Research Project
10219356
Corticosteroids provide an important drug class for treatment of numerous forms of heart failure and chronic inflammation, together affecting over 432 million people. In Duchenne muscular dystrophy (DMD), drugs that target corticosteroid receptors are used to treat heart and skeletal muscle. Our lab developed a first-in-class dissociative steroid that shows efficacy as both a heart-protective and anti-inflammatory drug. Our work in the mdx mouse model of DMD was critical for moving this drug, vamorolone, into DMD clinical trials (now in Phase 2b). In early cell and animal studies, vamorolone showed anti-inflammatory efficacy while avoiding key side effects. Subsequently, we discovered new readouts of drug activity and important impacts of corticosteroids on dystrophic hearts. Cardiomyopathy is a feature of both the severe muscle disease DMD (caused by loss of dystrophin) and the milder muscle disease Becker muscular dystrophy (dystrophin in-frame deletions). As promising new therapies are being developed that seek to convert severe DMD genotypes into milder Becker- like phenotypes, importance of treating dystrophic hearts should grow because cardiomyopathy is the leading cause of Becker mortality. Moving forward, it will be important to address knowledge gaps regarding the mechanisms of selective steroids, roles of specific steroid receptors in the heart, and impacts of steroids on Becker-like hearts. This knowledge is important because cardiomyopathy is a leading cause of DMD mortality and current corticosteroids have problematic safety profiles. Our long-term goal is to dissect mechanisms of steroid signaling that can be selectively targeted to improve treatment of chronic pediatric diseases. This can greatly improve outcomes for DMD in a way that also impacts much larger groups of heart, muscle and inflammatory diseases. The objective of this grant is to dissect mechanisms of corticosteroid receptors that impact dystrophic cardiomyopathy. The advanced expertise and tools developed by our lab place us in a unique position to accomplish this using a combination of cell culture, receptor mutation, tissue-specific knockout, micro-dystrophin gene therapy, and animal model systems. We propose the central hypothesis that 11?-hydroxysteroid agonists activate receptor transactivation to drive progression of dystrophic heart pathology. Our rationale is that identifying corticosteroid mechanisms which can be selectively targeted will provide a basis for the improved treatment of DMD and other diseases with heart failure or chronic inflammation.
