notably, the CNV profiles of cells cultured with Es8 medium included CNVs at loci 4q22.1, 8q23.1, 16p11.2, and Xq26.1, whereas cells cultured with RFF2 medium had CNVs at none of these loci. Additionally, cells cultured with RFF2 medium contained CNVs at the specific locus 14q32.33, and these CNVs were not detected in cells cultured with Es8 medium, indicating that the cell population cultured with Es8 medium was different from that cultured with RFF2 medium (Fig.1B). This observation led us to explore the mechanisms through which certain cell populations could be selected to expand under specific culture conditions.

Next, we explored the impact of cell culture medium on the metabolic systems of cultured cells. The major metabolic pathway used by PSCs and cancer cells is the glycolytic pathway7, which is coupled with suppression of mitochondrial activity, as reflected by a low mitochondrial membrane potential (M) and reduced ROS in the mitochondria8,9. We found that the majority of cells cultured with Es8 medium did not show marked ROX staining, which was used to detect ROS produced by mitochondrial activity; the exception was that cells along the rims of colonies did show ROX staining. Furthermore, JC-1 assays showed a suppression of mitochondrial membrane voltage, suggesting that there was no marked mitochondrial activity by day 3 of culture (Fig.2A). In contrast, cells cultured with RFF2 showed marked ROX staining in most cells and an activated mitochondrial membrane potential by the JC-1 assays, suggesting activated mitochondrial function in cells cultured with RFF2 (Fig.2A). RFF2 medium contained high concentrations (approximately 23mg/mL) of protein and various amino acids in addition to moderately high glucose (2.52g/L), which could support mitochondrial function. However, Es8 medium contained high glucose (3.1g/L) and a limited amount of amino acids. Thus, Es8 medium could support the glycolytic pathway and at the same time limit the activation of mitochondrial function. The suppressed mitochondrial membrane voltage of cells cultured with Es8 medium supported this idea. There was a reciprocal relationship between the expression of CHD7 and mitochondrial function when cells were maintained in an undifferentiated state (Fig.2A). Metabolic analysis showed that the RFF2 culture medium contained malate and citrate as a result of activation of the tricarboxylic acid cycle in cells, whereas the Es8 culture medium did not (Fig.2B), consistent with the above argument. Furthermore, 2-aminoadipic acid (2-AAA) was detected in the RFF2 medium but not in the Es8 medium (Fig.2B), indicating that the kynurenine catabolic pathway, which leads to loss of an undifferentiated state and initiation of ectoderm differentiation6, was activated in cells cultured with RFF2. This observation suggested that some cells cultured with RFF2 exhibited activated mitochondrial function and underwent spontaneous differentiation, but could not be maintained in RFF2 as this medium lacked the factors necessary to support differentiated cells, and therefore these cells died. Thus, only undifferentiated cells with mitochondrial activation below the permissible level not to undergo differentiation could be cultured and maintained with the RFF2 medium. A positive correlation between the activation of mitochondrial membrane voltage and the initiation of differentiation, as suggested by the secretion of 2-AAA, was observed during the culture of cells with RFF2. This observation was supported by additional experiments; namely, H9 cells cultured with Es6 medium depleted of basic fibroblast growth factor and transforming growth factor 1 compared with Es8 medium showed both an initiation of ectodermal differentiation, as demonstrated by gene expression profiling using RT-qPCR (Fig.2C, Fig. S1), and an elevated mitochondrial membrane voltage (Fig.2A,C). Thus, there is evidence that the activation of mitochondrial function is coupled with the initiation of differentiation processes. Next, we examined the impact of elevated CHD7 expression levels and the induction of spontaneous differentiation by introducing mCHD7 into undifferentiated cells.

