Glycolipid Replacement Therapy for Huntingtons Disease

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 intothe 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 becomethe first disease modifying treatment for HD.