Duchenne muscular dystrophy hiPSC-derived myoblast drug screen identifies compounds that ameliorate disease in mdx mice
PublisherThe American Society for Clinical Investigation
MetadataShow full item record
AbstractDuchenne 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-? 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.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85085961759&doi=10.1172%2fjci.insight.134287&partnerID=40&md5=5099853803723ca5519dbe8007a0af44; http://hdl.handle.net/10713/13082
- Engraftment of human induced pluripotent stem cell-derived myogenic progenitors restores dystrophin in mice with duchenne muscular dystrophy.
- Authors: He R, Li H, Wang L, Li Y, Zhang Y, Chen M, Zhu Y, Zhang C
- Issue date: 2020 May 19
- Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model.
- Authors: Choi IY, Lim H, Estrellas K, Mula J, Cohen TV, Zhang Y, Donnelly CJ, Richard JP, Kim YJ, Kim H, Kazuki Y, Oshimura M, Li HL, Hotta A, Rothstein J, Maragakis N, Wagner KR, Lee G
- Issue date: 2016 Jun 7
- Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.
- Authors: Kamdar F, Das S, Gong W, Klaassen Kamdar A, Meyers TA, Shah P, Ervasti JM, Townsend D, Kamp TJ, Wu JC, Garry MG, Zhang J, Garry DJ
- Issue date: 2020 Mar 17
- SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy.
- Authors: Sarathy A, Wuebbles RD, Fontelonga TM, Tarchione AR, Mathews Griner LA, Heredia DJ, Nunes AM, Duan S, Brewer PD, Van Ry T, Hennig GW, Gould TW, Dulcey AE, Wang A, Xu X, Chen CZ, Hu X, Zheng W, Southall N, Ferrer M, Marugan J, Burkin DJ
- Issue date: 2017 Jun 7
- Creation of Dystrophin Expressing Chimeric Cells of Myoblast Origin as a Novel Stem Cell Based Therapy for Duchenne Muscular Dystrophy.
- Authors: Siemionow M, Cwykiel J, Heydemann A, Garcia-Martinez J, Siemionow K, Szilagyi E
- Issue date: 2018 Apr