Huntington’s disease (HD) is a devastating degenerative brain disease with a 1 in 10,000 prevalence that inevitably leads to death. Because HD is genetically dominant, the disease has a 50% chance of being inherited by the children of patients. Symptoms of the disease include uncontrolled movements, difficulties in carrying out daily tasks or continuing employment, and severe psychiatric manifestations including depression. Current treatments only address some symptoms and do not change the course of the disease, therefore a completely unmet medical need exists. Human embryonic stem cells (hESCs) offer a possible long-term treatment approach that could relieve the tremendous suffering experienced by patients and their families. Because HD is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of hESCs may provide insights into treating brain diseases that are not caused by a single, known mutation. The ability to differentiate hESCs into neuronal populations offers a powerful and sustainable treatment opportunity. We have established the multidisciplinary team of investigators and consultants to integrate basic and translational research with the goal of generating a lead developmental candidate having disease modifying activity with sufficient promise to initiate IND-enabling activities for HD clinical trials.
In preliminary experiments, the transplantation of mouse neural stem cells, which survived in the brain for the four week period of the trial, provided protective effects in delaying disease progression in an HD mouse model and increased production of protective molecules in the brains of these mice. In the first year, the team has developed and established methods to differentiate hESCs into neural, neuronal and astrocyte precursors to be used for transplantation and has determined the correct cells to use that can be developed for future clinical development of these cells. In initial studies during this year, transplantation of neural stem cells (NSCs) provided both neurological and behavioral benefit to a HD mouse model. In addition, neuroprotective molecules were increased. Three immunosuppression regimens were tested to optimize methods for next stage preclinical trials. Finally, breeding of the three different HD mouse models has been initiated. Taken as a whole, progress supports the feasibility of the CIRM-funded studies to transplant differentiated hESCs into HD mice for preclinical development with the ultimate goal of initiating IND-enabling activities for HD clinical trials.