Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model

• DOI: 10.1172/jci.insight.146511
• Publication Date: 2021-03-02T17:00:44Z
• Authors: Zachary M. Howard; Lisa E. Dorn; Jeovanna Lowe; Megan D. Gertzen; Pierce Ciccone; Neha Rastogi; Guy L. Odom; Federica Accornero; Jeffrey S. Chambe...; Jill A. Rafael-Fo...
• Keywords: Heart Failure; Male; Mice, Knockout; 0303 health sciences; Utrophin; Cardiology; R; Mice, Transgenic; Genetic Therapy; 3. Good health; Dystrophin; Mice, Inbred C57BL; Muscular Dystrophy, Duchenne; Disease Models, Animal; Electrocardiography; 03 medical and health sciences; Medicine; Animals; Humans; Female; Cardiomyopathies; Research Article

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients DMD die from failure, cardiomyopathy undetectable until the teens, so trials young boys will be unknown a decade. Available animal models were sufficient to demonstrate micro-dystrophin on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency patients. However, no mouse progressed into dog showed highly variable progression insufficient evaluate or other therapies failure. To overcome this barrier, we have generated first model our knowledge that reproducibly progresses This shows cardiac inflammation fibrosis occur prior reduced function. Fibrosis does not continue accumulate, persists after function declines. We used test gene therapy prevention time. Micro-dystrophin prevented declines prohibited fibrosis. allow identification committed pathogenic steps testing genetic nongenetic optimize care DMD.