Year 1

Huntington’s disease (HD) is a devastating neurodegenerative disease with a 1/10,000 disease risk that always leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive caregiving and has a 50% chance of passing the mutation to the next generation. Current treatments treat some symptoms but do not change the course of disease. Symptoms of the disease include movement abnormalities, inability to perform daily tasks and psychiatric problems. A loss of specific regions of the brain are observed. The mutation for HD is an expansion of a region of repeated DNA in the HD gene and the longer the repeat, in general the earlier the onset of disease. While the length of this polyglutamine repeat largely determines the age-of-onset, there is variance in onset age that is not accounted for by repeat length but is determined by genetic and environmental factors. In addition, the symptoms can vary significantly among patients in a non-repeat dependent manner. There is a lack of early readouts to determine when to begin HD treatments. Because the disease mutation is known, preimplantation genetic diagnosis (PGD) is possible and mutant Htt embryos are available. We have obtained a number of HD PGD embryos with varying repeat lengths and genetic backgrounds to derive hES cell lines and provide new methods to identify genetic modifiers and readouts of disease progression. Development of multiple lines has begun during this funding period. The development of pluripotent stem cells, termed induced pluripotent stem (iPS) cells, derived directly from HD patient fibroblasts, also provide new methods for these analyses. We have begun the establishment of a bank of HD fibroblasts and have derived three new iPS lines to date with unique CAG repeat expansions. Characterization of the lines for HD phenotypes is in progress. An additional line is being generated and additional fibroblast collection from both HD patients and individuals who do not carry the HD gene is planned for the coming year to generate other sets of iPS lines. These lines will allow mechanistic studies and chemical compound screens to identify drugs that protect against the effect of mutant Htt protein expression in patient derived stem cells to be performed. Ultimately, the iPS cells will provide a way to transplant neurons or neuronal support cells from affected individuals or from unaffected family members having a normal range repeat. Such cells would help reduce immune rejection effects likely to occur with transplantation, however, while patient-derived cells overcome the problems of immune rejection, the mutant protein is still expressed. To overcome this problem we will genetically modify these stem cells to reduce the mutant protein and produce a normal gene in the next portion of the project.