Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. The current standard of care, corticosteroid treatment, delays the progression of muscle dysfunction but has serious side effects. DMD gene therapy and gene editing approaches are promising but face many challenges. Pharmacological approaches are being identified that could benefit DMD by modulating pathological mechanisms independent of the dystrophin mutation. However, many small molecule therapies have had difficulties showing efficacy while progressing through DMD clinical trials, possibly due to inadequate preclinical evaluation or to targeting mechanisms too late in the disease process. Although DMD is a progressive disease, there is evidence for early, embryonic- and fetal-stage defects in myogenesis and gene expression in DMD. In particular, our preliminary studies have identified one of the earliest known DMD phenotypes: a novel transcriptional trajectory of DMD human induced pluripotent stem cells (hiPSCs) undergoing myogenesis. By understanding how these early myogenic and transcriptional defects initiate and how they drive DMD pathology, we may be better positioned to identify and utilize DMD therapies. The hypothesis of this proposal is that epigenetic drugs, small molecules that target chromatin modifications and transcriptional regulation, can ameliorate early DMD transcriptional defects as well as improve downstream DMD pathology. Certain histone deacetylase inhibitors (HDACi) have shown promise for DMD in mice, zebrafish, and recent clinical trials. However, beyond these HDACi, epigenetic drugs have not been broadly and systematically studied for their efficacy and safety to treat DMD. The goals of this proposal are to identify novel epigenetic small molecules that are beneficial for DMD, by demonstrating effectiveness in multiple DMD models, and, in parallel, to better characterize the disrupted transcriptional and epigenetic mechanisms underlying DMD. We propose three Aims. First, we will identify the classes of epigenetic small molecules that improve the DMD phenotype, by screening an epigenetic drug library in dmd zebrafish. Our preliminary studies have already identified novel epigenetic drugs that rescue dmd zebrafish. Second, through single-cell genomics on hiPSC-derived DMD skeletal muscle, we will generate maps of transcriptome and chromatin packaging defects during the initiation and progression of DMD. We will test whether epigenetic drugs correct the novel transcriptional dysregulation phenotype, as well as functional deficits, that we have identified in hiPSC-derived DMD muscle. Third, we will evaluate epigenetic drugs for efficacy and safety in the DMD rat, assessing clinically relevant functional outcomes in skeletal and cardiac muscle. This project will provide novel basic scientific insight into the early epigenetic dysregulation occurring in DMD. The long-term impact will be the development of a three-model platform, zebrafish, rat and hiPSC lines, for DMD drug discovery and mechanistic and functional validation, taking advantage of each model system.

Public Health Relevance

This proposal will identify and characterize new epigenetic drug therapies for Duchenne muscular dystrophy (DMD). This proposal will also advance our understanding of the roles of epigenetic gene regulation in DMD. The proposed research is relevant to public health because this study will take advantage of three model systems, zebrafish, human cell lines, and rats, to advance potential new treatment options for DMD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Carifi, Emily Foran
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Seattle Children's Hospital
United States
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