Suppression of TDP-43 Proteinopathy in Mice by Targeting Rad-23
Abstract
Background information underlying rationale and feasibility: Normally, cells continually synthesize new proteins and dispose of old and damaged proteins. In ALS, damaged proteins are not properly eliminated, leading to their accumulation, and this compromises cell health. Major therapeutic efforts are underway worldwide to devise new strategies for enhancing elimination of damaged proteins. Several laboratories have shown that reducing the abundance of a key regulatory protein called RAD23 has a broad action of enhancing elimination of damaged proteins. In a variety of disease models this benefits neuronal health and survival. To translate these observations into a human, we will test the efficacy of a therapeutic technology called anti-sense oligonucleotides (ASO). The goal of this project is to determine whether ASO that target the destruction of RAD23 confer benefits on a mouse model of ALS. Ultimate applicability of research: If these studies show efficacy, we are positioned to bring them into the clinic. ASO technology has proven benefits in humans with the childhood motor neuron disease spinal muscular atrophy. ASO are in clinical trials for the treatment of rare individuals with mutations in the disease-causing protein SOD. What type of ALS patients will this help and how will it help them? Because loss of rad23 accelerates the destruction of a wide variety of damaged proteins, and because damaged proteins accumulate in all patients with ALS, we anticipate that ASO-mediated reduction in the abundance of rad23 will be applicable to patients with both sporadic and familial ALS. Potential clinical applications, benefits, and risks: ASO-mediated reduction in rad23 abundance could potentially be used in all ALS patients and, conceivably, a variety of other neurodegenerative diseases. ASO are administered by spinal tap and have been given this way to individuals with other neurodegenerative diseases, so extending their reach into sporadic ALS would be a huge benefit. Generally speaking, the risk of this approach is small, but clinical trials to examine this issue are underway. Projected time to achieve a patient-related outcome: In many ALS patients, disease progression is subacute with, on average, death within 3-5 years of diagnosis. If we find a benefit in the mouse model of ALS, we could potentially bring ASO targeting human rad23 into clinical trials within a year. If too basic for clinical applicability, what are the interim outcomes? Establishment of efficacy in mice will lead to human investigations. Likely contributions of this study in advancing the development of ALS therapeutics: There is a high potential for new drug development on the basis of these studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110236
Entities
People
- Robert Kalb
Organizations
- Northwestern University
- United States Army