Chemical Library Screening for Potential Therapeutics Using Novel Cell-Based Models of ALS
Abstract
Treatments for amyotrophic lateral sclerosis (ALS) that directly address the underlying genetic and molecular causes are urgently needed. While the causes of ALS are diverse, some are more common than others. For example, the leading genetic cause of ALS is the expansion of a natural repetitive sequence in a gene called C9ORF72. This expansion is also responsible for a portion of sporadic ALS, about 6%. The proposed project will tackle this specific form of ALS by developing new models of disease. It will then use these models to screen large libraries of chemical compounds for their ability to improve molecular and cellular defects associated with disease. Molecules that are effective in our screen can quickly be developed as potential therapeutics by improving their chemical properties and testing them in animal models of disease, which are the first steps to clinical testing on ALS patients. Thus, our approach will be promising for a large number of ALS patients who have repeat expansion mutations in the C9ORF72 gene. The drugs we seek to identify would specifically address the disease mechanism and not symptoms. We are looking for a cure. The proposed project focuses on identification of small molecules with therapeutic potential. Traditional drugs are small molecules. Therefore, the development of promising molecules from the proposed project would follow the traditional drug development pipeline. Alternative approaches, including gene therapy and personalized medicine, are on the horizon, but their development, safety, and approval are likely to take much longer to be realized. Thus, the results from the proposed study will have a high likelihood of helping patients in the near future if promising compounds can be identified. Optimistically speaking, if lead compounds are identified that do not need further chemical optimization, or are already approved by the Food and Drug Administration for other diseases or illnesses, then clinical trials could be accelerated and lead to actual drugs for patients in as a little as a few years. The proposed project is an early phase discovery-based approach. However, it leverages the currently known disease mechanisms with cutting-edge high-throughput chemical screening. Together, this approach is very likely to identify molecules that can improve molecular and cellular defects associated with ALS. This is one of the first steps toward drug development. Interim outcomes that could be expected from this project are (1) the development of a new cell-based model of c9FTD/ALS for drug discovery and disease mechanism studies and (2) the identification of promising molecules for further drug development. A plan is in place to then move the most promising molecules into preclinical animal model testing. For these reasons, the proposed project is likely to advance development of therapeutics for ALS. Even in the unlikely event that molecules are not identified that can be directly moved to animal model testing, we will have tested hypotheses of disease mechanism and the results will inform new rounds of screening. Results will also provide a blueprint for building and synthesizing successful therapeutic molecules based on what has been learned through this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610176
Entities
People
- Keith T Gagnon
Organizations
- Southern Illinois University
- United States Army