Activation of mitochondrial function is coupled with differentiation. (A) Morphology, CellROX (ROX) immunostaining, CHD7 copy numbers, and mitochondrial membrane voltage (JC-1 assays) in cells cultured with Es8 medium on VTN-Ncoated dishes (Es8/VTN) for 3days (left panels) or with RFF2 medium on VTN-Ncoated dishes (RFF2/VTN) for 3days (right panels) are shown. Mitochondrial membrane voltage was assessed by subtracting baseline electrons (after depolarization) from total electrons (red circle). The percentage of each fraction in the scatter plot of JC-1 assays is shown. (B) H9 cells were cultured with Es8 or RFF2 medium, and culture medium was collected and replaced with fresh medium every day for 3days. 2-Aminoadipic acid (2-AAA), malate, and citrate levels in culture medium were measured using LCMS/MS. The measured values were standardized as the mean area ratio/cell/h for 3days. The average values (n=3) with error bars (SD) are shown in the bar graphs. The results of three independent experiments are shown. (C) Morphology, ROX staining, mitochondrial membrane voltage (JC-1 assays; red circle), and gene expression profiles (RT-qPCR score card panels) of H9 cells cultured with Es8 medium on VTN-Ncoated dishes on day 5 (left panel: starting material for differentiation by Es6 medium) and Es6 medium on VTN-Ncoated dishes on day 5 are shown (right panel). The interpretation of gene expression levels by RT-qPCR is shown in the attached table. The results of three independent experiments are shown.

There was a positive correlation between the level of CHD7 expression in undifferentiated cells and the differentiation potential manifested by the number of EBs formed in the EB formation assay (Fig.1A). Interestingly, mCHD7 induced differentiation of the three germ layers simultaneously, as determined by RT-qPCR in cells cultured with both Es8 and RFF2 media (Fig.3A, Fig. S2), suggesting a positive role of CHD7 in both endodermal and mesodermal differentiation processes as well as in ectodermal development. Furthermore, this suggested that there is an upper permissible level of CHD7 being in an undifferentiated state. Es8 and RFF2 media are designed to support the proliferation of undifferentiated cells, not differentiated cells, and cells that forced to differentiate following the introduction of mCHD7, could not be maintained in these culture media. Consequently, the number of cells to form EBs was markedly reduced after introduction of mCHD7 (Fig.3A). Moreover, the introduction of siCHD7 reduced the differentiation potential of cells cultured with Es8, as reflected by the marked reduction in the number of EBs formed (Fig.3A). The introduction of siCHD7 to cells cultured with RFF2 further reduced the level of CHD7 and naturally led to no or few EBs being generated. These results provided evidence for the observation in Fig.1A, demonstrating that the differentiation potential of undifferentiated cells correlated with CHD7 expression.

CHD7 expression affected the differentiation potential and growth of undifferentiated cells. (A) H9 cells cultured with Es8 on VTN-Ncoated dishes (Es8/VTN, left panels) or with RFF2 on VTN-Ncoated dishes (RFF2/VTN, right panels) were transfected with mock (control), mCHD7, or siCHD7. The morphology, CHD7 copy numbers, gene expression profiles (RT-qPCR), EB morphology, and EB numbers formed at day 14 under different culture conditions are shown. The representative results of three independent experiments are shown. (B) CHD7 expression in H9 cells determined by flow cytometry after cells were transferred from RFF2 to Es8 on VTN-Ncoated dishes at passage 0 (P0), P5, and P7. Cells were cultured for 3days between passages. (C) Fold increase of H9 cells after 48h (upper panel) and CHD7 expression, as determined by RT-qPCR, after transfection of H9 cells with various doses of siCHD7 (lower panel). The average values (n=3) with error bars (SD) are shown in the bar graphs. Representative data from three independent experiments are shown.

It is interesting to note that both the increased expression of mCHD7 and the activation of mitochondrial function induced differentiation. Therefore, there must be a reciprocal relationship between these events in cells in an undifferentiated state. In other words, cells with activated mitochondrial function need to express a limited level of CHD7 to grow in an undifferentiated state at the expense of having a reduced differentiation potential, whereas cells with suppressed mitochondrial function could have relatively high CHD7 levels, enabling these undifferentiated cells to retain differentiation potential. The level of CHD7 that can ensure the differentiation potential of cells varied across cell lines and culture methods, therefore we cannot determine a universal cutoff value for every cell line. However, H9 cells with a CHD7 copy number of less than 2000 copies/5ng total RNA showed a limited differentiation potential when cultured on VTN-Ncoated dishes (Figs. 1B, 2A, 3A).

