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 caregiving. 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 have assembled a multidisciplinary team of investigators and consultants who will 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. The collaborative research team is comprised of investigators from multiple California institutions and has been assembled to maximize leverage of existing resources and expertise within the HD and stem cell fields.
The disability and loss of earning power and personal freedom resulting from Huntington's disease (HD) is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at a point when they are their most productive and have their highest earning potential. As the disease progresses, individuals require institutional care at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of individuals and their families, which brings the human cost into the thousands. For the potential of hESCs in HD to be realized, a very forward-thinking team effort will allow highly experienced investigators in HD, stem cell research and clinical trials to come together and identify a lead development candidate for treatment of HD. This early translation grant will allow for a comprehensive and systematic evaluation of hESC-derived cell lines to identify a candidate and develop a candidate line into a viable treatment option. 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.
We have assembled a strong team of California-based investigators to carry out the proposed studies. Anticipated benefits to the citizens of California include: 1) development of new human stem cell-based treatments for HD with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) transfer of new technologies and intellectual property to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies; and 4) reductions in extensive care-giving and medical costs. It is anticipated that the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.
This application for a Development Candidate Award focuses on a human embryonic stem cell (hESC)-derived cell therapy for Huntington’s disease (HD), a progressive, hereditary, neurodegenerative disease. The applicant presents preliminary data suggesting that transplantation of mouse neural stem cells (mNSCs) can ameliorate symptoms in a mouse model of HD. The applicant proposes to extend this work to human cells and move toward clinical translation in four Specific Aims: (1) to compare multiple protocols for immunosuppression in a mouse model of HD in order to optimize engraftment of hESC-derived cells; (2) to compare the short-term efficacy of three candidate hESC-derived cell types in the same mouse model of HD utilized in Aim 1; (3) to compare the long-term efficacy of these three cell types in two different and complementary mouse models of HD; and (4) to determine the molecular and cellular mechanisms by which hESC-derived cells modulate HD phenotypes.
The reviewers agreed that this proposal addresses a significant, unmet medical need and could have a profound impact if successful. Huntington’s disease is a devastating, untreatable disease for which the genetic mutation is known, making it an attractive and well-defined target for cell therapy. Reviewers found the scientific rationale for the proposal to be soundly based on preliminary data.
The reviewers described the research plan as rigorous and feasible. They praised the impressive preliminary data, which include not only behavioral analysis following mNSC transplant into a mouse model of HD, but also biochemical analysis of neuroprotective signaling pathways that may be modulated by the transplanted cells. The proposed use of three different mouse models of HD was cited as a strength of the proposal, along with the careful analyses of these models, which include behavioral and electrophysiological testing. Reviewers did raise concerns about Aim 1 however. They felt that the significant time and effort devoted to working out an optimal immunosuppression protocol for xenotransplantation are misplaced, given that these findings cannot be translated to the clinical allotransplant setting in humans and that others have worked out xenograft protocols. Reviewers suggested that the applicant would be better off focusing on Aims 2 through 4, as Aim 1 is not on the path to clinical translation. The reviewers also raised concerns about the fact that the cells to be used will be obtained from a commercial source and no information was provided describing the three proposed cell types, including their purity, degree of differentiation and potential for expansion or whether they have been handled in a manner appropriate for clinical development. Furthermore it was unclear to the reviewers whether the cells to be studied are derived from hESCs expressing green fluorescent protein (GFP). The reviewers noted that such cells could not be used in a clinical setting due to the presence of the GFP transgene. Under these circumstances, the proposal would not result in a cell candidate suitable for IND-enabling pre-clinical development. In light of these concerns, reviewers strongly recommended that the applicant use GMP-compatible cells for the proposed studies.
The reviewers described the principal investigator (PI) and research team as ideally suited to carry out the proposed research plan. They praised the expertise of the numerous collaborating investigators and appreciated the inclusion of a consultant with extensive experience designing clinical trials.
Overall, the reviewers found this proposal to be logical, feasible and well supported by preliminary data. They raised concerns about the proposed cell source, but were confident that the well regarded PI and research team could overcome this obstacle. Reviewers agreed that this proposal has the potential to make a significant impact on the treatment of Huntington’s disease.