A Novel Small Molecule Therapy for Tay-Sachs and Sandhoff Diseases

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Project Summary Using a novel high-throughput screening approach, we have recently identified the first selective small molecule inhibitors of the biosynthesis of gangliosides. The proposed funding will enable important preclinical development activities required to advance these promising compounds as a novel therapy for the GM2 gangliosidoses. GM2 gangliosidosis is a family of genetic diseases including Tay-Sachs, Sandhoff, and the AB variant that are caused by mutations in subunits of the enzyme complex required to degrade gangliosides. Due to the lysosomal enzyme deficiency, gangliosides build up to toxic levels leading to severe neurological decline and death. The ganglioside biosynthetic inhibitors would be expected to alleviate disease severity through a substrate reduction mechanism by selectively restricting the ganglioside flux through the compromised lysosomal degradative system. We will test if these compounds can reduce lysosomal ganglioside accumulation in fibroblasts from patients with GM2 gangliosidosis. Active scaffolds will then be tested for important physiochemical, pharmacological and medicinal chemistry properties to identify the most promising scaffolds for further development. When completed, these studies will lay the foundation for additional preclinical development of the first therapy for these devastating diseases. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to complete important early-stage product development activities for a new therapy to treat two related and devastating diseases: Tay-Sachs and Sandhoff diseases. These genetically-induced diseases are present from birth and lead to severe neurological damage and premature death. No effective treatments exist for these conditions. As a result, the proposed research has the potential to enable the first effective treatment for two devastating, childhood diseases associated with significant morbidity and mortality.