# 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.

## Key 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.