Funding opportunities

Funding Type: 
Early Translational I
Grant Number: 
Principle Investigator: 
Funds requested: 
$2 753 559
Funding Recommendations: 
Grant approved: 
Public Abstract: 

One in every ten thousand people in the USA have Huntington's Disease, and it impacts many more. Multiple generations within a family can inherit the disease, resulting in escalating health care costs and draining family resources. This highly devastating and fatal disease touches all races and socioeconomic levels, and there are currently no cures. Screening for the mutant HD gene is available, but the at-risk children of an affected parent often do not wish to be tested since there are currently no early prevention strategies or effective treatments.

HD is a challenging disease to treat. Not only do the affected, dying neurons need to be salvaged or replaced, but also the levels of the toxic mutant protein must be diminished to prevent further neural damage and to halt progression of the movement disorders and physical and mental decline that is associated with HD.

Our application is focused on developing a safe and effective therapeutic strategy to reduce levels of the harmful mutant protein in damaged or at-risk neurons. We are using an RNA interference strategy – “small interfering RNA (siRNA)” to prevent the mutant protein from being produced in the cell. This strategy has been shown to be highly effective in animal models of HD. However, the inability to deliver the therapeutic molecules into the human brain in a robust and durable manner has thwarted scale-up of this potentially curative therapy into human trials. We are using mesenchymal stem cells, the “paramedics of the body”, to deliver the therapeutic siRNA directly into damaged cells. We have discovered that these stem cells are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with a new tool to also reduce mutant protein levels. Our novel system will allow the therapy to be carefully tested in preparation for future human cellular therapy trials for HD.

The significance of our studies is very high because there are currently no treatments to diminish the amount of toxic mutant htt protein in the neurons of patients affected by Huntington’s Disease. There are no cures or successful clinical trials for HD. Our therapeutic strategy is initially examining models to treat HD, since the need is so acute. But this biological delivery system could also be used, in the future, for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where reduction of the levels of a mutant or disease-activating protein could be curative.

Development of this novel stem cell therapeutic and effective siRNA delivery system is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families.

Statement of Benefit to California: 

It is estimated that one in 10,000 CA residents have Huntington’s Disease (HD). While the financial burden of Huntington’s Disease is estimated to be in the billions, the emotional burden on the friends and families of HD patients is immeasurable. Health care costs are extremely high for HD patients due to the decline in both body and mind. The lost ability of HD patients to remain in the CA workforce and to support their families causes additional financial strain on the state’s economy. HD is inherited as an autosomal dominant trait, which means that 50% of the children of an HD patient will inherit the disease and will in turn pass it on to 50% of their children. Individuals diagnosed through genetic testing are at risk of losing insurance coverage. Since there are currently no cures or successful clinical trials for HD, many are reluctant to be tested. The proposed project is designed in an effort to reach out to these individuals who, given that HD is given an orphan disease designation, may feel that they are completely forgotten and thus have little or no hope for their future or that of their families.

To combat this devastating disease, we are using an RNA interference strategy, “small interfering RNA (siRNA),” to prevent the mutant htt protein from being produced in the cell. This strategy has been shown to be highly effective in animal models of HD. However the siRNA needs to be delivered to the brain or central nervous system in a continual manner, to destroy the toxic gene products as they are produced. There are currently no methods to infuse or produce siRNA in the brain, in a safe and sustained manner. Therefore the practical clinical use of this dramatically effective potential therapeutic application is currently thwarted.

Here we propose a solution, using adult mesenchymal stem cells (MSC) modified to infuse siRNA directly into diseased or at-risk neurons in the striata of HD patients, to decrease the levels of the toxic mutant htt protein. MSC are known as the “paramedics of the body" and have been demonstrated through clinical trials to be safe and to have curative effects on damaged tissue. Even without the modification to reduce the mutant protein levels, the infused MSC will help repair the damaged brain tissue by promoting endogenous neuronal growth through secreted growth factors, secreting anti-apoptotic factors, and regulating inflammation.

Our therapeutic strategy will initially examine models to treat HD, since the need is so acute. But our biological delivery system could also be applied to other neurodegenerative disorders such as ALS, some forms of Parkinson’s Disease, and Alzheimer’s Disease, by using siRNA to interfere with key pathways in development of the pathology. This would be the first cellular therapy for HD patients and would have a major impact on those affected in California. In addition, the methods that we are developing will have far-reaching effects for other neurodegenerative disorders.

Review Summary: 

This proposal is focused on the development of a unique cell-based therapy for Huntington’s disease (HD) using mesenchymal stem cells (MSCs) engineered to express silencing RNAs (siRNAs) that selectively target mutant huntingtin mRNA for degradation. In Aim 1 the applicant proposes to develop these engineered MSCs, testing the efficacy of siRNA transfer and extent of protein knockdown in vitro using target cells overexpressing different mutant forms of huntingtin. Specific Aim 2 will test these MSCs in vivo using novel mouse models of immunodeficiency injected with lentivirus to express mutant huntingtin in neural cells. These models will be analyzed for both molecular and functional signs of mutant protein reduction and these studies will form the basis for progression towards clinical trials using engineered MSCs in human HD patients.

Reviewers were uniformly very enthusiastic about the potential impact of this proposal. HD is an incurable, progressive neurodegenerative condition for which there is no therapy. Intracerebral transplantation of appropriate samples of human striatal brain tissue has been tested in a small number of patients with some minimal positive effects. Therefore, novel approaches that can either protect striatal neurons from the degenerative process or interfere with the neurotoxicity of mutant huntingtin are desperately needed. For this reason, reviewers agreed that HD is an excellent target for this cell-based therapy and any advances could have a significant impact on clinical treatment strategies. Reviewers praised the use of MSCs, citing the growing body of work employing them in clinical applications and the potential for autologous sourcing. Reviewers also noted that, if successful, the strategy of siRNA expressing MSCs could be applied to other neurodegenerative diseases.

Reviewers described the research plan as coherent and well crafted and commended the applicant’s novel and sophisticated approach. Their major criticism was that the proposal is ambitious and high-risk, but they still considered it feasible. The reviewers praised the quantity and quality of preliminary data and were convinced that MSCs could be efficiently engineered to produce siRNAs that can be taken up by nearby cells. However, a reviewer cautioned that the challenge will be to achieve long-term, stable siRNA delivery in vivo. One reviewer described the proposed clinical protocol as sound and sophisticated but another thought that it lacked the complete specific set of outcome measurements that will be required to advance a candidate for clinical development. Another reviewer noted that because the proposed treatment will not necessarily reverse established disease, it will have to be started pre-symptomatically or early in the disease course for optimal effect. Some reviewers raised issues of immunogenicity but others pointed out that MSCs are relatively less immunogenic than other cells and were, overall, convinced that the risks were justified by the potential to impact patients with HD.

Reviewers found the applicant eminently qualified to lead this project, specifically citing extensive pre-clinical and clinical experience with stem cells and gene therapy products. They noted that the applicant has assembled an excellent group of collaborators including a highly regarded HD neurologist, the director of a GMP facility and biophotonic experts. The research team has extensive experience with MSCs in vivo and is strengthened by an industry collaborator whose company has initiated clinical trials of human MSCs. There was some disagreement among reviewers about the budget, with one calling it modest and another commenting that it seems high, particularly in the areas of supplies, consultants and equipment. The resources and research environment were judged to be excellent.

Overall, the reviewers were highly enthusiastic about this proposal and felt it could have a significant impact in the treatment of HD. They acknowledged that the applicant’s therapeutic strategy is high-risk but were encouraged by the preliminary data and felt the risks were far outweighed by the potential rewards.