Zhou, YuanZhang, ChenXiao, WeidongHerzog, Roland W.Han, Renzhi2024-09-172024-09-172024-07-21Zhou Y, Zhang C, Xiao W, Herzog RW, Han R. Systemic delivery of full-length dystrophin in Duchenne muscular dystrophy mice. Nat Commun. 2024;15(1):6141. Published 2024 Jul 21. doi:10.1038/s41467-024-50569-6https://hdl.handle.net/1805/43354Current gene therapy for Duchenne muscular dystrophy (DMD) utilizes adeno-associated virus (AAV) to deliver micro-dystrophin (µDys), which does not provide full protection for striated muscles as it lacks many important functional domains of full-length (FL) dystrophin. Here we develop a triple vector system to deliver FL-dystrophin into skeletal and cardiac muscles. We split FL-dystrophin into three fragments linked to two orthogonal pairs of split intein, allowing efficient assembly of FL-dystrophin. The three fragments packaged in myotropic AAV (MyoAAV4A) restore FL-dystrophin expression in both skeletal and cardiac muscles in male mdx4cv mice. Dystrophin-glycoprotein complex components are also restored at the sarcolemma of dystrophic muscles. MyoAAV4A-delivered FL-dystrophin significantly improves muscle histopathology, contractility, and overall strength comparable to µDys, but unlike µDys, it also restores defective cavin 4 localization and associated signaling in mdx4cv heart. Therefore, our data support the feasibility of a mutation-independent FL-dystrophin gene therapy for DMD, warranting further clinical development.en-USAttribution 4.0 InternationalDependovirusGenetic therapyMyocardiumSarcolemmaArticle