Synthesis of Findings, Current Investigations, and Future Directions: Operation Brain Trauma Therapy

Abstract

Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. OBTT has identified, however, the early post-TBI administration of levetiracetam as a promising agent and has advanced it to a gyrencephalic large animal model--fluid percussion injury in micropigs. The sixth and seventh therapies have just completed testing (glibenclamide and Kollidon VA 64), and an eighth drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multicenter, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.

Keywords: biomarker; controlled cortical impact; drug; fluid percussion; micropig; penetrating ballistic-like brain injury; pre-clinical modeling; rat; reproducibility; therapy; traumatic brain injury.