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Targeting Dystroglycanopathies using Pluripotent-derived Myogenic Progenitors

使用多能源性肌源性祖细胞靶向肌营养不良症

基本信息

批准号：
10561375
负责人：
Rita C. R. Perlingeiro
金额：
$ 51.61万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-10 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561375
关键词：
Address Affect Age Allogenic Autologous Biochemical Biological Assay Cell Compartmentation Cell Therapy Cell Transplantation Cells Chronic Clinical Trials Complication Development Disease model Engraftment Environment Extracellular Matrix Proteins Fibrosis Future Generations Genes Genetic Diseases Human Human Characteristics Immunologic Deficiency Syndromes Impairment In Vitro Injury Investigation Limb-Girdle Muscular Dystrophies MDC1C Mesoderm Methods Molecular Molecular Profiling Mononuclear Mus Muscle Muscle Fibers Muscle satellite cell Muscular Atrophy Muscular Dystrophies Mutation Myopathy Natural regeneration Patients Play Pluripotent Stem Cells Population Regenerative Medicine Respiratory Diaphragm Role Skeletal Muscle Somatic Cell Technology Therapeutic Therapeutic Effect Transplantation Walker-Warburg syndrome alpha Dystroglycan cell type congenital muscular dystrophy design dystroglycanopathy early onset fukutin related protein gene correction glycosylation human pluripotent stem cell in vivo induced pluripotent stem cell mouse model muscle regeneration mutant post-transplant progenitor programs regeneration potential repaired respiratory response satellite cell single-cell RNA sequencing skeletal stem cell therapy tissue degeneration transcriptome

项目摘要

Summary The biochemical hallmark of FKRP-associated dystroglycanopathies is the hypoglycosylation of α-dystroglycan (α-DG), which leads to disruption in the interaction of α-DG with extracellular matrix proteins, ultimately leading to muscle wasting. Recessive mutations in FKRP are associated with a heterogeneous spectrum of muscle disorders, ranging from severe early-onset to mild late-onset limb-girdle muscular dystrophy (LGMD2I) to several forms of congenital muscular dystrophy (MDC1C), including severe Walker-Warburg Syndrome. Respiratory impairment due to loss of diaphragm function is a prominent complication of both LGMD2I and MDC1C. No approved therapy currently exists for dystroglycanopathies. There has been tremendous excitement for the therapeutic potential of reprogrammed induced pluripotent stem (iPS) cells in treating genetic diseases. The premise of this project is that stem cell-based therapy consisting of human skeletal myogenic progenitors derived from iPSCs will replenish diseased muscle with normal functional muscle fibers as well as muscle stem cells, which have the potential to provide long-term therapeutic effect in dystroglycanopathies. We have developed and extensively validated 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. Therefore, our technology comprises a cell therapy to rebuild functional skeletal muscle, robust to future damage, in hosts with muscular dystrophy. We have recently shown that mouse and human PSC-derived myogenic progenitors contribute to significant myofiber and satellite cell repopulation in the immunodeficient FKRPP448L-NSG mouse model that we generated. Of therapeutic relevance, we have evidence of successful delivery of these myogenic progenitors directly into the diaphragm of FKRP mice. In addition, we have developed a universal gene correction strategy for FKRP, applied this to patient-specific WWS and LGMD2I iPSCs, and demonstrated in vitro and in vivo rescue of functional α-DG glycosylation. In this application, we propose studies that are critical for the development of successful therapeutic approaches for dystroglycanopathies, including understanding 1) the effect of the environment on the engraftment of transplanted cells and 2) the long-term functionality and molecular characteristics of human gene edited WWS and unaffected iPSC-derived myogenic progenitors, important for both autologous and allogeneic future therapeutic applications, respectively.

总结