Identification of an ES cell-based development candidate for Huntington's disease

Funding Type: 
Early Translational I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

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.