Identifying RNA Processing Factors That Restore Expression of Motor Neuron-Enriched Genes in ALS
Abstract
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig s disease, is characterized by the rapid and progressive loss of motor nerve cells that control muscle contraction. Detailed examination of patient spinal cords under the microscope has consistently demonstrated that changes in the location of RNA binding proteins occur in sick or dying nerve cells in nearly all cases of ALS. Additionally, in several families with inherited forms of this disease, mutations in RNA binding proteins that reside in the nucleus of nerve cells are sufficient to cause disease. However, it is not clear how changes in RNA processing cause nerve cells to stop functioning properly in this devastating disease. Several advances in stem cell technology have enabled skin cells to be converted into proliferating stem cells that our lab then uses to generate millions of motor nerve cells in a dish, enabling studies of the cell type that is most affected in ALS. By directly studying human motor nerve cells, we can study causes of ALS and test potential treatments with a higher likelihood of success. We have previously used this method to identify molecular signs that indicate when neurons are stressed in disease. In this research proposal, we will investigate the relationship between RNA binding proteins and RNA-associated cellular pathways previously linked to ALS to better understand how this disease progresses. Specifically, we will examine how these proteins affect the expression of genes that are required to keep neurons healthy. Based on advances in gene-specific therapies, we will develop candidate therapeutics using stable nucleic acids called antisense oligonucleotides (ASOs) and validate their potential beneficial effects on nerve cell survival and regeneration. ASO-based therapies are advantageous because they can be designed to precisely alter the expression of a specific gene and can reach new drug targets that were previously thought to be undruggable. Recent clinical trials have demonstrated that delivering ASOs into the nervous system of ALS patients is safe and that ASOs likely function as expected upon reaching their targets in neurons. Upon the completion of this study, we expect to have candidate therapies that can be further modified and tested in relevant ALS animal models. By combining these technologies, our novel experimental approach will provide clear routes for the creation of safe and effective treatments for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310197
Entities
People
- Daniel Mordes
Organizations
- United States Army
- University of California, San Francisco