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

LEOPARD综合征（LS）因其表现而命名：多发性雀斑（L）、心电图传导异常（E）、眼距过远（O）、肺动脉狭窄（P）、生殖器异常（A）、生长迟缓（R）和感音神经性耳聋（D）。尽管肺动脉狭窄是LS首字母缩略词的一部分，但最常见的心脏表现是肥厚性心肌病（HCM），发生在大约70%的LS患者中。为了确定LS的生物学和功能机制，主要合作者生成了一种LS小鼠模型，该模型包含人类疾病中两种最常见的突变之一，即PTPN 11基因中的Y279 C突变。这些小鼠几乎概括了人类LS疾病的所有主要方面。研究人员确定Akt/mTor信号通路的过度活化是Y279 C在LS中引起HCM的机制，这意味着雷帕霉素是一种潜在的药理学干预。 LS是与RAS/MAPK通路基因相关的几种常染色体显性遗传疾病（RASopathies）之一。雷帕霉素已经被批准用于治疗肾癌，并正在进行多囊肾病的临床试验。该项目的目标是利用TRND支持开发必要的临床前包，以支持向美国食品药品监督管理局提交研究性新药（IND）申请和LS患者中HCM的临床试验。 TRND的研究人员正在用这种先导分子进行额外的动物疗效研究。这些研究的结果，加上已知的毒理学和其他支持性信息，将决定需要进行哪些进一步的研究来支持临床计划的制定，并将使向FDA提交IND申请以进入人体试验。

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.