Early Translational I
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 with national and international advisors, and has been assembled to maximize leverage of existing resources and expertise within the HD and stem cell fields in partnership with [REDACTED], a non-profit company, who will participate in assay development, high throughput small molecule screens and preclinical trials. We have also partnered with [REDACTED] to use a bank of HD-derived lines to evaluate primary neuronal subtypes known to be susceptible to neurodegeneration for the manifestation of key HD pathologies. Because the work proposed would entail the use of non-NIH approved hES cell lines, it is ineligible for Federal funding.
Statement of Benefit to California:
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. 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, 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 several promising approaches to identify a candidate and develop hESCs into viable treatments. 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 senior investigators to carry out the proposed studies. In addition, consultants having areas of expertise in stem cell biology, HD clinical trials, transplantation and regulatory affairs have been recruited and are productively interacting, in part through the resources of the CIRM [REDACTED] Planning award. 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 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) generation of new techniques for using stem cells (and derived cells) to deliver drugs or other agents to tissues, thereby developing new treatment methods; 4) 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 5) 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 proposal is focused on the development of novel therapies for Huntington’s disease (HD). HD is a fatal, inherited neurodegenerative disease with no known treatment. The applicant describes three distinct approaches to identify cell-based therapeutic candidates for HD. In Aim 1 the applicant proposes an integrated approach to identify a candidate human stem cell (hSC)-derived cell as a treatment option that will be validated in two mouse models of HD. The applicant will also evaluate the immunosuppressive and neuroprotective potential of mesenchymal stem cells (MSCs) in these mice. In Aim 2 the applicant proposes to develop a platform for high-throughput drug screening (HTS) and identify treatment candidates in ESCs derived from HD patients (with appropriate stem cell controls). In Aim 3 the applicant proposes to pursue a gene therapy approach, using viral delivery of growth factors to stimulate endogenous neurogenesis in the striatum of HD mice. The applicant will also develop a hSC-based reporter gene assay for screening compounds that promote neurogenesis and striatal neuron differentiation. Reviewers agreed that this proposal could have a significant impact if successful. The proposal addresses an important unmet clinical need, as there are currently no treatments that can cure or even modify HD progression. HD is entirely genetic and the mutation is known, providing a well-defined and relatively simple target. Some previous work supports the potential of stem cell (SC) therapy to treat this disease. A recent study demonstrated the feasibility of differentiating hESCs to striatal medium-sized spiny neurons, the subset affected in HD. Preclinical and clinical trials using human fetal striatal cells transplanted into HD patients have led to some disease amelioration. These studies provide a rationale for expecting that implantation of neural stem cells (NSCs) or their differentiated progeny might be therapeutic. Moreover, the applicant presents preliminary data showing improved locomotion in a mouse model of HD after striatal mNSC injection and survival of these cells two weeks post-transplantation. While the data are encouraging, a reviewer noted that no detail is provided on the duration of the efficacy of the treatment. This treatment also led to increased levels of a neurotrophic factor, BDNF, and decreased BDNF expression in HD is implicated in disease pathogenesis. Reviewers raised a number of questions about the research plan as well as some doubts about its feasibility. They described some of the proposed experiments as highly speculative and noted a lack of detail in the research plan, including limited discussion of potential pitfalls and alternative approaches. Reviewers found the preliminary data provocative but not substantial enough to inspire full confidence. With regard to Aim 1, a reviewer noted that while MSCs may be a promising strategy for immunosuppression, no clear rationale is provided for using them over other immunosuppressive regimens. This reviewer also pointed out that while testing hESC-derived neural progenitors in HD mice may be informative, there is no evidence presented that rejection of these cells can be prevented for the long time periods necessary for their ongoing examination. Another reviewer noted that brains collected post-engraftment will be hemisected and split for biochemical and immunohistological analysis but cautioned that placement, survival and migration pattern may not be the same in both hemispheres. With regard to Aim 2, a reviewer commented that it is unclear whether any of the in vitro assays would correlate with in vivo phenomena and thus be predictive of drug efficacy. Reviewers praised the impressive research team assembled for this proposal. The team consists of experts in many relevant fields and includes neurologists with expertise in human clinical trials. Reviewers were concerned about the large number of key personnel (39) included in the proposal. One reviewer commented that while it is clear the applicant has the scientific expertise to lead this project, the leadership experience to coordinate this extremely ambitious and broad-based research plan involving collaborators around the world was not sufficiently highlighted in the application. Another reviewer felt that more than 15% effort would be required from the PI to manage a project of this size. But in general, reviewers found the research team to be highly qualified and judged the resources and research environments at the various institutions to be outstanding. Overall, reviewers appreciated the potential impact of this proposal but found it overly ambitious and lacking sufficient supportive experimental detail and preliminary data.