Approximately 5,600 people in the U.S. are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated that as many as 30,000 Americans may have the disease at any given time. There are no effective therapies of ALS to-date. Recent genetic discoveries have pinpointed mutations that lead to the aberrant function of two proteins that bind to RNA transcripts in neurons. Misregulation of these RNA binding proteins is responsible for the aberrant levels and processing of hundreds of RNA representing genes that are important for neuronal survival and function. In this proposal, we will use neurons generated from patient cells that harbor the mutations in these RNA binding proteins to (1) prioritize a RNA “signature” unique to neurons suffering from the toxic function of these proteins and (2) as an abundant source of raw material to enable high-throughput screens of drug-like compounds that will bypass the mutations in the proteins and “correct” the RNA signature to resemble that of a healthy neuron. If successful, our unconventional approach that uses hundreds of parallel measurements of specific RNA events, will identify drugs that will treat ALS patients.
Our research aims to develop drug-like compounds that are aimed to treat Amyotrophic Lateral Sclerosis (ALS), which may be applicable to other neurological diseases that heavily impact Californians, such as Frontotemporal Lobar Degeneration, Parkinson’s and Alzheimer’s. The cellular resources and genomic assays that we are developing in this research will have great potential for future research and can be applied to other disease areas. The cells, in particular will be beneficial to California health care patients, pharmaceutical and biotechnology industries in terms of improved human models for drug discovery and toxicology testing. Our improved knowledge base will support our efforts as well as other Californian researchers to study stem cell models of neurological disease and design new diagnostics and treatments, thereby maintaining California's position as a leader in clinical research.
This Development Candidate Feasibility proposal intends to identify new small molecule drugs to treat amyotrophic lateral sclerosis (ALS). Genetic mutations have been discovered in ALS patients that lead to incorrect processing of RNA for genes important for neuron survival and function. This project will look for RNA signatures unique to neurons experiencing toxicity from this incorrect RNA processing and then screen for drugs that can correct the defect. The objective is to establish preclinical proof of concept for this therapeutic approach using animal models of ALS.
Objective and Milestones
- Target Product Profile was viewed as reasonable
- The objective of developing a therapeutic candidate for which neither the molecular target nor a proposed mechanism of action is known is a weakness of the proposal. The pharmacology of any possible hits would need to be improved which will be difficult with these unknowns.
Rationale and Significance
- The lack of preliminary data demonstrating a role of RNA processing errors in ALS pathology was viewed as a weak point.
- Reviewers agreed that this is a major unmet medical need, even though only a small fraction of ALS patients have the mutation targeted by this approach.
- It was speculated that, if successful, the project could also benefit sporadic ALS patients.
Research Project Feasibility and Design
- Reviewers questioned the feasibility that this phenotype of aberrant RNA processing, which is a complex biological process, could be corrected with a single small molecule drug.
- High risk project, but a very innovative approach and design.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- PI is highly accomplished.
- Outstanding integrated research team.
Collaborations, Assets, Resources and Environment
- Good collaborators and strong institutional support.
Responsiveness to the RFA
- No relevant concerns were highlighted by reviewers under this review criterion.
- A motion was made to move this application into Tier 1 (Recommended for Funding). The programmatic reasons provided were that ALS is a devastating disease that is not well-represented in CIRM’s portfolio.
- There were divergent views among reviewers, reflected by a large standard deviation of the scores. Reviewers summarized the positives and negatives of the proposal. They agreed that ALS is a major unmet medical need and a high-risk approach may be warranted. The motion carried.