? PROJECT 2 ? PRECLINICAL MODEL FOR ANTIEPILEPTOGENIC THERAPY SCREENING IN POST-TRAUMATIC EPILEPSY There is currently no validated antiepileptogenic therapy for acquired epilepsies, such as post-traumatic epilepsy. Despite the grave human cost of post-traumatic epilepsy, undertaking the effort to perform a clinical antiepileptogenesis trial is currently hugely difficult, due to the significant cost, time to follow up, and very high numbers of subjects needed to treat to eventually observe antiepileptogenic effect. The availability of a biomarker that predicts, at an early stage, who will develop epilepsy and who might benefit from the antiepileptogenic effect of a treatment would significantly accelerate and de-risk the process of identifying an antiepileptogenic therapy. Furthermore, the concern that animal studies report several promising discoveries that do not always translate into clinically relevant findings has discouraged efforts to sponsor rigorous antiepileptogenesis trials in humans, when there is a significant risk of failure. In this study, Project 2 of the EpiBioS4Rx Center Without Walls, we aim to create a rigorous and effective preclinical model to screen antiepileptogenic therapies for posttraumatic epilepsy by trying to fill two important gaps (a) identify and validate a biomarker of posttraumatic epileptogenesis that can predict the antiepileptogenic effect of a treatment and (b) enhance the reproducibility of the study by creating the first multicenter, double-blinded, vehicle controlled, randomized preclinical antiepileptogenesis study following the high standards of rigor advocated by NINDS, the AES/ILAE Translational Research Task Force and the ARRIVE guidelines. We have formed a collaborative group of four international preclinical testing centers (Albert Einstein College of Medicine, University of Melbourne, UCLA, University of Eastern Finland), supported by experts in pharmacokinetic modeling (University of Minnesota), and experts in peripheral electrophysiology and imaging biomarker discovery, as well as neurotherapeutics. A preclinical Data Safety Monitoring Board will be overseeing the progress and advise on strategies and the preparation of a clinical cohort for the future clinical trial. We have selected 5 novel treatments that target different mechanisms and using a multimodal screening process for target engagement and modification of candidate biomarkers of posttraumatic epileptogenesis, we aim to identify (a) at least one treatment to screen in this rigorous model for its antiepileptogenic potential, and (b) at least one biomarker of posttraumatic epileptogenesis that can predict early the antiepileptogenic effect. Our investigators work closely with Project 1 (discovery of biomarkers of epileptogenesis in animals), Project 3 (discovery of biomarkers of epileptogenesis in humans), the Informatics and Analytics Core, and the Public Engagement Core.

Public Health Relevance

? PROJECT 2 ? PRECLINICAL MODEL FOR ANTIEPILEPTOGENIC THERAPY SCREENING IN POST-TRAUMATIC EPILEPSY There is currently no therapy that can prevent the development of epilepsy after brain trauma. Here we propose to test the efficacy of novel compounds, and determine their efficacy and tolerability in an animal model of posttraumatic epilepsy. We also aim to identify and validate novel biomarkers that can predict who will develop epilepsy and who may respond to a treatment that can prevent epilepsy, in hope that this may accelerate and optimize future efforts to develop new antiepileptogenic therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS100064-04
Application #
9849340
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Katsarou, Anna-Maria; Li, Qianyun; Liu, Wei et al. (2018) Acquired parvalbumin-selective interneuronopathy in the multiple-hit model of infantile spasms: A putative basis for the partial responsiveness to vigabatrin analogs? Epilepsia Open 3:155-164
Harte-Hargrove, Lauren C; Galanopoulou, Aristea S; French, Jacqueline A et al. (2018) Common data elements (CDEs) for preclinical epilepsy research: Introduction to CDEs and description of core CDEs. A TASK3 report of the ILAE/AES joint translational task force. Epilepsia Open 3:13-23
Pitkänen, Asla; Ekolle Ndode-Ekane, Xavier; Lapinlampi, Niina et al. (2018) Epilepsy biomarkers - Toward etiology and pathology specificity. Neurobiol Dis :
Ali, Idrish; Silva, Juliana C; Liu, Shijie et al. (2018) Targeting neurodegeneration to prevent post-traumatic epilepsy. Neurobiol Dis :
Tubi, Meral A; Lutkenhoff, Evan; Blanco, Manuel Buitrago et al. (2018) Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A longitudinal study. Neurobiol Dis :
Duncan, Dominique; Vespa, Paul; Pitkänen, Asla et al. (2018) Big data sharing and analysis to advance research in post-traumatic epilepsy. Neurobiol Dis :
Scharfman, Helen E; Galanopoulou, Aristea S; French, Jacqueline A et al. (2018) Preclinical common data elements (CDEs) for epilepsy: A joint ILAE/AES and NINDS translational initiative. Epilepsia Open 3:9-12
Kamnaksh, Alaa; Puhakka, Noora; Ali, Idrish et al. (2018) Harmonization of pipeline for preclinical multicenter plasma protein and miRNA biomarker discovery in a rat model of post-traumatic epileptogenesis. Epilepsy Res 149:92-101
Saletti, Patricia G; Ali, Idrish; Casillas-Espinosa, Pablo M et al. (2018) In search of antiepileptogenic treatments for post-traumatic epilepsy. Neurobiol Dis :
Katsarou, Anna-Maria; Galanopoulou, Aristea S; Moshé, Solomon L (2018) Epileptogenesis in neonatal brain. Semin Fetal Neonatal Med 23:159-167

Showing the most recent 10 out of 39 publications