Approximately 1 in 50 people who suffer a traumatic brain injury (TBI) will develop post-traumatic epilepsy (PTE)—with the risk of PTE significantly higher in people with severe TBI. PTE is characterized by recurring seizures that begin a week or more after the brain injury, and there is currently no way to identify those at risk for developing PTE or to prevent its onset.
Now, researchers at Albert Einstein College of Medicine, led by Aristea Galanopoulou, M.D., Ph.D., have received a five-year, $11 million grant from the National Institutes of Health (NIH) to look for novel biomarkers that predict a person’s risk for developing PTE and for treatments to prevent the condition. Dr. Galanopoulou will lead an international, multicenter collaboration with faculty at the University of California, Los Angeles; University of Southern California; Uniformed Services University of the Health Sciences; University of Minnesota; and Monash University in Australia, a team established by EpiBioS4Rx, a previous PTE research “center without walls” grant. The investigators will first conduct preclinical studies, with the goal of future clinical trials to evaluate promising diagnostics and interventions.
“Traumatic brain injuries are one of the most common causes of epilepsy, particularly among people aged 15 to 24 and the elderly,” said Dr. Galanopoulou, professor in the Saul R. Korey Department of Neurology and the Dominick P. Purpura Department of Neuroscience. “For that reason, PTE requires specialized attention. Our fruitful research collaboration over the past five years laid the groundwork for this grant, and we look forward to translating our findings to the clinic in the coming years, so we can provide hope for patients.”
Establishing Biomarkers for PTE
One research focus is to establish biomarker panels—a collection of tests that together reliably identify those at high risk for developing PTE following an injury or those likely to respond to treatments following TBI. Such candidate biomarkers include blood tests measuring protein markers, such as phosphorylated tau, a protein associated with TBI; the presence of abnormal high-frequency oscillations in the brain captured by electroencephalogram (EEG); and indicators of structural brain abnormalities captured by magnetic resonance imaging (MRI).
Under the new grant, the Einstein-led team will confirm these biomarkers in a rat model and identify new ones that help improve the panel. The ultimate goal is to develop a biomarker panel that can validly identify people at high risk for PTE and predict their response to treatment. Based on the biomarker findings, qualifying patients will then receive a drug that the researchers will be studying.
Testing Promising Drugs
The preclinical EpiBioS4Rx work identified a number of possible targets for treating TBI and PTE. The new grant will specifically use a chelating agent that removes excess iron from the body and is currently used to treat certain blood disorders. Since chelating agents also reduce tissue damage associated with brain hemorrhages, the researchers hypothesize that the drug may help to prevent PTE, which usually results from brain hemorrhages.
Dr. Galanopoulou and her colleagues will initially evaluate the efficacy of the chelating agent in an animal model in double-blinded, randomized studies at multiple institutions, as is typically done in clinical trials. If the treatment proves successful in animal studies, it will be evaluated in the future in human clinical trials.
The grant, titled “Translational platform for epilepsy therapy and biomarker discover,” was provided by the National Institute on Neurological Disorders and Stroke (NINDS), part of the NIH (R01NS127524). Grant collaborators at Einstein are Solomon L. Moshé, M.D., Craig Branch, Ph.D., and Wenzhu Bi Mowrey, Ph.D. Additional collaborators are Andrey Mazarati, M.D., Ph.D., and Richard Staba, Ph.D., at UCLA; Dominique Duncan, Ph.D., at University of Southern California; Denes Agoston, M.D., Ph.D., at Uniformed Services University; Lisa Coles, Ph.D., at University of Minnesota; and Terence O’Brien, M.D., at Monash University in Australia.
In addition to the NINDS grant, Drs. Galanopoulou and Mazarati have received two, two-year grants from the U.S. Department of Defense totaling nearly $1.95 million to develop more realistic animal models of traumatic brain injury and to study how inflammation and the gut microbiome influence the onset of PTE.
“PTE has been poorly understood, but we are encouraged by our recent advances in untangling the factors that trigger it,” said Dr. Galanopoulou. “We are hopeful we can find a way to avert the onset of PTE and spare people the challenges that accompany the disease.”