A Novel Therapeutic Approach for Targeting TDP-43 in ALS
Abstract
The goal of this proposed work is to test a treatment strategy that targets a common pathogenic protein identified in amyotrophic lateral sclerosis (ALS) using a mouse ALS model. ALS is a neurodegenerative disease affecting motor neurons, causing progressive muscle weakness, impaired breathing, and eventual death. Currently, no cure or disease-modifying treatments are available. Approved drugs treat symptoms that improve quality of life and prolong life by only a few months. Ninety to ninety-five percent of ALS cases are sporadic with no known cause. TAR DNA-binding protein 43 (TDP-43) is a protein that normally controls the expression of thousands of genes by orchestrating RNA processing, transport and metabolism, located primarily in the cell nucleus. In almost all sporadic cases of ALS (sALS), the TDP-43 protein is found abnormally aggregated in motor neurons. Mutations in the gene coding for TDP-43 also occur in about 5% of affected individuals with a family history of the disease, defined as familial ALS (fALS). The nearly ubiquitous presence of aberrant TDP-43 in sALS, and its prevalence as one of the four most commonly mutated genes in fALS, identifies this protein as a key ingredient both early in disease initiation and in propagation, and an important target for disease modifying treatment strategies. Pathogenic proteins are altered versions of normal cellular proteins that acquire disruptive properties due to modifications, proteolytic cleavage, or mutations that enhance the aggregative properties. The altered proteins assume an inappropriate three-dimensional structure and bind to and induce normal proteins to aggregate, creating a domino effect of misfolded proteins, a phenomenon first described in prion disease. In ALS, TDP-43 is found in aggregated, cleaved, hyper-modified forms, indicating that profound disruption of the normal state has occurred. The neurodegeneration in ALS spreads from the site of initiation, suggesting that some disease-promoting entity is transferred from diseased areas to healthy areas. Once altered, by whatever means, TPD-43 may promote the spread of disease by passing the aggregated proteins between cells and promoting TDP-43 aggregation in neighboring cells as it travels. These aggregated proteins are thought to exit damaged cells and subsequently enter undamaged healthy cells, promoting the pathway to a disease state. Abnormal TDP-43 is also present in frontotemporal dementia and a number of other neurodegenerative diseases, widening the potential of TDP-43 targeted therapies for diseases beyond ALS. We previously identified small-molecule compounds, GISMOs (Glycosaminoglycan-Interfering-Small-MOlecules) that prevent pathogenic proteins with similar prion-like properties from binding to and entering cells, and have showed efficacy against amyloid beta and tau in an Alzheimer s disease mouse model. We propose a similar therapeutic strategy could prevent the spread of pathogenic TDP-43 in ALS. We have identified a small molecule compound that inhibits TDP-43 from binding to heparin, a surrogate molecule for cell surface glycosaminoglycans present on neuronal cell membranes. This GISMO compound also prevents TDP-43 from binding to human brain cell cell membranes. Our hypothesis is that the small-molecule inhibitor prevents binding of TDP-43 to cell surface glycosaminoglycans present on neuronal surfaces and could therefore prevent uptake of pathogenic TDP-43 by healthy cells and the cell-to-cell spread of disease. In this study, we propose to test our theory in a mouse model of ALS that contains a mutant form of human TDP-43 found in human fALS. The primary goal of this project is to test whether oral administration of the Gismo compound reduces ALS-associated symptoms present in this mouse model. Successful identification of disease-modifying properties will provide the evidence needed to pursue additional funding for preclinical work and eventually clinic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210379
Entities
People
- Myunghee Kim
Organizations
- Gismo Therapeutics (United States)
- United States Army