Grant: Fellowship - Priority Announcement: Huntington's Disease

Huntington disease (HD) is an inherited, fatal, neurodegenerative disease characterized by chorea, dementia and psychiatric disturbance. Death usually occurs 15-20 years after onset of symptoms, and there is currently no effective therapy. Huntington disease is caused by a mutation in a protein called huntingtin. Preventing the generation of this mutant protein by gene silencing could prevent or delay HD. The normal huntingtin protein is important for neuronal health and disrupting or silencing of this gene could have detrimental effects. We are developing a strategy of silencing only the mutant copy of a patient's huntingtin gene as a novel treatment for HD. Our lab has identified DNA sequence variations that are more common in human mutant huntingtin genes than normal huntingtin genes. We have generated reagents targeting these variations that reduce expression of the mutant but not the normal protein in cellular models of HD. We have also generated a humanized mouse model of HD that recapitulates these DNA variations. I will deliver candidate therapeutics to the brains of these mice and evaluate them for efficacy in reducing expression of the mutant protein in the living brain and for benefit to the abnormal behavior and brain pathology of these mice.