Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model
| Autor: | Neha Rastogi, Lisa E. Dorn, Megan D. Gertzen, Jeovanna Lowe, Zachary M. Howard, Guy L. Odom, Jill A. Rafael-Fortney, Jeffrey S. Chamberlain, Federica Accornero, Pierce C. Ciccone |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cardiac function curve Male musculoskeletal diseases medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Utrophin Duchenne muscular dystrophy Genetic enhancement Cardiomyopathy Cardiology Inflammation Mice Transgenic Mouse models Dystrophin 03 medical and health sciences Electrocardiography 0302 clinical medicine Gene therapy Fibrosis Internal medicine medicine Animals Humans Heart Failure Mice Knockout business.industry General Medicine Genetic Therapy medicine.disease Cardiovascular disease Clinical trial Mice Inbred C57BL Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Heart failure Medicine Female medicine.symptom business Cardiomyopathies Research Article |
| Zdroj: | JCI Insight, Vol 6, Iss 7 (2021) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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 with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD. |
| Databáze: | OpenAIRE |
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