Restoring Autoregulation of TDP43 in Sporadic Amyotrophic Lateral Sclerosis Using Splice-Switching Antisense Oligonucleotides
Abstract
Mutations in about 30 known genes can cause ALS that passes down through families (familial ALS), while there are also other genetic and environmental causes that may lead to ALS without a clear pattern of inheritance (sporadic ALS). Sporadic ALS accounts for the vast majority of ALS cases and may be caused by multiple factors that accumulate to give rise to disease. Despite potential differences in the causes of sporadic ALS, one major similarity is in the build-up of a protein called TDP-43 that clumps together in ALS motor neurons. Aggregates (sticky clumps of the protein that accumulate) of TDP-43 can be found in the motor neurons of 97% of cases of ALS, suggesting that TDP-43 is a central protein in causing the disease, or at least some of the effects of the disease. TDP-43 has an important function in healthy motor neurons and many other cell types. It binds to DNA and RNA to regulate the expression of other proteins in the cell. In ALS these aggregates of TDP-43 can cause toxicity to motor neurons. Additionally, the neurons are also significantly affected by the loss of the normal function of TDP-43, as aggregation of TDP-43 prevents it from performing its normal task of regulating other proteins. Furthermore, TDP-43 normally regulates its own protein levels and the loss of this auto-regulation further compounds the toxic changes inside motor neurons. Gene therapy is a potential approach that is showing great promise across multiple diverse diseases. Targeting specific genes may have much greater specificity than can be provided with drugs as well as the potential to pursue the exact mechanism that has been affected in the disease condition. Recent research has identified a gene, STMN2, that is important in maintaining motor neuron health and that creates a protein called stathmin-2. We believe that by targeting both TDP-43 with gene therapy, while also boosting the expression of stathmin-2, we will be able to reverse the negative effects of TDP-43 deficits, while maintaining motor neuron health. To do this, we have developed two novel RNA therapeutics for a gene therapy approach, designed to prevent toxic effects of the TDP-43 protein and restore motor neuron function, and survival. We will test the abilities of these drugs to improve motor neuron health. This research will provide critical evidence on the translational potential of this therapeutic approach for sporadic ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210448
Entities
People
- Lezanne Ooi
Organizations
- United States Army
- University of Wollongong