Sustained siRNA production from human MSC to treat Huntingtons Disease and other neurodegenerative disorders
Early Translational I
$2 753 559
Statement of Benefit to California:
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.