A hESc-based Development Candidate for Huntington’s Disease

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.

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.

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 Investigational New Drug (IND) enabling activities for HD clinical trials. We have completed several rounds of transplantation of human neural stem cells into an HD mouse model and found that the cells survived in the brain for the four-week period of the trial, provided protective effects in delaying disease progression and increased production of protective molecules in the brains of these mice. In the last year the team differentiated hESCs into neural, neuronal and astrocyte precursors and performed transplantation studies to determine the best cell candidate to use and develop for future clinical work. We determined that the human neural stem cells produce the most robust effect. We have now selected a GMP grade hNSC line that will be carried forward for further testing in both rapidly progressing and slower progressing HD mice, as well as in mouse preclinical dosing studies. 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 on initiating IND-enabling activities for HD clinical trials.

Huntington’s disease (HD) is a devastating degenerative brain disease with a 1 in 10,000 prevalence that inevitably leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive care-giving. HD has no effective treatment or cure and symptoms unstoppably progress for 15-20 years, with onset typically striking in midlife. 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. HD is the 3rd most prevalent neurodegenerative disease, but because it 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. Trials in mice where protective factors were directly delivered to the brains of HD mice have been effective, suggesting that delivery of these factors by hESCs may help patients. Transplantation of fetal brain tissue in HD patients suggests that replacing neurons that are lost may also be effective. The ability to differentiate hESCs into neuronal populations offers a powerful and sustainable alternative for cell replacement. Further, hESCs offer an opportunity to create cell models in which to identify earlier markers of disease onset and progression and for drug development. We assembled a multidisciplinary team of investigators and consultants who integrated basic and translational research and have now generated a lead developmental candidate neural stem cell having disease modifying activity with sufficient promise to initiate Investigative New Drug-enabling (IND) activities for HD clinical trials. We are now ready to utilize the collaborative research team, additional clinical investigators and FDA consultants to finalize work that will lead to an IND meeting with the FDA and a path forward for clinical trials with the neural stem cell developmental candidate.