Noonan Syndrome with Multiple Lentigines (NSML), previously referred to as LEOPARD Syndrome (LS), derived its name from 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), which occurs in approximately 70 percent of NSML patients. To determine the biological and functional mechanisms in NSML, the lead collaborators generated an NSML 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 NSML disorder. The investigators identified a hyperactivation of the Akt/mTor signaling pathway as the mechanism by which Y279C causes HCM in NSML, implicating rapamycin as a potential pharmacologic intervention. NSML 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 (FDA) and clinical trials for HCM in NSML patients. The efforts in this project have focused on further characterization of the NSML mouse models using magnetic resonance imaging (MRI) to measure overall changes in heart structure and function, in comparison to echocardiography, to better inform clinical endpoints. TRND researchers are conducting additional animal efficacy studies with the lead molecule and another mTOR inhibitor. The results of these studies, in addition to known toxicology and other supporting information, will determine whether the data will enable filing an IND with the FDA to enter human trials for this indication.
