Epigenetic Therapy for Post-Traumatic Epilepsy
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity in military Service Members and Veterans, which carries a large cost burden to society. TBI is a highly complex brain condition that inflicts long-lasting pain and suffering to affected persons and their family. As per the Centers for Disease Control and Prevention (CDC), an estimated 2.87 million individuals suffer a TBI annually in the USA. Post-traumatic epilepsy (PTE) with spontaneous seizures often occurs within a few months or years after TBI in up to 50% of cases, especially in severe brain injury among the Veterans. PTE is a poorly prognostic brain disease characterized by repeated seizures that are often medically uncontrollable. However, the pathophysiology of PTE is poorly understood, and there is currently no drug therapy for preventing PTE in TBI-affected Soldiers and Veterans. A greater insight is required to advance the field of PTE; there is especially an urgent need to identify at least one critical mechanistic therapy for PTE. A few mechanisms such as excitotoxicity and inflammation are proposed, but epigenetic therapies are not widely studied in PTE. Epigenetics refers to a set of functional changes to the genome that can impact gene expression without altering the DNA sequence. Epigenetic mechanisms, such as histone alterations, can regulate a broader neuronal gene networks and thus contribute to PTE pathology. Thus, epigenetics is a revolutionary research tool for finding new therapies for PTE in people at risk. Recently, we identified an epigenetic pathway in TBI and its inhibition to prevent the development of acquired epilepsy; hence, our team is uniquely qualified to develop a breakthrough treatment for PTE for Soldiers and victims of head injuries. In this Level II (advanced) project, we seek to investigate the potential of epigenetic HDAC inhibition as novel intervention for preventing PTE after TBI, with the pragmatic goal of identifying the most effective, U.S. Food and Drug Administration (FDA)-approved repurposed drug for stopping the development of PTE. For over 20 years, our team has been studying ways to prevent epilepsy. During that time, we have found that some subjects develop epilepsy after TBI when a pathway in the brain called HDAC is elevated. This project builds on a prior Department of Defense (DOD)-funded study, which demonstrated that in an animal model of PTE, HDAC activity levels are increased and such signaling can be blocked with a drug that blocks the enzyme responsible for activating it, called histone deacetylase (HDAC). Our goal is to optimize and test this potential epilepsy-preventing strategy in the hopes of creating disease-modifying treatment options. Importantly, vorinostat, an FDA-approved broad-spectrum HDAC inhibitor, can be used efficiently to inhibit the HDAC pathway; other FDA-approved drugs, romidepsin or entinostat, can also inhibit that pathway and thus may represent a practical therapy for preventing PTE in at-risk people, such as Soldiers with moderate to severe TBI. Thus, we are poised to succeed with a promising drug to treat PTE. The main goal of this project is to develop an epigenetic therapy to prevent or modify the development of PTE after brain injury using FDA-approved drugs. The primary emphasis is to investigate the impact of broad- vs. narrow-spectrum HDAC inhibition in PTE, which will represent a novel intervention of much higher clinical impact and application in human TBI patients. We propose that TBI imparts activation of epigenetically regulated HDAC pathway that facilitates the epileptogenesis, and therefore, selective HDAC inhibition is sufficient to promote robust antiepileptogenic effects in preventing or modifying the development of PTE. We will test this hypothesis by addressing two specific aims using a well-characterized controlled cortical impact (CCI) model of TBI in mice: Aim #1: To investigate the antiepileptogenic efficacy of broad-spectrum (vorin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210275
Entities
People
- Doodipala Reddy
Organizations
- Texas A&M Health Science Center
- United States Army