In the previous sections, we have shown (1) the introduction of mCHD7 induced spontaneous differentiation (Fig.3A), (2) the differentiation process was coupled with the activation of mitochondrial function (Fig.2C), and (3) there was a reciprocal relationship between the CHD7 expression level and the degree of mitochondrial function in undifferentiated cells (Fig.2A). The question is how the CHD7 expression and the degree of mitochondrial function corelated each other. We showed culture medium selected a cell population to grow (Fig.1B), and the activation of mitochondria of cells in culture is directly affected by the formula of culture medium (Fig.2A). While, we could not demonstrate the relationship between formula of the medium and the expression of CHD7, rather the CHD7 expression level in cells as assessed by flow cytometry showed a broad coefficient of variation (CV) just after the culture medium was changed from RFF2 to Es8 (Fig.3B, P0). Then, the level of CHD7 expression came to converge at the highest level during the culture (Fig.3B, P5 and P7). This result suggests that cells with a higher CHD7 expression have a growth advantage and become dominant during the culture. This presumption was manifested by the CHD7 knockdown experiment using siCHD7. This experiment indicated that the level of CHD7 was positively correlated with cell proliferation potential (Fig.3C) and cells with a higher CHD7 expression became dominant due to a growth advantage after a couple of passages. This would explain the observation that the expression of CHD7 reached its highest level during the late passages, as shown in Fig.3B (P7).

In addition to the differentiation potential, the retention of self-renewal potential is a key feature of PSCs. PSCs require cell-to-cell contact to grow and, therefore, PSCs need to form colonies. For the clinical application of PSCs, we must focus on an animal-free cell culture system. Therefore, synthetic ECM was used as the dish-coating material based on regulatory considerations. However, cells on the rims of the 2-dimensional (2-D) colonies lack the signals triggered by cell-to-cell contact at one open end, which is in sharp contrast with the majority of cells located in the middle of the colony that are surrounded by other cells along their cell membrane without interruption. Cells along the rim of the colony have an uneven distribution of molecules and ion flux related to the cell-to-cell contact-mediated signals and undergo uneven segregation in mitosis. This, then, results in a break of the self-renewal state where two identical daughter cells are generated from a mother cell, triggering spontaneous differentiation10,11,12. Indeed, cells on the rims of the colonies were positively stained with anti-superoxide dismutase 2 (SOD2) antibodies (Fig.4A). SOD2 is an enzyme that belongs to the Fe/Mn superoxide dismutase family, which scavenges excess ROS generated as a result of mitochondrial activation. SOD2 gene expression in H9 cells in the culture showed that these cells committed ectoderm and mesoderm differentiation (Fig.4A). Consequently, the population of undifferentiated cells would decrease if the spontaneously differentiated cells were not properly removed from the culture. Notably, the percentage of SOD2-positive cells (4.9%) on day 5 of culture with Es8/L511 was reduced after cells were seeded in single-cell suspensions on VTN-N(0.9%), L521-(2.6%), or L511-(2.8%) coated dishes after 30h (Fig.4B). This suggests that the ability of cells to adhere to the ECM was reduced in differentiated cells compared with undifferentiated cells, and the cell-binding ability of L511 or L521 for differentiated cells was higher than that of VTN-N. Gene expression profiles showed that cells cultured on L511 or L521 were committed to ectoderm and mesoderm differentiation (Fig.4B). Thus, by exploiting the reduced cell adhesion properties of differentiated cells and the less potent cell-binding properties of VTN-N, differentiated cells could be effectively eliminated from the culture at a single-cell level by seeding cells in a single-cell suspension at each passage.

The removal of differentiated cells by seeding on a less adhesive material. (A) H9 cells cultured with Es8 on L511-coated dishes for 5days were stained with anti-SOD2 antibodies (upper left panel), and SOD2-positive (red dots) and SOD2-negative (black dots) cells were sorted (upper right panel) to examine the ectodermal or mesodermal gene expression patterns of each population by RT-qPCR (bottom panel). (B) H9 cells cultured with the conditions described in panel A (total 2.1106 cells, 4.9% SOD2-positive cells) were collected and 5.0104 cells from them were seeded as single-cell suspensions either on L511-, L521-, or VTN-Ncoated dishes and cultured for 30h with Es8. The total cell numbers harvested and the percentages of SOD2-positive cells under different culture conditions are shown. The ectodermal or mesodermal gene expression levels of cells cultured under relevant conditions as determined by RT-qPCR are shown in the lower bar graph. The interpretation of gene expression levels determined by RT-qPCR is shown in the attached table. Representative results from three independent experiments are shown.

