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  3. Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice

  • JCI Insight. 2020 Jun 4;5(11):e134287. doi: 10.1172/jci.insight.134287.
Congshan Sun 1 2,  In Young Choi 3,  Yazmin I Rovira Gonzalez 2 4,  Peter Andersen 3 5,  C Conover Talbot Jr 6,  Shama R Iyer 7,  Richard M Lovering 7 8,  Kathryn R Wagner 1 2,  Gabsang Lee 1 3
Affiliations

Affiliations

  • 1 Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 2 Center for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland, USA.
  • 3 Institute for Cell Engineering.
  • 4 Cellular and Molecular Medicine Graduate Program, and.
  • 5 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 6 The Johns Hopkins School of Medicine Institute for Basic Biomedical Sciences, Baltimore, Maryland, USA.
  • 7 Department of Orthopaedics and.
  • 8 Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
PMID: 32343677 DOI: 10.1172/jci.insight.134287
Abstract

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy. In the present study, when human induced pluripotent stem cells (hiPSCs) were differentiated into myoblasts, the myoblasts derived from DMD patient hiPSCs (DMD hiPSC-derived myoblasts) exhibited an identifiable DMD-relevant phenotype: myogenic fusion deficiency. Based on this model, we developed a DMD hiPSC-derived myoblast screening platform employing a high-content imaging (BD Pathway 855) approach to generate parameters describing morphological as well as myogenic marker protein expression. Following treatment of the cells with 1524 compounds from the Johns Hopkins Clinical Compound Library, compounds that enhanced myogenic fusion of DMD hiPSC-derived myoblasts were identified. The final hits were ginsenoside Rd and fenofibrate. Transcriptional profiling revealed that ginsenoside Rd is functionally related to FLT3 signaling, while fenofibrate is linked to TGF-β signaling. Preclinical tests in mdx mice showed that treatment with these 2 hit compounds can significantly ameliorate some of the skeletal muscle phenotypes caused by dystrophin deficiency, supporting their therapeutic potential. Further study revealed that fenofibrate could inhibit mitochondrion-induced Apoptosis in DMD hiPSC-derived cardiomyocytes. We have developed a platform based on DMD hiPSC-derived myoblasts for drug screening and identified 2 promising small molecules with in vivo efficacy.

Keywords

Human stem cells; Muscle Biology; Skeletal muscle; Stem cells.

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