Systemic Delivery of Full-Length Dystrophin in DMD Mice

TL;DR

Researchers developed a new gene therapy to deliver full-length dystrophin in mice with Duchenne muscular dystrophy, improving muscle function and heart health.

Contribution

A triple vector system enables systemic delivery of full-length dystrophin, restoring functional domains missing in current therapies.

Findings

Full-length dystrophin was successfully expressed in skeletal and cardiac muscles of dystrophic mice.

The therapy improved muscle histopathology, contractility, and overall strength.

Unlike miniaturized dystrophin, it restored defective ERK signaling in the heart.

Abstract

Current gene therapy for Duchenne muscular dystrophy (DMD) utilizes adeno-associated virus (AAV) to deliver miniaturized dystrophin (micro-dystrophin or µDys), which does not provide full protection for striated muscles as it lacks many important functional domains within full-length (FL) dystrophin. Here we develop a triple vector system to deliver FL-dystrophin into skeletal and cardiac muscles. We rationally split FL-dystrophin into three fragments (N, M, and C) linked to two orthogonal pairs of split intein, allowing efficient, unidirectional assembly of FL-dystrophin. The three fragments packaged in myotropic AAV (MyoAAV4A) restore FL-dystrophin expression in both skeletal and cardiac muscles in male
mdx

4cv

mice. Dystrophin-glycoprotein complex components are also restored in 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 ERK signaling in heart. The FL-dystrophin gene therapy therefore promises to offer superior protection for DMD.