cGMP ipsc衍生肌源性祖细胞产品治疗肌营养不良的临床前质量、安全性和有效性

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-07-17 DOI:10.1016/j.ymthe.2025.07.007

Karim Azzag,Alessandro Magli,James Kiley,Darin Sumstad,Diane Kadidlo,Sarah B Crist,Beverly Norris,Aaron Ahlquist,Laura L Hocum Stone,John Everett,Jill Schappa Faustich,Davis Seelig,Parthasarathy Rangarajan,Hyunkee Kim,Craig Flory,Frederic Bushman,Sabarinathan Ramachandran,Peter B Kang,Robert J Schumacher,John E Wagner,Michael Kyba,Melanie L Graham,David H McKenna,Rita C R Perlingeiro

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引用次数: 0

摘要

多能干细胞（PSC）衍生疗法正处于终末分化或瞬时所需细胞类型的临床试验中，但迄今为止，尚未批准PSC衍生试验提供组织特异性干细胞，也没有任何基于PSC的骨骼肌再生试验。我们描述了一个符合现行良好生产规范（cGMP）的过程，以产生大规模冷冻保存的pax7诱导的肌源性祖细胞，从psc中重建纤维和卫星细胞。我们对这种临床级细胞产品MyoPAXon进行了GLP条件下小鼠的生物分布、毒性和致瘤性研究，无不良反应，并证明了长期植入（bb10 - 1年）和对营养不良小鼠的疗效。将3700万至6000万MyoPAXon细胞移植到免疫抑制的非人灵长类动物中，显示出人类对肌纤维和卫星细胞的贡献，没有安全性问题。FDA最近批准了这一完全表征的现成cGMP产品，用于Duchenne MD的首次人体临床试验，代表了首个ipsc来源的组织特异性干细胞治疗。

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Preclinical quality, safety, and efficacy of a cGMP iPSC-derived myogenic progenitor product for the treatment of muscular dystrophies.

Pluripotent stem cell (PSC)-derived therapies are in clinical trials of terminally differentiated or transiently-required cell types, but to date no PSC-derived trial contributing tissue-specific stem cells has been approved, nor any PSC-based skeletal muscle regeneration trial. We describe a process in accordance with current good manufacturing practices (cGMP) to generate large-scale cryopreserved PAX7-induced myogenic progenitors, that reconstitute both fibers and satellite cells, from PSCs. We subjected this clinical-grade cell product, MyoPAXon, to biodistribution, toxicity, and tumorigenicity studies in mice under GLP conditions with no adverse effects, and demonstrate long-term engraftment (> 1 year), and efficacy in dystrophic mice. Transplantation of 37-60 million MyoPAXon cells into immunosuppressed non-human primates showed human contribution to muscle fibers and satellite cells, with no safety concerns. The FDA has recently authorized this fully characterized off-the-shelf cGMP product, for a first-in-human clinical trial in Duchenne MD, representing the first iPSC-derived tissue-specific stem cell therapy.

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.