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

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.

Keywords: disease models; genetic modification; iPSC; muscular dystrophy; preclinical studies; stem cell therapy.

Figure 1

Flowchart of iPSC-derived myogenic cell production process for preclinical trials (A) and clinical trials (B). (A) In preclinical trials, cells obtained from a third party or in-house are reprogrammed into iPSCs and genetically modified (if applicable), according to the therapeutic requirements. The edited iPSCs are subject to myogenic differentiation, purification, and expansion. These are cryopreserved for preclinical trials in animal models. (B) In clinical trials, the manufacturing process needs to comply with appropriate FDA regulations. Cells that are obtained from a consenting donor (for example, blood cells) are reprogrammed into iPSCs. The iPSCs are cryopreserved as a primary cell stock (if applicable). These cells undergo genetic modification (if applicable), allowing for the creation of a secondary cell stock of edited iPSCs. The edited iPSCs are subject to myogenic differentiation, purification, and expansion. The expanded cells will be formulated into a final product and transplanted into clinical trial subjects. (Created with BioRender.com).