Preclinical studies of pluripotent stem cell-derived myogenic progenitors in non-human primates

非人灵长类多能干细胞来源的肌源祖细胞的临床前研究

• 批准号: 10311166
• 负责人: Melanie Lynn Graham
• 金额: $ 60.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311166
• 关键词: Address; Adverse event; Alleles; Allogenic; Animal Model; Autologous; Biochemical; Biodistribution; Biological Assay; Cell Therapy; Cell Transplantation; Cell membrane; Cells; Cessation of life; Chronic; Clinical; Collaborations; Companions; Complex; Consultations; Cyclic GMP; Defect; Disease; Dose; Duchenne muscular dystrophy; Dystrophin; Engraftment; Environment; Future; Generations; Genetic; Genetic Diseases; Glycoproteins; Goals; Grant; Homologous Transplantation; Human; Immunosuppression; Impairment; Injury; Investigational Drugs; Knowledge; Laboratories; Lead; MHC Class I Genes; MHC Class II Genes; Methods; Minnesota; Modeling; Mononuclear; Movement; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Muscular Dystrophies; Myopathy; Outcome Measure; Patients; Phase; Physiological; Pluripotent Stem Cells; Positioning Attribute; Protocols documentation; Regenerative Medicine; Research; Research Personnel; Route; Safety; Skeletal Muscle; Surgeon; System; Technology; Therapeutic; Therapeutic Effect; Time; Transplantation; United States Food and Drug Administration; United States National Institutes of Health; Universities; Xenograft procedure; base; cell type; clinical application; clinical translation; cohort; cost; effective therapy; experimental study; first-in-human; immunosuppressed; induced pluripotent stem cell; injured; muscle regeneration; nonhuman primate; pre-clinical research; preclinical study; primary outcome; progenitor; programs; response; satellite cell; skeletal; stem cell therapy; tissue degeneration; virtual

Summary Muscular dystrophies are genetically and clinically heterogeneous disorders characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common, Duchenne Muscular Dystrophy (DMD), is caused by genetic and biochemical defects of the dystrophin-glycoprotein complex (DGC). These alterations lead to cell membrane damage and death of muscle cells, resulting in chronic tissue degeneration and impaired muscle contractility. Although no effective treatment is available at present, one attractive therapeutic approach is to use cell-based therapies to promote muscle regeneration. There has been tremendous excitement for the therapeutic potential of induced pluripotent stem (iPS) cells in treating genetic diseases since these cells have virtually unlimited proliferation potential, and can differentiate into all cell types. We have pioneered a method to generate engraftable skeletal myogenic progenitors from pluripotent stem cells through conditional expression of Pax3 or Pax7. This approach results in highly efficient generation of therapeutic myogenic progenitors, which when transplanted into dystrophic mice locally or systemically produce large quantities of functional skeletal muscle tissue that incorporates normally into the host muscle. Importantly, a fraction of transplanted cells remains mononuclear, and displays key features of skeletal muscle stem cells, including satellite cell localization, response to re-injury, and contribution to muscle regeneration in secondary transplantation assays. Based on these encouraging findings, we have begun the manufacturing of these cells under cGMP compatible conditions and performed preclinical studies in murine recipients. The results from these studies are promising but before moving this therapy towards clinical translation, it would be ideal to assess scalability, delivery, distribution, safety, and engraftment in larger animal models. Therefore, here we propose preclinical studies to investigate these parameters using non-human primates (NHP) as recipients. It will also be critical to understand the impact of HLA mismatch on muscle engraftment, and NHP represent the ideal system to properly address this question. The transplantation of NHP iPS cell-derived myogenic progenitors into NHP recipients will provide critical knowledge for understanding tolerance in the allogeneic setting. This aspect, which has important implications for regenerative medicine, has been mostly overlooked in the pluripotent stem cell field. These are all critical prerequisites to advance this therapy towards successful clinical translation.

概括 肌肉营养不良是遗传性和临床上异质性疾病，其特征是进行性疾病 控制运动的骨骼肌的虚弱和变性。最常见的，杜钦（Duchenne） 肌肉营养不良（DMD）是由肌营养不良蛋白糖蛋白的遗传和生化缺陷引起的 复杂（DGC）。这些改变导致细胞膜损伤和肌肉细胞的死亡，导致慢性 组织变性和肌肉收缩性受损。尽管目前尚无有效的治疗 一种有吸引力的治疗方法是使用基于细胞的疗法来促进肌肉再生。有 对于诱导多能茎（IP）细胞的治疗潜力而引起了极大的兴奋 遗传疾病由于这些细胞几乎具有无限的增殖潜力，并且可以区分所有细胞 类型。我们开创了一种从多能茎产生可植入的骨骼肌祖祖细胞的方法 细胞通过PAX3或PAX7的条件表达。这种方法导致高效的生成 治疗性肌源性祖细胞，当将其移植到局部或全身产生的营养不良小鼠中 大量的功能性骨骼肌组织通常融入宿主肌肉。重要的是， 一小部分移植细胞仍然是单核的，并且显示骨骼肌干细胞的关键特征， 包括卫星细胞定位，对重伤的反应以及对次级肌肉再生的贡献 移植测定。基于这些令人鼓舞的发现，我们已经开始制造这些细胞 在CGMP兼容条件下，并在鼠受体中进行了临床前研究。这些结果 研究很有希望，但是在将这种疗法转向临床翻译之前，评估是理想的选择。 较大动物模型中的可伸缩性，分配，分布，安全和植入。因此，我们在这里提出 临床前研究使用非人类灵长类动物（NHP）作为接受者研究这些参数。也将是 了解HLA不匹配对肌肉植入的影响至关重要，而NHP代表理想系统 正确解决这个问题。 NHP IPS细胞衍生的肌祖细胞的移植到NHP 接收者将提供关键的知识，以理解同种异体环境中的宽容。这方面，哪个 对再生医学具有重要意义，在多能干细胞中大多被忽略了 场地。这些都是将这种疗法推向成功临床翻译的关键先决条件。