Combination therapy for Huntington's disease; feasibility studies for transplantation of hESC-derived cells expressing the apical domain of CCT1.
Early Translational IV
$1 596 974
Huntington’s disease (HD) is a devastating degenerative brain disease that inevitably leads to death. Because it is genetically dominant, children of patients have a 50% chance of inheriting HD. The prevalence of 1 in 10,000 does not fully reflect the large societal and familial costs of HD, which requires extensive caregiving. Symptoms include uncontrolled movements, difficulty carrying out daily tasks or continuing employment and psychiatric manifestations such as depression, which progress inexorably for 15-20 years. Onset is typically in mid-life, however children are also affected, and current treatments only address some symptoms and do not change the onset or 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 of patients and their families. Our proposed feasibility studies will transplant stem cell lines programmed to deliver a neuroprotective protein that can unravel and clear the mutant HD protein in the brain. We have assembled a team of investigators and consultants with a goal of establishing the feasibility of using the proposed stem cell-derived development candidate to alter the course of disease following transplantation in HD mice These preclinical studies will provide information for future development of this stem cell-derived candidate as a potential treatment of HD.
Statement of Benefit to California:
Disability and loss of earning power and personal freedom resulting from Huntington's disease (HD), the 3rd most prevalent neurodegenerative disease, is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at their most productive and with highest earning potential. As HD progresses they require institutional care at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of patients and families; thousands could benefit. This early translation feasibility grant will fund a comprehensive, systematic evaluation of hESC-derived cell lines secreting a neuroprotective protein, to define the approach’s feasibility and develop a candidate viable treatment option. Because HD is entirely genetic and the mutation known, a diagnosis can be made with certainty. Clinical applications of hESCs may provide insights into other brain diseases not caused by a single, known mutation. Future benefits to the citizens of California include: 1) discovery and development of new treatments for HD, with application to other more prevalent diseases ; 2) transfer of new technologies and intellectual property to the public realm, resulting in revenues and possible creation of new biotechnology companies; and 3) reductions in extensive care-giving and medical costs. We anticipate that the return to the State in terms of revenue, health benefits and job creation will be significant.
This is a Development Candidate Feasibility award proposal to evaluate the feasibility of using a combination approach to treat Huntington’s disease (HD). HD is an inherited and fatal neurodegenerative disorder caused by a mutant form of the Huntingtin (HTT) protein that leads to widespread neuronal dysfunction and impairments in movement, cognition and psychiatric well-being. No treatment currently exists that can slow or prevent the progression of HD. The proposed intervention strategy will involve transplantation of genetically modified cells that secrete a chaperone protein designed to prevent mutant HTT protein misfolding and accumulation. These modified cells are proposed to provide neuroprotection and lessen or eliminate HD symptoms. The team proposes three aims. In Aim 1, they will generate clonal hESC lines genetically modified to secrete the targeted chaperone protein. In Aim 2, they plan to differentiate the hESC lines into two candidate cell populations and evaluate expression and activity of the secreted protein in the differentiated cell populations. Finally, during Aim 3, the team plans to determine the efficacy of the differentiated, genetically modified cells after transplantation in a rodent model of HD. Objective and Milestones - The overall objective to use cells as delivery systems that would contribute multiple potential therapeutic advantages is a rational approach. - Reviewers considered some key elements of the plan to be vague or premature and thought that additional preliminary work is necessary. In particular, further development of the stem cell-derived, genetically modified cell types and further work to demonstrate that the secreted candidate protein can work in vivo are required before a stem cell-based delivery approach is attempted. - The proposed milestones appear focused and logical. Rationale and Significance - Overall, the rationale is clear and the approach to the delivery of biologically active protein to the brain is logical. However, significant additional preliminary work is needed prior to initiating the activities outlined in the proposal. - The significance is high. HD is a fatal and progressive neurodegenerative disease with no effective therapy. There is currently no disease-modifying treatment. Feasibility and Design - The preliminary data provides the rationale and justification for several aspects of the proposed study. However, reviewers found critical gaps in the experimental design and preliminary data. More extensive preliminary data supporting the project’s feasibility would have strengthened the proposal. - An important concern was the lack of evidence that the cells can secrete enough chaperone protein to produce the desired biologic effect. Reviewers suggested that this could be tested in a co-culture experiment where chaperone protein-secreting cells were shown to have neuroprotective effects on Htt-expressing neurons. Moreover, given the complexities associated with using cells as a delivery system, it would be useful to first demonstrate that the chaperone protein can produce a beneficial effect in vivo by direct infusion into the brain in the HD rodent model. - Although the concept of delivering the chaperone protein via differentiated stem cells is a rational approach, reviewers were concerned that the applicants have underestimated the challenges associated with achieving this. - The research plan is generally well organized and logical, except for the caveats outlined above. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The applicant has an excellent track record and is a successful and well-established investigator working in the area of HD molecular genetics and molecular mechanisms of disease. - Overall, reviewers viewed the team as strong, particularly in their expertise and experience in studying the pathogenesis and biochemistry of HD. Collaborations, Assets, Resources and Environment - The environment, resources and support are appropriate. Responsiveness to the RFA - The Proposal is for a development candidate feasibility award and is responsive to the RFA.