Glycolipid Replacement Therapy for Huntingtons Disease

描述(申请人提供)：亨廷顿病(HD)是一种神经退行性疾病，以舞蹈和进行性运动、精神和认知能力下降为特征。在临床前研究中，GM1耗竭被确认为亨廷顿病(HD)的治疗靶点 在这种情况下，GM1的替代极大地保护了神经。然而，GM1的药理学特性如此之差，必须将其注射到脑室系统中以绕过血脑屏障，因此无法用于治疗这种毁灭性的慢性疾病。我们已经开发出新的有效的口服生物可用GM1类似物，可以解决这一障碍，并成为第一个治疗HD的疾病修正疗法。我们在这个项目中的目标是从其中选择铅类似物，评估它们在HD小鼠模型中的PK和药效学特性，使用标准的遗传小鼠模型验证它们对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：GM1耗竭在临床前研究中被确认为亨廷顿病(HD)的治疗靶点，在这些研究中，GM1替代显著地具有神经保护作用。然而，GM1的药理学特性如此之差，必须将其注射到脑室系统中以绕过血脑屏障，因此无法用于治疗这种毁灭性的慢性疾病。我们已经开发出新的有效的口服生物可用GM1类似物，可以解决这一障碍，并成为第一个治疗HD的疾病修正疗法。

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.