ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Life expectancy of ALS patients averages 2–5 years from diagnosis. About 5,600 people in the U.S. are diagnosed with ALS each year, and about 30,000 Americans have the disease. There is a clear unmet need for novel ALS therapeutics because no drug blocks the progression of ALS. This may be due to the fact that multiple proteins work together to cause the disease and therapies targeting individual toxic proteins will not prevent neurodegeneration due to other factors involved in the ALS disease process. We propose to develop a novel ALS therapy involving small molecule drugs that stimulate a natural defense system in MNs, autophagy, which will remove all of the disease-causing proteins in MNs to reduce neurodegeneration. We previously reported on a class of neuronal autophagy inducers (NAIs) and in this grant will prioritize those drugs for blocking neurodegeneration of human iPSC derived MNs from patients with familial and sporadic ALS to identify leads that will then be tested for efficacy in vivo in animal models of ALS to select a clinical candidate. Since all of our NAIs are FDA approved for treating indications other than ALS, our clinical candidate could be rapidly transitioned to testing for efficacy and safety in treating ALS patients near the end of this grant.
Neurodegenerative diseases such as ALS as well as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s Disease (HD) are devastating to the patient and family and create a major financial burden to California (CA). These diseases are due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. This suggests that common mechanisms may be operating in these diseases. The drugs we are developing to treat ALS target this common mechanism, which we believe is an impairment of autophagy that prevents clearance of disease-causing proteins. Effective autophagy inducers we identify to treat ALS may turn out to be effective in treating other neurodegenerative diseases. This could have a major impact on the health care in CA. Most important in our studies is the translational impact of the use of patient iPSC-derived neurons and astrocytes to identify a new class of therapeutics to block neurodegeneration that can be quickly transitioned to testing in clinical trials for treating ALS and other CNS diseases. Future benefits to CA citizens include: 1) development of new treatments for ALS with application to other diseases such as AD, HD and PD that affect thousands of individuals in CA; 2) transfer of new technologies to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies and resulting job creation; and 3) reductions in extensive care-giving and medical costs.
In patients with Amyotrophic Lateral Sclerosis (ALS), motor neurons degenerate, leading to paralysis and ultimately death typically within a few years of diagnosis. This Development Candidate Feasibility proposal builds on the hypothesis that accumulation of abnormal proteins causes motor neuron death in ALS. The goal is to identify therapeutic molecules that stimulate a cellular activity called autophagy, a process by which a cell removes unnecessary or dysfunctional proteins. Expanding on previous work, in which the team identified small molecules that induce autophagy in neurons, they now plan on prioritizing these compounds using in vitro assays based on human induced pluripotent stem cells (iPSC) derived from ALS patients and differentiated into motor neurons. The efficacy of candidate molecules will then be tested in ALS preclinical models.
Objective and Milestones
- The timeline clearly sets out how the work will be performed; the proposed studies can be completed within the 3 year period.
- The milestones are specific and quantitative with clearly defined endpoints. Reviewers were, however, unclear regarding the desired potency of the target product and suggested that the applicant strive for potency in the micromolar range.
Rationale and Significance
- A confluence of genetic, pathologic and experimental data suggests that targeting autophagy is a rational approach for treating ALS.
- While focusing on the accumulation of neurotoxic proteins was viewed as an oversimplification of the complex ALS disease process, elevated autophagy will probably be beneficial.
- ALS is a devastating disease with no therapy. Success in this project would have a major impact on the treatment of this disease.
- The target product, if successful in the treatment of ALS, may also be useful for the treatment of a number of other neurological disorders.
Feasibility and Design
- The applicant presents a large amount of highly supportive preliminary data. He/she has identified small molecule autophagy inducers with desirable effects on neurons using an elegant and unbiased approach.
- Although the project is somewhat high risk, the potential gains are great. Some reviewers felt that there is a good chance that a suitable compound for further development will be identified.
- The research plan is appropriate, logical and exciting; reviewers were very enthusiastic about several of the proposed technologies to be employed.
- iPSC lines from ALS patients represent state-of-the-art, physiological models for neuronal dysfunction in ALS; reviewers were highly supportive of their use.
- Reviewers praised many aspects of the ALS iPSC-based assays that have already been developed. They did however observe that the assay using sporadic ALS iPSC is not as robust as the one using familial ALS iPSC.
- While some reviewers appreciated the proposed combination of in vitro and in vivo approaches, others expressed concern about the selected transgenic animal models, as they do not appropriately reflect the human condition and their use in the past has not led to the successful development of drugs.
- The compounds to be tested in this proposal are FDA-approved for treating medical conditions other than ALS, have thus undergone extensive preclinical and clinical testing in the past and could be rapidly moved to clinical testing.
Qualifications of the PI (Co-PI, Partner PI, if applicable) and Research Team
- The PI has an outstanding track record in neurological disease and is extremely well published and well funded.
- Reviewers expressed concern that the total percent effort committed by staff is too low for the scope of this project.
- Overall justification for the budget is not detailed enough, and the cost for a subcontract for the animal model work is not provided.
Collaborations, Assets, Resources and Environment
- The applicant institution offers an excellent academic environment, highly suitable for undertaking the proposed work.
- Excellent collaborators for in vivo imaging, animal model work and advice on the drug development process, key to the success of this effort, are mentioned in the proposal, but are not listed in the administrative parts of the application, thus raising concern about the scope of their involvement.
Responsiveness to the RFA
- This proposal is responsive to the RFA in that the use of human iPSC is necessary to achieve the outcomes of the proposed research.
- The proposed therapeutic approach is novel to CIRM, there is no other proposal funded to use ALS patient iPSC to identify drugs that stimulate autophagy.