Caspase 6: YAC mice expressing caspase-6 resistant mhtt have a dramatically ameliorated neurodegenerative phenotype compared o mice expressing similar levels of unchanged full-length mutant Htt. The caspase-6 resistant mice were protected from neuronal degradation, had a significant delay in accumulation of N-mhtt fragments in the nucleus, and had a dramatic decrease of the behavioral phenotype related to HD. Furthermore, caspase-6 resistant mice were protected from excitotoxic cell death, as initiated by N-methyl-D-aspartic acid, quinolinic acid and staurosporine. These data are highly suggestive that cleavage at the caspase-6 site in mhtt is a crucial rate-limiting step in the pathogenesis of HD. Hence, blocking the cleavage by inhibition of caspase-6 is an exciting new approach for the direct treatment of HD patients.

Huntington's Disease

Huntington’s Disease (HD) has 5-10 cases per 100,000 worldwide and is the most prevalent hereditary neurodegenerative disease. There are believed to be approximately 30,000 cases in the US and approximately 150,000 individuals directly at risk. This devastating neurological disorder is characterized by progressive motor dysfunction, cognitive decline, psychiatric disturbances and ultimately death--which occurs 10-15 years after disease onset.

There is no treatment or cure for HD.

HD is caused by a trinucleotide repeat (CAG) encoding glutamine near the N-terminus of the protein huntingtin (htt). The number of CAG repeats corresponds with the risk and age of onset of the disease. Normal range is about 28 while greater than 60 results in juvenile onset HD. Htt is a 348 kDa multidomain protein, which is widely expressed, but whose functions are poorly understood. In both human and mouse model HD, mutant N-terminal fragments of htt (N-mhtt) accumulate in the cytoplasm and nucleus forming inclusions. The presence of mutant N-terminal fragments results in neural degradation primarily located at the basal ganglia.

We are targeting HD through two approaches. One approach is to target PDE10A. Administration of PDE10 inhibitors has been shown to provide symptomatic and neuropathological improvements in mouse models as well as extending lifespan. Our second approach is to target caspase-6. Caspase-6 is believed to be the requisit cleavage event that releases toxic mutant htt N-terminal peptides. Mutation of the caspase-6 cleavage site in vivo eliminates the onset of HD in mice.

PDE10A: Our most advanced HD program is targeting PDE10A. We have completed an experimental fragment screen (nanocalorimetry method) identifying over 20 hits and their corresponding crystal structures at ultra-high resolution. Elaboration of these compounds into early leads has yielded unique chemical structures. Using iterative structure-guided design, specific inhibitors have been identified.

Huntington's Disease

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