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. 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 conducted additional animal efficacy studies with the lead molecule and another mTOR inhibitor. Milestones of in vivo efficacy were not met in the mouse models tested. The project has not continued into further development.