In previous sections, we showed data using ESC H9 cells as the standard control PSC clone to avoid possible arguments about iPSC clones having diverse genetic and epigenetic backgrounds. Therefore, there is a strong need to standardize iPSC clones to develop iPSC-based cell therapy. In the previous section, we showed that the differentiation potential of even ESC H9 cells, which have relatively homogenous genetic and epigenetic profiles, could be altered by culture medium (Fig.1) and there is a possibility that we can improve the differentiation potential by optimizing culture conditions. Optimized culture conditions may include the selection of an appropriate culture medium that supports the glycolytic pathway, the seeding of cells as single-cell suspensions during passaging, and the culture of cells on an ECM substrate with a relatively weak cell-binding capacity, such as VTN-N, to minimize the inclusion of differentiated cells in undifferentiated cell cultures and to maintain the self-renewal population for the expansion of cell clones. To verify that culture conditions improved the differentiation potential of established iPSC clones, we cultured the iPSC clones 253G113, 201B75, PFX#9, and SHh#24 and the ESC clone H9 (control) with iPSC medium4 or mTeSR1 and maintained them on feeder cells or on L511- or L521-coated dishes that were transferred to Es8 medium, cultured on VTN-Ncoated dishes, and passaged as single-cell suspensions. The CHD7 expression profile by flow cytometry and the number of EBs formed before and after the transition to Es8/VTN-N culture were measured. Notably, increased levels of CHD7 expression by flow cytometry before and after recloning (Fig.5A) may be a good index for an improved differentiation potential of cells, as manifested by an increase in the number of EBs formed (Fig.5B). The convergence of CHD7 expression by flow cytometry (Fig.5A) may represent a decreased variance in the differentiation potential among iPSCs in a given culture.

Recloning of cells with differentiation potential based on culture conditions. (A) iPSC clones (201B7, PFX#9, SHh#2, or 253G1 cells) or ESC clones (H9 cells) were cultured either on feeder cells or on L511- or L521-coated dishes with iPSC or mTeSR1 medium. Clones were then transferred to Es8 medium and cultured on VTN-Ncoated dishes. The mean and convergence of CHD7 expression of cell clones was determined by flow cytometry before (gray histogram) and after (red histogram) changing culture conditions. Representative results from three independent experiments are shown. (B) Flow cytometric analysis of cell clones for the mean and coefficient of variation (CV) measured before (circle) and after (square) changing culture conditions are plotted on the left panel and the differentiation potential before and after changing the culture conditions was assessed by the number of EBs formed and is shown on the right panel. The data set shown in (B) was generated from the same samples shown in (A).

Although we cannot alter the genetic background of individual cells by changing culture conditions, a cell population with a higher differentiation potential could be selected to grow, or be recloned, by culture conditions that support the glycolytic pathway and by eliminating spontaneously differentiated cells by seeding on an ECM with a less potent cell-binding capability, thus exploiting their reduced adhesive properties. This could also reduce the variability in differentiation potential, especially among iPSC clones.

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When coronary arteries are blocked, starving the heart of blood, there are good medications and treatments to deploy, from statins to stents. Not so for heart failure, the leading factor involved in heart disease, the top cause of death worldwide.

Its whats on death certificates, said cardiologist Christine Seidman.

Seidman has long been interested in heart muscle disorders and their genetic drivers. She studies heart failure and other conditions that affect the myocardium the muscular tissue of the heart not the blood vessels where atherosclerosis and heart attacks come from, although their consequences are also felt in the myocardium, including heart failure.

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With her colleagues at Brigham and Womens Hospital and Harvard Medical School, she and a long list of international collaborators have been exploring the genetic underpinnings of heart failure. Based on experiments deploying a new technique called single-nucleus RNA sequencing on samples from heart patients, on Thursday they reported in Science their discovery of how genotypes change the way the heart functions.

Their work raises the possibility that some of the molecular pathways that lead to heart failure could be precisely targeted, in contrast to treating heart failure as a disease with only one final outcome.

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Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting, she said. To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

Seidman talked with STAT about the research, including how snRNAseq solves the smoothie problem, and what it might mean for patients. The conversation has been edited for clarity and brevity.

What happens in heart failure?

The heart becomes misshapen in one of two ways. It either becomes hypertrophied, where the walls of heart muscle become thickened and the volume within the heart is diminished, in what we call hypertrophic cardiomyopathy. Or it becomes dilated, when the volume in the heart is expanded and the walls become stretched. I think of it as an overinflated balloon, and that is called dilated cardiomyopathy.

