Micro-dystrophin gene therapy demonstrates complete long-term cardiac efficacy in a severe Duchenne muscular dystrophy cardiomyopathy model


Pre-Clinical Research

Poster Number: 135


Arden Piepho, Ohio State University, Jeovanna Lowe, The Ohio State University, Laurel Cumby, Lisa Dorn, PhD, Dana Lake, Megan Gertzen, Guy Odom, PhD, Federica Accornero, PhD, The Ohio State University, Jeffrey Chamberlain, PhD, University of Washington, Jill Rafael-Fortney, PhD, The Ohio State University

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by a lack of dystrophin protein resulting in skeletal and cardiac muscle membrane instability. Cellular damage in heart leads to inflammation and fibrotic replacement of cardiomyocytes. The resulting cardiomyopathy and heart failure is now the leading cause of death in affected male patients and cardiomyopathy is a prevalent feature in carrier females. However, the disease process in the heart is still poorly understood, due to lack of animal models that recapitulate human DMD heart failure progression. This lack of knowledge has also inhibited the ability to develop specific therapies that prevent cardiomyopathy progression. Additionally, since DMD patients don’t develop clinically detectable signs of cardiomyopathy until their late teens to early twenties, the efficacy of micro-dystrophin gene therapies currently in clinical trials will not be known for another decade.
Our lab has developed a novel mouse model that demonstrates progression of DMD cardiomyopathy to heart failure with reduced ejection fraction which will now enable study of the full spectrum of disease and development of therapies to prevent progression. We have previously published validation of the model and demonstration that treatment with an earlier form of micro-dystrophin gene therapy was able to prevent pathology and functional decline in this model through one year. We now show that a second micro-dystrophin gene therapy, currently in clinical trials, can entirely prevent pathology and maintain normal ejection fraction through 18 months. We are now using this model to define the roles of inflammation and fibrosis throughout heart failure progression to develop specific and temporal therapies for DMD cardiomyopathy.