Use of human iPSC-derived neurons from Huntington’s Disease patients to develop novel, disease-modifying small molecule structural corrector drug candidates targeting the unique, neurotoxic conformation of mutant huntingtin

Funding Type: 
Early Translational IV
Grant Number: 
Award Value: 
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Public Abstract: 
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.
Statement of Benefit to California: 
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.
Progress Report: 
The long-term objective for this project was to develop a first-in-class, disease-modifying drug to treat Huntington's disease (HD). This drug would comprise a small molecule that binds to and ameliorates the neurotoxicity of the mutant huntingtin protein (mHtt) that causes HD. The goal of the research conducted under the CIRM Award was to demonstrate development candidate feasibility in vitro with a novel small molecule mHtt detoxifier early lead compound that is potent and efficacious in neurons from HD patients generated using stem cell technology (HD i-neurons) as well as suitable for use in mice as experimental models for HD. The original project strategy was to 1) acquire or synthesize new samples of compounds identified as potential mHtt detoxifiers in the screening campaign conducted 7 years ago; 2) establish or re-establish the cell-free and cultured neuron biological assays needed to characterize potential small molecule mHtt detoxifiers (this work was carried out in the laboratory of our collaborator, Dr. Steven Finkbeiner of the J. David Gladstone Institutes); 3) acquire or synthesize new/novel analogs of the initial hits; 4) test new/novel compounds for activity in a cell-free assay for potential mHtt detoxifier activity; 5) test hits for efficacy in HD and non-HD i-neurons; and 6) profile the in vitro and in vivo pharmacokinetics and absorption, distribution, metabolism and elimination (PK/ADME) profiles of compounds that displayed selective neuroprotection toward HD i-neurons. Specific achievements of the first year of the Project include: • Acquiring 205 previously identified hits or analogs thereof from commercial sources; • Synthesizing an additional 84 novel, designed analogs; • Generating the reagents, re-establishing and implementing the screening assay; • Testing all compounds acquired or synthesized in the screening assay; • Establishing a counterscreen for false positives in the screening assay; • Preliminary screening 48 previously reported hits in the counterscreen; • Testing 14 previously or newly identified hits side-by-side in full concentration-response assays in both the screening and counterscreening assays; • Profiling 11 diverse hits in in vitro PK/ADME assays; • Testing 17 compounds for their ability to ameliorate neurotoxicity in a rodent primary neuron model; and • Preliminary testing 2 previously identified hits in human HD i-neurons. Unfortunately and surprisingly, we observed that all compounds displayed essentially identical profiles in full concentration-response studies in both the screening and counterscreening assays. We interpret this result to indicate that these compounds and structurally related compounds that we considered to be most promising and tested do not in fact bind to mHtt, i.e., they are all false positives. Since no valid starting points exist for continued work, the Project will be terminated after the first award period.