Huntington's disease (HD) is an inherited autosomal dominant disorder of the central nervous system. The disease is passed from parent to progeny with a 50 percent chance of inheritance. HD is a polyglutamine disorder. Normal individuals have 7 to 34 CAG repeats in the Huntingtin (Htt) gene which encode glutamine amino acids in the Htt protein. The CAG repeats are expanded and unstable in HD patients, with repeat lengths inversely correlating with age of disease onset. Repeat lengths greater than 40 glutamines invariably cause HD, and repeats of greater than 100 glutamines typically cause juvenile onset. HD is a neurodegenerative disease characterized by movement disorder, dementia, and psychiatric disturbance which typically develops in the fourth or fifth decade of life with a disease duration of 10 to 30 years. Thirty thousand Americans have HD at an annual cost to American society of $2.5 billion with another 250,000 individuals at risk to inherit the disease. There is no cure or preventative for HD. Theories of HD pathogenesis include excitotoxicity, inappropriate apoptosis, mitochondrial dysfunction, and transcriptional dysregulation. Present treatment of HD is management of symptoms with currently marketed therapeutics. There is great interest in the development of an effective therapeutic for HD. Numerous published investigations have shown effectiveness in preclinical studies of a significant number of compounds but few if any results have translated to efficacy in humans. Human HD therapeutics based on the underlying pathogenic mechanisms of HD have great promise in preventing or stopping progression of the disease. There are indications in model systems as well as in humans that enzymatic processing or cleavage of Htt is a prerequisite for HD. One key mechanistic intervention point appears to be the cleavage of Htt by caspase 6 at amino acid 586. Studies have shown that preventing caspase 6 cleavage at Htt586 by changing the amino acids of the caspase 6 recognition site prevents development of the HD like neuropathogenesis in a HD mouse model system. Therefore, development of a caspase 6 enzymatic activity inhibitor would seem to be a advantageous therapeutic goal. However, caspase 6 processes many other important biological substrates and therefore such an inhibitor would predict significant side effects. With an innovative approach, we propose to identify and develop molecules that bind at or near Htt586 to prevent caspase 6 from binding and cleaving specifically at the Htt586 site. We call such a compound a substrate binding inhibitor molecule (SBIM). Because the amino acid sequence around the caspase 6 Htt586 cleavage site is different from other caspase 6 substrate sites, such a SBIM would be specific to the Htt586 and specific to HD. The identification of a Htt586 SBIM will validate the SBIM strategy, set the stage for development of an HD therapeutic in Phase II research and provide a potentially promising route to the development of an effective HD therapeutic. PUBLIC HEALTH RELEVANCE: Thirty thousand Americans currently have Huntington's disease (HD) at a cost to American society of over $2.5 billion per year. Huntington's disease (HD) is an inherited autosomal dominant neurodegenerate disorder that is caused by increased repeats of CAG in the Huntingtin gene. HD symptoms, characterized by movement disorder, dementia, and psychiatric disturbance, typically begin developing in the third and fourth decade of life, with a disease duration of 10 to 30 years. Currently there is no cure or treatment for HD. We are identifying a substrate binding inhibitor molecule, an innovative approach to the development of a HD therapeutic.