Challenges and Considerations of Preclinical Development for iPSC-Based Myogenic Cell Therapy

Authors

Congshan Sun
Carlo Serra
Brianna Harley Kalicharan
Jeffrey Harding
Mahendra Rao

Publication Date

3-29-2024

Journal

Cells

DOI

10.3390/cells13070596

PMID

38607035

PMCID

PMC11011706

PubMedCentral® Posted Date

3-29-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Induced Pluripotent Stem Cells, Muscle, Skeletal, Muscular Dystrophies, Cell- and Tissue-Based Therapy, Cell Differentiation, iPSC, stem cell therapy, muscular dystrophy, preclinical studies, disease models, genetic modification

Abstract

Cell therapies derived from induced pluripotent stem cells (iPSCs) offer a promising avenue in the field of regenerative medicine due to iPSCs' expandability, immune compatibility, and pluripotent potential. An increasing number of preclinical and clinical trials have been carried out, exploring the application of iPSC-based therapies for challenging diseases, such as muscular dystrophies. The unique syncytial nature of skeletal muscle allows stem/progenitor cells to integrate, forming new myonuclei and restoring the expression of genes affected by myopathies. This characteristic makes genome-editing techniques especially attractive in these therapies. With genetic modification and iPSC lineage specification methodologies, immune-compatible healthy iPSC-derived muscle cells can be manufactured to reverse the progression of muscle diseases or facilitate tissue regeneration. Despite this exciting advancement, much of the development of iPSC-based therapies for muscle diseases and tissue regeneration is limited to academic settings, with no successful clinical translation reported. The unknown differentiation process in vivo, potential tumorigenicity, and epigenetic abnormality of transplanted cells are preventing their clinical application. In this review, we give an overview on preclinical development of iPSC-derived myogenic cell transplantation therapies including processes related to iPSC-derived myogenic cells such as differentiation, scaling-up, delivery, and cGMP compliance. And we discuss the potential challenges of each step of clinical translation. Additionally, preclinical model systems for testing myogenic cells intended for clinical applications are described.