RNA-Based Approach to Decrease TDP-43 Pathology and Neurotoxicity in ALS
Abstract
This proposal is responsive to ongoing efforts to treat and cure Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig s disease. ALS is a devastating neurodegenerative disorder for which there is no cure or efficient detection tools. We seek to accelerate the development of new therapeutic molecules to reduce neurodegeneration and toxicity in ALS. Overview of the Research Project. Central problem to be addressed: ALS is a late onset neurodegenerative and fatal disease that affects women and men worldwide and leads to muscle atrophy in patients. In a portion of these cases, ALS is linked to cognitive impairment associated with frontotemporal lobar degeneration or frontotemporal dementia. On average, ALS strikes patients in their 60s and some clinicians have reported an increase in the number of 20- to 30-year-old patients diagnosed with ALS. According to existing evidence, military men and women are twice as likely to be affected by ALS than non-military individuals, regardless of whether the individual served in combat or not. Among the possible explanations for this increased risk are elevated stress and traumatic brain injury during training or combat. ALS causes the death of individuals, often from respiratory failure, two to five years post-diagnosis. Therefore, it is imperative to develop strategies to decrease the factors contributing to the development of ALS. Research Description: The aggregation of the TAR DNA binding protein (TDP-43) is the hallmark feature of ALS. TDP-43 aggregates found in the brain and spinal cord of almost all ALS patients are associated with toxicity and loss of cell viability. Our project will leverage our position as experts in TDP-43 biology and use the tools we have developed to analyze TDP-43 aggregation and inhibit this pathogenic process. We recently found that RNA molecules are potent inhibitors of TDP-43 aggregation, which leads us to ask: Can specific RNA molecules be used to prevent TDP-43 aggregation and decrease neurotoxicity? This question will be tested using our established methods using purified TDP-43, human cellular models, and mouse models of ALS. Dr. Timothy Miller, the co-Principal Investigator in this proposal, and his team are experts in using RNA to reduce neurodegeneration in various models and in first-in-kind patient clinical trials. Further, Dr. Miller is the director of the Washington University ALS Center. As a physician, Dr. Miller is dedicated to providing quality care and state-of-the-art treatment to ALS patients. Together, our team will screen and identify new molecules to effectively reduce TDP-43 aggregation and its associated pathology. Ultimate Applicability and Impact of the Research: The short-term impact of this work will be to provide key data needed to develop new strategies for ALS. The long-term impact will be to accelerate drug design and introduction into clinical testing, and eventually into use for the afflicted ALS patient population. Development of new effective and selective drugs will help reduce the disease, suffering, and premature deaths caused by ALS, which is not only devastating for the patients but also for their families and care givers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010241
Entities
People
- Yuna M Ayala
Organizations
- Saint Louis University
- United States Army