@article{4c131de8d982490ea8ffd5bc98d570ea,
title = "Duchenne muscular dystrophy hiPSC–derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice",
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.",
author = "Congshan Sun and Choi, {In Young} and {Rovira Gonzalez}, {Yazmin I.} and Peter Andersen and {Conover Talbot}, C. and Iyer, {Shama R.} and Lovering, {Richard M.} and Wagner, {Kathryn R.} and Gabsang Lee",
note = "Funding Information: We thank members of the Wagner laboratory and the Lee laboratory for valuable discussions. Especially, we thank Hotae Lim (Institute for Cell Engineering, Johns Hopkins University School of Medicine) and Carlo Serra (Center for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger Institute) for providing technical support. This work was supported by NIH grants R01NS093213 and R01AR070751, the Maryland Stem Cell Research Fund (MSCRF), the Muscular Dystrophy Association (MDA) and the Global Research Development Center program from the Korea National Research Foundation (all to GL). This work was also funded by Stand Strong, Ryan?s Quest, Michael?s Cause, and Pietro?s Fight (all to KRW); a Maryland Stem Cell Fellowship (to CS); and American Heart Association Career Development Award 19CDA34760161 (to PA). Funding Information: We thank members of the Wagner laboratory and the Lee laboratory for valuable discussions. Especially, we thank Hotae Lim (Institute for Cell Engineering, Johns Hopkins University School of Medicine) and Carlo Serra (Center for Genetic Muscle Disorders, Hugo W. Moser Research Institute at Kennedy Krieger Institute) for providing technical support. This work was supported by NIH grants R01NS093213 and R01AR070751, the Maryland Stem Cell Research Fund (MSCRF), the Muscular Dystrophy Association (MDA) and the Global Research Development Center program from the Korea National Research Foundation (all to GL). This work was also funded by Stand Strong, Ryan{\textquoteright}s Quest, Michael{\textquoteright}s Cause, and Pietro{\textquoteright}s Fight (all to KRW); a Maryland Stem Cell Fellowship (to CS); and American Heart Association Career Development Award 19CDA34760161 (to PA). Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = jun,
day = "4",
doi = "10.1172/jci.insight.134287",
language = "English (US)",
volume = "5",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "11",
}