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

一种治疗泰萨克斯病和桑德霍夫病的新型小分子疗法

• 批准号: 8057620
• 负责人: BRETT E CRAWFORD
• 金额: $ 34.29万
• 依托单位: ZACHARON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057620
• 关键词: Behavior; Biological Assay; Birth; Boxing; Cell Culture Techniques; Cells; Ceramide glucosyltransferase; Cessation of life; Characteristics; Childhood; Collection; Development; Disease; Drug Kinetics; Enzymes; Fibroblasts; Foundations; Funding; Future; Ganglioside Biosynthesis Pathway; Gangliosides; Gangliosidoses; Gangliosidoses GM2; Gangliosidosis GM1; Glucosylceramides; Glycolipids; Goals; Hereditary Disease; In Vitro; Inhibitory Concentration 50; Intervention; Lead; Link; Lipids; Lysosomal Storage Diseases; Measures; Metabolic; Modeling; Morbidity - disease rate; Multienzyme Complexes; Mutation; Nervous System Trauma; Neurologic; Orphan Disease; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Polysaccharides; Probability; Property; Research; Risk; Sandhoff Disease; Series; Severity of illness; Small Business Innovation Research Grant; Solubility; Solutions; Staging; System; Tay-Sachs Disease; Testing; Toxic effect; Variant; Work; analog; base; cost; design; effective therapy; enzyme deficiency; family genetics; high risk; high throughput screening; in vitro Model; in vivo; inhibitor/antagonist; mortality; novel; pre-clinical; premature; product development; programs; scaffold; small molecule; success

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.

描述（由申请人提供）： 利用一种新的高通量筛选方法，我们最近确定了神经节苷脂生物合成的第一个选择性小分子抑制剂。 拟议的资金将使重要的临床前开发活动所需的推进这些有前途的化合物作为一种新的治疗GM 2神经节苷脂。 GM 2神经节苷脂沉积症是一个家族的遗传性疾病，包括泰-萨二氏病、桑德霍夫病和AB变异体，这些疾病是由降解神经节苷脂所需的酶复合物亚基突变引起的。 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衰退和死亡。 预期神经节苷脂生物合成抑制剂通过底物减少机制，通过选择性地限制神经节苷脂通过受损的溶酶体降解系统的流量，来减轻疾病的严重程度。 我们将测试这些化合物是否可以减少GM 2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累。 然后将测试活性支架的重要理化、药理学和药物化学特性，以确定最有前途的支架，供进一步开发。 完成后，这些研究将为这些毁灭性疾病的第一种疗法的进一步临床前开发奠定基础。 公共卫生相关性： 相关性本提案的目标是完成重要的早期产品开发活动，用于治疗两种相关的毁灭性疾病：泰-萨克斯病和桑德霍夫病。 这些遗传性疾病从出生就存在，并导致严重的神经损伤和过早死亡。 对于这些病症没有有效的治疗方法。 因此，拟议的研究有可能首次有效治疗两种与严重发病率和死亡率相关的毁灭性儿童疾病。