Regenerative Epigenetic Therapy for Gulf War Illness
Abstract
Overarching Challenge: This project propose addressing an overarching challenge of GWIRP to develop a regenerative epigenetic therapy for curing Gulf War Illness (GWI) with U.S. Food and Drug Administration (FDA)-approved drugs and using magnetic resonance imaging (MRI), neuropsychiatric, and neuropathology techniques. This application is consistent with the goals of the FY20 GWIRP Idea Award, which is intended to support exploratory, high-risk/high-reward research with the potential to yield new treatment of GWI. About 250,000 Veterans who served in the Persian Gulf War have chronic multi-symptom illness that defines GWI. Cognitive and mood impairments are among the conspicuous brain-related symptoms in GWI Veterans and in animal models of GWI. Multiple studies suggest that GWI in Veterans is linked to a combination of chemical exposures during the Gulf war, including pyridostigmine bromide (PB), DEET (a mosquito repellent), and permethrin (PM, an insecticide). However, presently there are no proven treatment for GWI. Animal models have been developed to replicate features of GWI. We propose to use a validated model for identifying novel epigenetic therapy for GWI. A short-term (3-week) epigenetic therapy would offer long-lasting benefits in GWI, such as “no GWI and no side effects,” an ideal therapy for curing GWI or reducing its burden in thousands of Veterans afflicted with GWI. Objective and Rationale: The main goal of this project is to develop a regenerative epigenetic treatment for permanent reduction of peripheral and central symptoms of GWI using FDA-approved HDAC inhibitors. Experiments are designed to investigate a delayed (10 and 15 months) epigenetic treatment for GWI in an established rat model of GWI. The overarching hypotheses to be tested are (1) the long-term health consequences associated with GWI are caused by persistent activation of epigenetic HDAC function induced by exposure to a combination of GW-relevant neurotoxic chemicals and stress, and (2) therapeutic inhibition of epigenetic HDAC pathway is a clinically effective treatment to improve cognitive performance and neurological symptoms in GWI. The proposed delayed therapy (10 months = human 25 years!) fits within the target timeline for current GW Veteran cohort. This project will test the curing or reversal ability of three FDA-approved broad- (vorinostat), medium- (belinostat) and narrow-spectrum (romidepsin) HDAC inhibitors in a chronic GWI model. Since GWI is caused by exposure to certain chemicals that activates HDAC pathway, HDAC inhibition can be effective therapy as evident from our recent work with OP chemical neurotoxicity. Moreover, this strategy has not studied in GWI. Thus, in this project, we will test the protective effect of three different drugs (vorinostat, belinostat, and romidepsin) in rat GWI model under three aims: Aim 1: To determine the efficacy of HDAC inhibitors against GWI agent-induced brain damage using MRI scanning. Aim 2: To determine the efficacy of HDAC inhibitors against GWI-induced pain, behavioral and memory deficits. Aim 3: To determine the efficacy of HDAC inhibitors against GWI agent-induced neuropathological changes. Our research team will employ established methods and a well-validated rat model of chronic GWI by Shetty lab. Rats will be randomly assigned to control group or GWI groups (N=20) receiving GWIR-chemicals PB, PM, and DEET. The test drugs (vorinostat, belinostat, and romidepsin) will be given for 3 weeks as delayed therapy (10 and 15 months later), which is equivalent of 25 and 35 years that many GW Veterans have had GWI. Brain neuropathology will be measured by MRI scanning and behavior at our vivarium facility. The outcome of project will: (i) identify the potential of HDAC inhibition by three FDA-approved drugs in chronic GWI model; and (ii) identify the efficacy of lead drug therapy in GWI for attenuating GWI-related peripheral, cognitive, and neurological dysfunction. We prop
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110305
Entities
People
- Samba Reddy
Organizations
- Texas A&M University
- United States Army