Abstract: Mutations in the DMD gene are responsible for a range of rare diseases known as dystrophinopathies, that negatively impact cardiac and skeletal muscle function. The lack of available cures has devastating consequences for afflicted patients and their families, and reflects a need for new human-specific preclinical models to study disease mechanisms and develop effective treatments. To help address this unmet need, this study established induced pluripotent stem cell (iPSC) lines from 8 patients with DMD-related dystrophinopathies, including Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-Linked Dilated Cardiomyopathy (XLDCM). DMD, the most common and severe form, is characterized by early onset progressive skeletal muscle weakness and subsequent cardiomyopathy. The less common BMD presents with milder skeletal muscle weakness but can have severe cardiomyopathy. XLDCM, the rarest form, is distinguished by early onset severe cardiomyopathy without initial skeletal muscle weakness. IPSCs from 1 DMD, 2 BMD, and 1 XLDCM patients were differentiated into cardiomyocytes (iPSC-CMs), and their transcriptomic differences were analysed using bulk RNA sequencing, comparing to healthy and isogenic control data. Bioengineered human ventricular cardiac tissue strips (hvCTS) were also created to evaluate contractility. The findings revealed enrichment in KEGG pathways and multiple biological processes, including cardiomyopathies, cardiomyocyte structure organization, signal transduction, metabolism, cell adhesion, cell-matrix interaction, and repair response. Notably, DMD-derived iPSC-CMs showed significantly more dysregulated gene expressions, mirroring DMD's severe clinical phenotype. The study further indicated that a reduction in contractile force of patient-derived hvCTS could be linked to the dysregulated gene expressions and pathways, potentially impairing biological functions like cardiac contractility. This study provides vital insights into the cellular and molecular mechanisms underlying dystrophinopathy and underscores the potential of patient-derived iPSCs, and the derived cardiac cells and tissues, as a model for studying these conditions and accelerating the development of new therapies including cardiac gene therapy for clinical trials.
Funding Source: Start-Up Research Grant & Seed Fund for Basic Research (201711159006) by HKU General Research Fund (17123122) by RGC, UGC Innovation and Technology Fund (PRP/062/21FX) by ITC, HKSAR
