Huntington’s disease (HD) is a devastating degenerative brain disease with a 1 in 10,000 risk of having a mutation 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 progress without stopping 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. Specific regions of the brain are severely affected, most notably the striatum. Current treatments only treat 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 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. In addition, transplantation of fetal brain tissue in HD patients suggests that replacing neurons that are lost may also be effective. While encouraging, 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.
A core group of HD and stem cell experts together with clinicians experienced in stem cell and HD clinical trials have been assembled by the PI to initiate the planning process for a hESC-based therapeutic trial for HD within four years. While feasible, in order for the potential of hESCs in HD to be realized, a very forward thinking disease team effort will allow the most experienced investigators in HD, stem cell research and clinical trials to come together and determine the best way to treat the disease. This planning grant would allow for these interactions to occur in a structured and consistent manner. The planning award will be used to identify critical gaps in our knowledge, available technology, and areas of expertise that need to be addressed prior to moving hESC-based therapy for HD into the clinic. Because the work proposed would entail the use of non-NIH approved hES cell lines, it would be ineligible for Federal funding.
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. Further, as the disease progressives, individuals require institutional care facilities 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. Further, hESCs from HD patients will help us understand the factors that dictate the course of the disease and provide a resource for drug development. For the potential of hESCs in HD to be realized, a very forward thinking disease team effort will allow the most experienced investigators in HD and stem cell research and clinical trials to come together and determine the best way to treat the disease. This planning grant would allow for these interactions to occur in a structured and consistent manner. California researchers need the resources needed to allow researchers having the necessary expertise and technologies to come together as a team to develop hESCs into viable treatments. The federal constraints on hESCs create a critical need for the development of treatments using hESCs supported and staffed with non-federal funds.
We have assembled a strong core team of California-based senior investigators to plan goals and strategies for taking hESCs from the lab to the clinic. The planning award will be used to identify critical gaps in our knowledge, available technology, and areas of expertise that need to be addressed prior to moving SC-based therapy for HD into the clinic. We will also put in place critical milestones to be met and to formalize a management plan that will ensure that the milestones are achieved. We will build on existing regional stem cell resources used by scientists from California institutions. Anticipated benefits to the citizens of California include: 1) development of new cell-based treatments for Huntington's disease 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) development of intellectual property that could form the basis of new biotech startup companies; and 4) improved methods for drug development that could directly benefit citizens of the state. With the proposed disease team our vision of bringing treatments for HD and other neurodegenerative diseases to the clinic can become a reality.
The goal of this project is to conceptualize a human embryonic stem cell (hESC)-based therapeutic trial for Huntington’s disease (HD) that could move to the clinic within 5 years. This applicant proposes to assemble a group of experts in HD and stem cells to design a plan of action to achieve this goal. A team will be assembled to discuss gaps identified by a focus group. Within the context of team meetings and smaller focus groups, preclinical and clinical milestones will be established and critical gaps defined. Already identified gaps include: 1. whether sustained delivery of trophic factors will be sufficient to protect normal brain regions; 2. whether hESCs will differentiate into functional striatal neurons or whether neural progenitor cells (NPCs) are sufficient; 3. necessary optimization of transplantation methods; 4. determination of optimal outcome measurements; 5. appropriate immunosuppression regimens; 6. methods to increase neurogenesis. The goals are multiple, including proof-of-concept studies for application of trophic factors in HD transgenic (tg)-mice, maximizing knowledge on differentiation of stem cells into neurons and activation of endogenous stem cells.
HD is a devastating neurodegenerative disease that is relatively rare. It is a uniformly inherited disease with a 50% chance of transmission to the next generation. There is no known cure for this disease, so the significance of the research is high. Overall, reviewers commented on the feasibility of the project and the existing infrastructure supporting research in this area. The field is scientifically mature, there is a long history of collaboration in the field of HD research, and a collaboration of the investigator’s team with companies and groups capable of carrying out clinical trials already exists.
