Year 2

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.

We previously performed transplantation of human neural stem cells into an HD mouse model and found that a subset of cells survived in the brain for the four week period of the trial, providing protective effects in delaying disease progression. In the past year, we have increased production and characterization of human neural stem cells (hNSCs) into neuronal (hNPC) and astrocyte (hAPC) precursors to be used for transplantation and optimized methods for shipping and implantation. Immunosuppression regimens were improved to optimize cell survival of implanted cells in HD mice. Transplantation of both human NSCs and NPCs are neuroprotective to HD mice and transplantation of hAPCs is in progress. Once completed, the cell giving the greatest protective benefit will be transplanted into mice that display slower progression over a longer time frame to validate and optimize approach for subsequent human application. All three HD mouse models have been bred and are ready for stem cell transplants. Taken as a whole, progress supports the feasibility of the CIRM-funded studies to transplant differentiated hESC-derived cell types into HD mice for preclinical development with the ultimate goal of identifying a lead candidate cell type and initiating IND-enabling activities for HD clinical trials.