Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

Abstract

Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments are urgently needed. From this perspective, it is particularly important to establish reliable in vitro models of human muscle that allow the recapitulation of disease features as well as the screening of genetic and pharmacological therapies. We herein review and discuss advances in the development of in vitro muscle models obtained from human induced pluripotent stem cells, which appear to be capable of reproducing the lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential. In addition, these platforms have been used to assess genetic correction strategies such as gene silencing, gene transfer and genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as well as to evaluate novel small molecules aimed at ameliorating muscle degeneration. Furthermore, we discuss the challenges related to in vitro drug testing and provide a critical view of potential therapeutic developments to foster the future clinical translation of preclinical muscular dystrophy studies.

Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases

“…The skeletal muscle is a dynamic tissue that continuously renews during adult life. A pool of muscle stem cells, also called satellite cells, is present within muscles during all life stages [ 62 , 63 ]. Satellite cells are usually quiescent but can activate after muscle injury, differentiating into myoblasts and myocytes [ 45 ].…”

hiPSC-Derived Cells as Models for Drug Discovery 2.0

“…Abati et al [ 11 ] reviews the development of in vitro iPSC-derived muscle models for muscular dystrophies. These models recapitulate these diseases, e.g., lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential.…”