Use of Rapamycin for the Treatment of Hypertrophic Cardiomyopathy in Patients with LEOPARD Syndrome

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LEOPARD Syndrome (LS) is named for its presenting manifestations: multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular hypertelorism (O), pulmonic stenosis (P), abnormal genitalia (A), retardation of growth (R) and sensorineural deafness (D). Despite the fact that pulmonic stenosis is part of the LS acronym, the most common cardiac manifestation is hypertrophic cardiomyopathy (HCM), occurring in approximately 70 percent of LS patients. To determine the biological and functional mechanisms in LS, the lead collaborators generated an LS mouse model harboring one of the two most common mutations in the human disease, the Y279C mutation in the PTPN11 gene. These mice recapitulated nearly all major aspects of the human LS disorder. The investigators identified a hyperactivation of the Akt/mTor signaling pathway as the mechanism by which Y279C causes HCM in LS, implicating rapamycin as a potential pharmacologic intervention. LS is one of several autosomal dominant disorders associated with RAS/MAPK pathway genes (RASopathies). Rapamycin already is approved for treatment of renal cancer and is undergoing clinical trials for polycystic kidney disease. The goal of this project is to leverage TRND support to develop the necessary pre-clinical package to support filing an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration and clinical trials for HCM in LS patients. TRND researchers are conducting additional animal efficacy studies with the lead molecule. The results of these studies, in addition to known toxicology and other supporting information, will determine what further studies will be needed to support development of a clinical plan, and will enable filing an IND Application with the FDA to enter human trials.