Leslie Leinwand's research focuses on how cardiac and skeletal muscle adapt to stimuli, particularly the pathways involved in heart enlargement in response to exercise and disease. Using the issue of human health and disease, her HHMI project includes an interdisciplinary science course and a laboratory research program for undergraduates, a mentor training program, and a lecture series open to the public and workshops for high school teachers.
Pediatric Hypertrophic Cardiomyopathy Caused by Myosin Mutations
Affecting nearly 0.5 percent of the general population, hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders. The disease contributes to a significant percentage of sudden unexpected cardiac death. Thirty percent of HCM cases are caused by mutations in the β-cardiac MyHC gene, hereafter referred to as β-myosin (MYH7).
The vast majority of β-myosin mutations have been described in postadolescent populations. Recently, two groups reported novel mutations in β-myosin in children (from 8 months to 11 years of age) with idiopathic cardiac hypertrophy. Unexplained early-onset cardiac hypertrophy is associated with a very poor prognosis; rates of death and cardiac transplantation approach 40 percent.
Our first goal is to determine the functional defects in a group of pediatric HCM mutant myosin motors. This will be accomplished by analyzing the functional properties of recombinant human mutant myosin motors using a novel expression system developed in our lab for this purpose. Our second goal is to test the therapeutic effects of a small-molecule activator of myosin function on these mutants. This small-molecule myosin activator, omecamtiv mecarbil, has shown efficacy in phase II studies in heart failure.
Our study will be the first small-molecule intervention that directly affects the cause of the disease rather than a secondary or tertiary consequence. We believe that the methods proposed will provide a comprehensive analysis of one of the most important genetic heart diseases, which is also the most common cause of sudden death in young people.