Glycolipid Replacement Therapy for Huntingtons Disease

描述（由申请人提供）：亨廷顿病（HD）是一种神经退行性疾病，其特征为舞蹈病和进行性运动、精神和认知下降。在临床前研究中，GM1耗竭被验证为亨廷顿病（HD）的治疗靶点 其中GM1替代物具有显著的神经保护作用。然而，GM1具有如此差的药理学特性，以至于它必须被注射到脑的脑室系统中以绕过血脑屏障，因此不能用作这种毁灭性慢性疾病的治疗。我们已经开发了新的有效的，口服生物可利用的GM1类似物，可以解决这一障碍，并成为第一个疾病改善治疗HD。我们在该项目中的目标是从中选择先导类似物，评估其在HD小鼠模型中的PK和药效学特性，使用标准遗传小鼠模型验证其对HD的潜在疗效，并最终进行非临床ADMET研究和IND。 公共卫生相关性：在临床前研究中，GM1耗竭被验证为亨廷顿病（HD）的治疗靶点，其中GM1替代具有显著的神经保护作用。然而，GM1具有如此差的药理学特性，以至于它必须被注射到脑的脑室系统中以绕过血脑屏障，因此不能用作这种毁灭性慢性疾病的治疗。我们已经开发了新的有效的，口服生物可利用的GM1类似物，可以解决这一障碍，并成为第一个疾病改善治疗HD。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea and progressive motor, psychiatric and cognitive decline. GM1 depletion is validated as a therapeutic target for Huntington's disease (HD) in preclinical studies in which GM1 replacement is dramatically neuroprotective. However, GM1 has such poor pharmacologic properties that it must be injected into the ventricular system of the brain to bypass the blood brain barrier and is thus not useable as a treatment in this devastating chronic disease. We have developed novel potent, orally bioavailable analogs of GM1 which can solve this road-block and become the first disease modifying treatment for HD. Our goal in this program is to select lead analogs from amongst them, assess their pK and pharmacodynamic properties in HD mouse models, validate their potential efficacy for HD using standard genetic mouse models, and ultimately proceed to nonclinical ADMET studies and an IND. PUBLIC HEALTH RELEVANCE: GM1 depletion is validated as a therapeutic target for Huntington's disease (HD) in preclinical studies in which GM1 replacement is dramatically neuroprotective. However, GM1 has such poor pharmacologic properties that it must be injected into the ventricular system of the brain to bypass the blood brain barrier and is thus not useable as a treatment in this devastating chronic disease. We have developed novel potent, orally bioavailable analogs of GM1 which can solve this road-block and become the first disease modifying treatment for HD.