Reversing Post-Traumatic Epilepsy

Principal Investigator: CASILLAS ESPINOSA, PABLO

Proposal Number: EP200022

Award Number: W81XWH-21-1-0925

Period of Performance: 9/30/2021 - 9/29/2025

PUBLIC ABSTRACT

Epilepsy, with uncontrolled, unprovoked and recurrent seizures, is a common consequence following a traumatic brain injury (TBI), in both the general population as well as in military personnel and Veterans. For those that develop epilepsy, this condition adds a considerable additional disability burden to their lives and risk of mortality. In addition to the seizures, people with epilepsy after TBI also commonly develop significant anxiety, depression, mobility and memory problems that compound the disability burden to their life. To control the seizures, patients often are required to take more than one drug. The cumulative effect of taking multiple anti-seizure drugs, in addition to the epilepsy and psychiatric comorbidities, creates a massive toll on the quality of life of people with epilepsy. However, the available treatments are not able to control the seizures in more than 30% of the people that suffer post-traumatic epilepsy. In addition, the current available treatments do not improve the anxiety, depression, mobility and memory problems that haunt patients with epilepsy and TBI. The only current way to improve the overall symptoms is epilepsy surgery, but this is only available to a small proportion of patients (<5%). The risks, cost, time, and expertise involved in epilepsy surgery, in addition to its limited applicability, make this a less than ideal solution to the problem.

There is currently a poor understanding of why epilepsy develops after a TBI in some individuals but not others, so it remains unclear who is most at risk. Identification of this subset of “at-risk” patients would be a major leap forward by allowing for improved prediction of long-term outcomes for patients, as well as the identification of new treatment targets to reduce or reverse epilepsy after TBI.

In this proposal, we hypothesize that a novel treatment could help to “reverse” the symptoms of epilepsy, which means less seizures, no psychiatric, memory or mobility problems, which will result in a great improvement in the quality of life of people that suffer epilepsy. We have preliminary data that shows encouraging evidence that our intervention would be the “holy grail” for patients that suffer this devastating condition. The results of this study will prove if this novel approach can become a “surgery in a pill” for patients with epilepsy after TBI but applicable to more people and without the costs, problems, and risks associated with epilepsy surgery. Similarly, our novel treatment could be the first-ever described to reverse psychiatric, memory, or mobility problems in epilepsy after TBI, which until now were thought to be irreversible.

Aim 1 of this proposal will test if our novel treatment is able to reverse epilepsy after TBI using a well-established rat model of the disease. In Aim 2, using the same model, we will evaluate if our novel treatment is able to reverse the psychiatric (anxiety, depression, memory and mobility) problems associated with epilepsy after TBI. Aim 3 will look for markers that could help us to understand why epilepsy and the psychiatric problems develop and why these are difficult to treat. This approach will help to personalize the treatment for our patients.

This proposal is particularly unique and innovative as it offers a new approach to help people that suffer this devastating disorder. We integrate experts across different disciplines: neuroscience, clinical neurology, and bioinformatics. Together, these studies will represent a transformational advancement in understanding the mechanisms that underlie the development of epilepsy after TBI. Findings are expected to validate our novel treatment as a therapy to reverse epilepsy and its associated psychiatric disorders, with critical implications to improve the quality of life of military, Veterans, and civilian populations.

TECHNICAL ABSTRACT

Post-traumatic epilepsy (PTE) develops months to years after an epileptogenic brain injury (i.e., brain trauma due to a battlefield injury, penetrating trauma, etc.). PTE is one of the most common types of epilepsy in adults that is difficult to treat, with more than 30% of patients suffering seizures despite multiple anti-seizure medications (ASM). PTE is accompanied by disabling psychiatric and sensorimotor comorbidities, which along with the seizures, are the major determinant of reduced quality of life. Disease modification in epilepsy indicates the ability to reverse in an enduring manner the severity of the underlying disease. Surgical resection of the epileptogenic zone is the only currently available disease-modifying (DMT) treatment, which can render drug-resistant PTE into drug-responsive in highly selected patients. However, only a minority of PTE patients (<5%) are suitable for epilepsy surgery, which is highly resource and expertise intensive, and in 20%-40% of the “best” candidates, surgery fails to control their seizures post-operatively. Therefore, the key challenge for translational epilepsy therapy research is to develop pharmacological DMTs for PTE that have the disease-modifying benefits of epilepsy surgery – but would be applicable to many more patients. However, not all the people with PTE have the same prognosis (e.g., not all patients are responsive to ASM treatment). Therefore, to identify appropriate patient populations and target interventions it is critical to find accurate prognostic biomarkers of the neuropathophysiological processes underpinning PTE Importantly, the team’s pilot data shows that selenate, a novel protein phosphatase 2A (PP2A) enhancer that decreases hyperphosphorylated tau (h-tau), may be the first-ever DMT for PTE and associated comorbidities. Our pilot data also shows that proteomic changes in the h-tau molecular pathway are promising molecular biomarkers of PTE.

Aim 1: Investigate if sodium selenate is disease-modifying, reducing spontaneous recurrent seizures in a preclinical trial of PTE. It is hypothesized that selenate treatment will have an enduring DMT effect to mitigate the number and severity of seizures in the lateral fluid percussion injury (LFPI) PTE model.

Aim 2: To investigate if treatment with selenate in chronically epileptic animals attenuates the neuropsychiatric comorbidities seen in PTE. It is hypothesized that selenate will have an enduring DMT effect to mitigate the behavioral, sensorimotor, and cognitive deficits of PTE.

Aim 3: To utilize a systems biology approach to integrate targeted and untargeted multi-omics datasets (transcriptomics, proteomics, and phosphoproteomics) from preclinical PTE to find prognostic biomarkers of PTE, comorbidities, and responsiveness of selenate treatment. It is hypothesized that the systems-level integration of molecular profiles of PTE rats will identify biomarkers able to predict disease severity and outcomes. It is further hypothesized that this network approach will reveal the mechanism of action by which selenate acts as a DMT in PTE.

Innovation and Impact:

The development of a medical DMT to mitigate the severity of epilepsy is the “holy grail” for epilepsy researchers and clinicians. The results of this study will provide novel proof-of-concept data that this “surgery in a pill” approach for patients with PTE is possible. Similarly, selenate could be the first-ever treatment to reverse the neuropsychiatric comorbidities in PTE, which until now were thought to be irreversible. Importantly, selenate has already been shown to have a favorable safety profile in early phase clinical trials for other diseases, facilitating the translation of the results of this preclinical study into a clinical trial of DMT for PTE. Our comprehensive systems biology analyses integrating prospective and longitudinal multi-omics and disease progression/modification data in PTE rats will provide unparalleled insight into the mechanism of action of selenate as well as the role of the tau pathway in the progression and long-term effects of PTE.

Military, Veteran, and Civilian Relevance:

The long-term effects of TBI, such as PTE, are common to both civilian and military populations. Research findings may be paradigm-shifting in medical management of these people, as well providing biomarkers to identify individuals at particular PTE risk enabling the development of personalized treatment. This will also pave the way for future development of novel therapeutic strategies using our multiomics data (proteomics and phosphoproteomics).