This is a strong application. The field and the applicant’s research are relatively mature: a mouse model already exists, the applicant has well-developed connections with a company and with an HD study group, and the plan includes very clear and achievable clinical milestones. The rationale for doing the experiments is clear as this is an important disease. The applicant identifies gaps in developing therapies for this disorder, such as the difficulty in generating striatal neurons, and proposes novel approaches to addressing them including stimulating differentiation of endogenous cells. An existing consortium of many investigators across California with significant expertise in basic and clinical research for HD make this application unique and gave confidence that the proposed team would collaborate effectively on the project. Reviewers were particularly positive about the involvement of a non-profit organization pursuing a biotech approach to discover and develop drugs that prevent or slow Huntington disease, as this collaboration provides added clinical experience in the proposal.
Reviewers identified a few weaknesses. Importantly, the principal investigator is an associate professor that lacks the strong track record generally required to lead a project like this, although s/he does have some leadership experience. The planning approach was rather diffuse, mentioning multiple viable therapeutic options without prioritizing them and establishing no specific milestones for the planning process. The planned timeline is unrealistic given the need to develop stem cells, validate them, derive appropriate cell types, and to address toxicology issues, surgical delivery issues, and required safety demands of the FDA. Nevertheless, reviewers were convinced that a disease team planning award will help set up the core structure required to develop a clinical trial.
The goal of this project is to develop a human ES cell based therapeutic trial for HD within 4 years. Within the context of team meetings and smaller focus groups, preclinical and clinical milestones will be established and critical gaps defined. Already identified gaps are delivery of trophic factors into vulnerable brain regions including stem cells; differentiation of ES cells into neurons in the striatum, optimization of transplantation techniques; defining outcomes – immunosuppressive regimens – methods for adult neurogenesis – bone marrow transplantation. A long history of collaboration in the field of HD research and a collaboration with companies and groups capable of carrying out clinical trial already exist.
Reviewer One Comments
- Rationale is clear, important disease, “classical” target for cell replacement therapy or for the delivery of trophic factors;
- Preexisting HD research is outstanding, consortium of many investigators across California with significant expertise in basic and clinical research for HD make this proposal unique
- Associate professor with good publication record
- Not MD and has not worked with disease groups in the past
- Some leadership experience
- Outstanding environment
- Rather diffuse, mentioned is every viable therapeutic option however there is not priority, no specific milestone for the planning process
Reviewer Two Comments
Huntington’s disease is a devastating neurodegenerative disease that is relatively rare. There is no known cure for this disease. It’s a uniformly inherited disease with a 50% chance of transmission to the next generation. In this proposal a group of Huntington’s disease and stem cell experts with established Huntington’s disease clinical trials experience, and structure will be assembled to begin the planning process of a human embryonic stem cell-based therapeutic trial for Huntington’s disease within 4 years.
A team will be assembled and gaps identified by a focus group, these meetings will include: 1. Whether sustained delivery of trophic factors will be sufficient to protect normal brain regions 2. Whether human embryonic stem cells will differentiate into functional striatal neurons or whether neuronal progenitor cells are sufficient 3. Optimization of transplantation methods 4. Determination of optimal outcome measurements 5. Immunosuppression regimes 6. Methods to increase neurogenesis
Overall this is a well planned team to attack the proposal of putting together a plan for clinical trials in 5 years. That said, the planned timeline is completely unrealistic given the huge demands necessary to develop stem cells, validate them, derive appropriate cells, toxicology issues, surgical delivery issues and required safety demands of the FDA. Nevertheless, a disease planning approach would help set up the core structure. The principal investigator (PI) is highly experienced in the Huntington’s disease field, although not with clinical experience and ultimately this is a clinical based approach. To offset that, the PI put together a team including experience cell biologist and basic science including Larry Goldstein and Fred Gage, various researchers from the GladStone Institute including neurologists and importantly CHDI, an organized non-profit focused on a therapeutic approach to Huntington’s disease. If not for CHDI, this team would largely be unprepared for the clinical design of the approach. CHDI provides an enormous advantage.