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

描述(由申请人提供)： 项目概述利用一种新的高通量筛选方法，我们最近发现了第一个选择性小分子神经节苷脂生物合成抑制剂。拟议的资金将使重要的临床前开发活动成为必要的，以推动这些有希望的化合物成为治疗GM2神经节苷脂增多症的新疗法。GM2神经节苷脂沉积症是一类遗传性疾病，包括Tay-Sachs、Sandhoff和AB变异，这些疾病是由降解神经节苷脂所需的酶复合体亚单位突变引起的。由于溶酶体酶缺乏，神经节苷脂积累到有毒水平，导致严重的神经功能下降和死亡。神经节苷脂生物合成抑制剂有望通过底物减少机制，通过受损的溶酶体降解系统选择性地限制神经节苷脂的通量，从而减轻疾病的严重性。我们将测试这些化合物是否可以减少GM2神经节苷脂沉积症患者成纤维细胞中溶酶体神经节苷脂的积聚。然后将对活性支架进行重要的物理化学、药理和药物化学特性测试，以确定最有希望进一步开发的支架。完成后，这些研究将为开发针对这些毁灭性疾病的第一种疗法的额外临床前开发奠定基础。 公共卫生相关性： 相关性这项提议的目标是完成重要的早期产品开发活动，为治疗两种相关和毁灭性的疾病：泰-萨克斯病和桑德霍夫病的新疗法。这些由基因引起的疾病从出生起就存在，并导致严重的神经损伤和过早死亡。对于这些疾病，目前还没有有效的治疗方法。因此，拟议的研究有可能首次有效地治疗两种与严重发病率和死亡率相关的破坏性儿童疾病。

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.