Multi-Center Pre-clinical Consortia to Enhance Translation of Therapies and Biomarkers for Traumatic Brain Injury: Operation Brain Trauma Therapy and Beyond

Abstract

Current approaches have failed to yield success in the translation of neuroprotective therapies from the pre-clinical to the clinical arena for traumatic brain injury (TBI). Numerous explanations have been put forth in both the pre-clinical and clinical arenas. Operation Brain Trauma Therapy (OBTT), a pre-clinical therapy and biomarker screening consortium has, to date, evaluated 10 therapies and assessed three serum biomarkers in nearly 1,500 animals across three rat models and a micro pig model of TBI. OBTT provides a unique platform to exploit heterogeneity of TBI and execute the research needed to identify effective injury specific therapies toward precision medicine. It also represents one of the first multi-center pre-clinical consortia for TBI, and through its work has yielded insight into the challenges and opportunities of this approach. In this review, important concepts related to consortium infrastructure, modeling, therapy selection, dosing and target engagement, outcomes, analytical approaches, reproducibility, and standardization will be discussed, with a focus on strategies to embellish and improve the chances for future success. We also address issues spanning the continuum of care. Linking the findings of optimized pre-clinical consortia to novel clinical trial designs has great potential to help address the barriers in translation and produce successes in both therapy and biomarker development across the field of TBI and beyond.

Antioxidant Therapies in Traumatic Brain Injury

“…Due to the heterogeneity of TBI and limited knowledge of the underlying pathophysiological mechanisms, there are no current standardized surgical and pharmacological treatments for TBI patients. Despite their promising preclinical outcomes, many intervention strategies have failed to demonstrate beneficial effects in randomized controlled trials so that TBI patients are still waiting for the discovery of drugs capable of decreasing mortality and disability associated with this pathology [11]. The primary insult resulting from the application of mechanical force in TBI occurs immediately and is inevitable.…”

“…At present, the drugs most frequently administered are aimed at controlling intra-cranial pressure (ICP) within normal levels (<22 mm Hg) [13], maintaining cerebral blood flow and decreasing secondary injury associated damage [12]. A list of these drugs is summarized in Table 2 [10][11][12][13][14]. Table 2.…”

Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy

“…[1][2][3][4] At present, there are no approved therapeutics to treat CTE. 31,32 Based on the knowledge that CTE is a tauopathy, characterized by elevated levels of pTau in the CNS, we hypothesized that gene transfer-mediated expression of an anti-pTau monoclonal in the CNS would function to clear pTau from the CNS, thus eliminating a central pathobiologic process in the pathogenesis of CTE. Using direct CNS administration of an rh.10 serotype AAV to transfer an anti-pTau monoclonal coding sequence to the CNS, the data demonstrate effective clearance of pTau, suggesting a possible therapy for this disorder.…”

“…30 At present, there is no therapy for CTE. 31,32 Systemic anti-pTau antibody therapy has been successful in treating a murine model of CTE, 33,34 but this strategy is unlikely to be successful in humans, as has been found with systemic administration of anti-pTau in clinical studies of Alzheimer's disease [35][36][37] ; the blood/brain barrier limits the amount of systemically administered antibodies reaching the brain to <0.5% of the administered dose. 38 To circumvent the blood/ brain barrier, we hypothesized that direct CNS administration of an adeno-associated virus (AAV) gene transfer vector coding for an anti-pTau antibody would mediate expression of the anti-pTau antibody within the brain, leading to suppression of the accumulation of pTau following TBI.…”

Resuscitation Strategies for Traumatic Brain Injury

“…The prevention of the secondary brain injury has been the subject of significant research over last 3 decades. However, despite promising data from numerous preclinical trials, no therapy to date has improved outcomes in humans [5]. Furthermore, we still have little definitive evidence about the effectiveness of nearly every aspect of our management of TBI [6].…”