The long-term objective of this project is to develop a drug to treat Huntington’s disease (HD), the most common inherited neurodegenerative disorder. Characterized by involuntary movements, personality changes and dementia, HD is a devastatingly progressive disease that results in death 10–20 years after disease onset and diagnosis. No therapy presently exists for HD; therefore, this project is highly innovative and ultimately aims to deliver something transformative for the HD patient population. The specific goal of the proposed research will be to achieve preclinical proof-of-concept with a novel small molecule that binds to and ameliorates the neurotoxicity of the mutant huntingtin (mHtt) protein that causes HD. Rationale for development of such compounds comes from previous research that found that mHtt assumes a shape that is selectively toxic to neurons, and that small molecules that disrupt this shape can reduce mHtt’s toxicity in primary neurons. Critical to the proposed studies will be assays that employ human striatal neurons derived from adult and juvenile HD patients and generated with induced pluripotent stem cell (iPSC) technology. These HD i-neurons display many characteristics that are also observed in striatal neurons of HD patients, including reduced survival times. They provide the most genetically precise preclinical system available to test for both drug efficacy and safety.
The long-term objective of this project is to develop a first-in-class, disease-modifying drug to treat Huntington’s disease (HD), a devastatingly progressive genetic disorder that results in death 10–20 years after disease onset and diagnosis. No therapy presently exists for HD; therefore, this highly innovative project aims to deliver a medical breakthrough that will provide significant benefit for California’s estimated > 2000 HD patients and the family members, friends and medical system that care for them. The proposed research will be performed at a biotechnology startup, a leading academic research center and two contract research organizations, all of which are California-based. The work will over time involve more than 10 California scientists, thereby helping to employ tax-paying citizens and maintain the State’s advanced technical base. Finally, an effective, proprietary drug for the treatment of HD is expected to be highly valuable and to attract favorable financial terms upon out-licensing for development and commercialization. These revenues would flow to the California companies and institutions (including CIRM) that would have a stake in the proceeds.
Huntington's disease (HD) is caused by mutations in the Htt gene that result in an expansion of an amino acid repeat in Htt beyond the normal 4-35 contiguous amino acids. The mutant form of the protein (mHtt) causes the degeneration of medium spiny neurons (MSN). This Development Candidate Feasibility (DCF) application proposes to use HD patient induced pluripotent stem cells (iPSC) to develop novel drug therapies for HD. The goal is to use iPSC-based assays to optimize already identified compounds capable of binding to mHtt and disrupting its neurotoxic activity, and to characterize the pharmacological activity of these compounds in mice.
Objective and Milestones
- The development pathway is well described; the chemistry and biological assays provide meaningful outcome measures and fully meet DCF criteria.
- The milestones are well defined, focused and logical, as appropriate for a drug discovery and validation program.
Rationale and Significance
- This proposal targets an important, devastating disease that has no cure or disease modifying treatments. If successful it would have a very significant impact on patient care.
- This proposal represents an excellent use of iPSC-based modeling, as this approach enables access to the relevant cell type from HD patients.
- The scientific rationale for targeting mHtt as proposed is very strong, and the pursuit of this first-in-class therapy is innovative.
- Success with the proposed product would provide proof of concept for a more general approach with implications for many other neural and non-neural diseases.
- The neuronal death in HD is selective to MSN. Some reviewers argued it is thus important to generate and study this critical neuronal subtype, rather than the cortical neurons described by the applicant. Other reviewers, however, felt this to be less critical, especially since preliminary data on cortical neurons do display a relevant phenotype.
Feasibility and Design
- Compelling preliminary data are presented in support of the feasibility of the various aspects of this project.
- Reviewers appreciated the drug discovery approach described in the application, from molecular high throughput screen to functional validation in neurons.
- The research plan is thorough and well described.
- Since the applicant proposes to use iPSCs from HD patients with relatively large repeat expansions, i.e. those who usually present with a severe juvenile form of the disease, it is possible that this project is relevant only to that small proportion of HD patients and not to those with more common adult onset HD. Reviewers did, however, emphasize that this did not significantly diminish their enthusiasm for this proposal.
Qualifications of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The qualifications of the PI and team are excellent; all necessary expertise appears to be in place.
Collaborations, Assets, Resources and Environment
- The biotech–academia collaboration in this project is very appropriate; the roles of each collaborator are clearly justified.
- The participating companies seem well resourced to perform their part.
- In vivo efficacy work in HD mouse models will be directly supported by one of the collaborators on this proposal. This adds value to the award.
Responsiveness to the RFA
- The project clearly fits the RFA, given the central role of the iPSC-derived HD neurons for validating hits.
- CIRM’s portfolio contains 2 other programs targeting HD, but the proposed small molecule approach to correct toxic mHtt is unique.
- This project aligns with CIRM’s mission extremely well.