Use of Rapamycin for the Treatment of Hypertrophic Cardiomyopathy in Patients with Noonan Syndrome with Multiple Lentigines (NSML)

LEOPARD syndrome (LS) is a rare genetic disease affecting only about 200 patients worldwide. Nearly all cases of LS result from mutations in a single gene, PTPN11. In the heart, the most common manifestation of LS is hypertrophic cardiomyopathy (HCM), a thickening of the walls of the heart. There is no existing treatment for LS patients who have HCM, and end-stage heart failure can lead to early death. The lead collaborator has shown that rapamycin can prevent and reverse HCM in animal models of LS. The purpose of this project is to develop rapamycin or similar compounds as effective HCM therapies for LS patients.

Scientific Synopsis

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 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. 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 preclinical package to support filing an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and clinical trials for HCM in LS patients.

Lead Collaborator

Beth Israel Deaconess Medical Center, Boston

Maria Kontaridis, Ph.D.

Public Health Impact

There is no treatment for LS, and hypertrophic cardiomyopathy often leads to early death among LS patients. Developing a better understanding and innovative therapeutic approach to LS may have broader application to other congenital heart defects.


To facilitate therapeutic development, the TRND team further characterized 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 scientists conducted additional animal efficacy studies with the lead molecule and another mTOR inhibitor. As milestones of in vivo efficacy were not met in the mouse models tested, the project did not continue into further development.