Jerome Engel, Jr., MD, PhD, on EpiBioS4Rx and Epilepsy-Preventive Therapies

Decades of research has shed light on the many causes of epilepsy and has led to various antiepileptic medications and novel nondrug therapies. However, there are no treatments that prevent epilepsy. More needs to be done to better understand how to develop epilepsy-preventive therapies.

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4R_x) project¹ aims to do just that, then use that data to develop more-effective clinical trials of epilepsy-prevention therapies.

To answer our questions about EpiBioS4R_x, Neurology Consultant reached out to the Project Director of EpiBioS4R_x Jerome Engel, Jr., MD, PhD, who is the director of the Seizure Disorder Center at the University of California, Los Angeles (UCLA); a professor of neurology, neurobiology, and psychiatry at UCLA; and a member of the Brain Research Institute at UCLA.

He will also be speaking about EpiBioS4R_x at the American Epilepsy Society (AES) 2019 Annual Meeting.

NEURO CON: What is EpiBioS4R_x, and how did you become involved with it?

Jerome Engel: About a decade ago, the National Institute of Neurological Disorders and Stroke (NINDS) decided to fund several Centers Without Walls (CWOWs) to support collaborative research projects on epilepsy among several institutions. These would be 5-year grants of approximately $3 million per year in direct funds, on specific topics determined by NINDS. The first CWOW was devoted to the genetics of epilepsy and was awarded to the University of California at San Francisco, the University of Melbourne in Australia, and Duke University. The second was devoted to sudden unexpected death in epilepsy (SUDEP) and was awarded to Case Western Reserve and Baylor University. Both of these are now essentially completed.

The third CWOW was devoted to antiepileptogenesis and was awarded to 7 principal investigators at 5 centers. In addition to myself as project director and Paul Vespa at UCLA, the principal investigators include Arthur Toga at the University of Southern California, Solomon Moshé and Aristea Galanopoulu at Albert Einstein College of Medicine, Asla Pitkänen at the University of Eastern Finland, and Terence O’Brien at Monash University in Australia.

This project, the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4R_x), is now approaching the end of its third year of funding. The research was designed to address a major obstacle to the development of antiepileptogenic therapy (ie, that clinical trials of potential antiepileptogenic drugs are prohibitively expensive at the present time, because a very large number of participants would be necessary, and participants would need to be followed for many years. Biomarkers of epileptogenesis, however, could greatly reduce the cost of these clinical trials if they could be used to reliably determine who would develop epilepsy following an epileptogenic insult, in order to enrich the subject population, and also reliably determine whether the epileptogenic process has been aborted, without waiting for epileptic seizures to occur.

The EpiBioS4R_x research project, therefore, is designed to identify biomarkers of posttraumatic epilepsy (PTE) following traumatic brain injury (TBI), as this is the most appropriate patient population for future clinical trials of potential antiepileptogenic agents. Standardized animal studies are being carried out on a rat model of TBI at 4 laboratories, and parallel human studies are underway at 13 clinical TBI centers.

The objective of the human research is to validate the biomarkers identified in the animal laboratories, and beginning in year 4, identified biomarkers will be used to investigate the efficacy of several potential antiepileptogenic interventions in the animal laboratories. The overall objective is to obtain sufficient data by the end of this funding period to design an economically feasible clinical trial of at least one potential antiepileptogenic intervention.

NEURO CON: What has the EpiBioS4R_x project taught us so far about post-TBI epilepsy?

JE: The most important information gained from EpiBioS4R_x during the first 3 years has been the importance of standardizing the preclinical studies to enable the combined analysis of large amounts of data and also the importance of standardizing the clinical studies in a manner that allows comparisons with the results of animal studies. It is unlikely that a single reliable biomarker of epileptogenesis will emerge, and emphasis is being placed on identifying a profile involving molecular, cellular, electrophysiological, and imaging data that can be easily obtained noninvasively early after TBI.

NEURO CON: How might the findings from the EpiBioS4Rx project impact clinical practice and how post-TBI epilepsy is managed?

JE: If successful, the data obtained from EpiBioS4R_x will be used to design economically feasible clinical trials of potential antiepileptogenic agents following TBI. This is believed to be the most productive approach to developing clinically effective antiepileptogenic agents. Once one or more agents are determined to be effective for preventing PTE, they can also be tested in other situations (for instance, in patients following a stroke, in infants with tuberous sclerosis, in patients with brain infections—particularly parasitic infections such as neurocysticercosis—and other, less-common conditions).

Biomarkers of epileptogenesis may also be biomarkers of epilepsy itself, which, if true, could revolutionize the treatment of epilepsy by making it possible to diagnose epilepsy after a single seizure, distinguish between epilepsy and conditions that mimic epilepsy (such as psychogenic nonepileptic seizures), determine the effectiveness of specific antiseizure drugs, confirm that epilepsy no longer exists, and diagnose drug-refractory epilepsy to facilitate referral of appropriate patients for alternative treatments such as surgery.

Furthermore, identifying biomarkers of epileptogenesis will undoubtedly yield insights into fundamental mechanisms underlying the development and maintenance of epileptic conditions, which, if pursued, could lead to identification of novel targets for treatment, prevention, and perhaps even cure.

Reference:

1. EpiBioS4R_x (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy). University of Southern California’s Mark and Mary Stevens Neuroimaging and Informatics Institute. https://epibios.loni.usc.edu/. Accessed November 25, 2019.