Year 3

Huntington’s disease (HD) is a devastating neurodegenerative disease that strikes in mid-life and inevitably leads to death. As it is genetic, offspring of affected individuals are 50% at risk. Current medications treat some symptoms, which include movement abnormalities, inability to perform daily tasks and psychiatric problems, but do not change the course of disease. The mutation for HD is an expansion of a region of repeated DNA in the HD gene. In general, the longer the repeat 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 HD PGD embryos and have derived a line that is now fully characterized as a stem cell line that is capable of becoming brain cells. The development of pluripotent stem cells, termed induced pluripotent stem (iPS) cells, derived directly from HD patient skin cells (fibroblasts), also provide new methods for these analyses. We have established a bank of HD fibroblasts and have derived seven new iPS lines with unique CAG repeat expansions. Characterization of the lines for HD symptoms is either complete or in progress. Additional lines are being generated and additional skin cells collected from both HD patients and individuals who do not carry the HD gene. These lines are allowing 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. Finally, we are developing a method to reduce the level of the mutant protein to provide options for future transplantation from an individual’s own skin cells to prevent immune rejection.