Hypertrophy and dilatation are known to cause the heart over time to have profoundly diminished functional capacity. And clinically, we call that heart failure, much more commonly arising from dilated cardiomyopathy.

What does it feel like to patients?

When we see patients clinically, theyre short of breath, they have fluid retention. When we look at their hearts, we see that the pump function is diminished. That has led to a hypothesis of heart failure as sort of the end stage of many different disorders, but eventually the heart walks down a final common pathway. Then you need a transplant or a left ventricular assist device, or youre going to die prematurely.

What can be done?

Heart failure is a truly devastating condition, and it can arise early in life, in middle age, and in older people. There is no treatment for it, no cure for it, except cardiac transplantation, of course, which provides a whole host of other problems.

How did you approach this problem?

One of the questions we wanted to answer is, are there signals that we can discern that say there are different pathways and there are molecules that are functioning in those pathways that ultimately converge for failure, but through different strategies of your heart?

We treat every patient with heart failure with diuretics. We give them a series of different medications to reduce the pressure against which the heart has to contract. Im clinically a cardiologist, but molecularly Im a geneticist, so it doesnt make sense. If your house is falling down because the bricks are sticking together or if its falling down because the roof leaks and the water is pooling, you do things differently.

Tell me how you used single-cell RNA sequencing to learn more.

Looking at RNA molecules gives us a snapshot of how much a gene is active or inactive at a particular time point. Until recently, we couldnt do that in the heart because the approach had been to take heart tissue, grind it all up, and look at the RNAs that are up or down. But that gives you what we call a smoothie: Its all the different component cells those strawberries, blueberries, bananas mixed together.

But theres a technology now called single-cell RNA sequencing. And that says, what are the RNAs that are up or down in the cardiomyocytes as compared to the smooth muscle cells, as compared to the fibroblasts, all of which are in the cells? You get a much more precise look at whats changing in a different cell type. And thats the approach that we use, because cardiomyocytes [the cells in the heart that make it contract] are very large. Theyre at least three times bigger than other cells. We cant capture the single cell it literally does not fit through the microfluidic device. And so we sequenced the nuclei, which is where the RNA emanates from.

What did you find?

There were some similarities, but what was remarkable was the degree of differences that we saw in cardiomyocytes, in endothelial cells, in fibroblasts. Theres a signature thats telling us I walked down this pathway as compared to a different one that caused the heart to fail, but through activation or lack of activation of different signals along the way.

And that to me is the excitement, because if we can say that, we can then go back and say, OK, what happens if we were to have tweaked the pathway in this genotype and a different pathway in a different genotype? Thats really what precision therapy could be about, and thats where we aim to get to.

Whats the next step?

It may be that several genotypes will have more similarities as compared to other genotypes. But understanding that, I think, will allow us to test in experimental models, largely in mice, but increasingly in cellular models of disease, in iPS [induced pluripotent stem] cells that we can now begin to use molecular technologies to silence a pathway and see what that does to the cardiomyocytes, or silence the fibroblast molecule and see what that does in that particular genotype.

To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

What might this mean for patients?

If we knew that an intervention would make a difference thats where the experiments are we would intervene when we saw manifestations of disease. So the reason I can tell you with confidence that certain genes cause dilated cardiomyopathy is theres a long time between the onset of that expansion of the ventricle until you develop heart failure. So theres years for us to be able to stop it in its tracks or potentially revert the pathology, if we can do that.

What else can you say?

I would be foolish not to mention the genetic cause of dilated cardiomyopathy. Ultimately, if you know the genetic cause of dilated cardiomyopathy, this is where gene therapy may be the ultimate cure. Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting.

My colleagues have estimated that approximately 1 in 250 to 1 in 500 people may have an important genetic driver of heart muscle disease, cardiomyopathy. Thats a huge number, but not all of them will progress to heart failure, thank goodness. Around the world, there are 23 million people with heart failure. Its what ends up on most peoples death certificate. It is the most common cause of death.

Its a huge, huge burden. And there really is no cure for it except transplantation. We dont have a reparative capacity, so were going to have to know a cause and be able to intervene precisely for that cause.

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Creative Biolabs stem cell platform offers expertise in the generation, bioprocess scale-up, and differentiation of iPSCs.

New York, USA August 3, 2022 Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from somatic cells. iPSC technology has evolved rapidly since its inception in 2006 and has been widely used for disease modeling.

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