TBI is a leading cause of death and long-term disability worldwide. Although TBI is a significant medical crisis, there are no FDA-approved pharmacological therapies that have been shown to improve functional outcomes. The long-term goal of this project is to improve the immediate and long-term outcomes of patients inflicted with severe TBI. Successful translation of the therapy to the clinical care of patients with TBI would have an enormous direct impact on function, wellness, and overall quality of life of victims of TBI, while shifting the current clinical treatment paradigm to one that includes a restorative thrust. The product of this SBIR, B27- HYD is an intravenous (IV) peptide drug, used in conjunction with the current standard of care, administered to patients within hours of their suffering a severe TBI. The following two specific aims will be pursued: 1) Determine the dose-response effects of intravenous B27-HYD on a TBI biomarker panel, as well as the drug's effects on general health and physiological measurements in sham and severe TBI rats. Milestone: A safe and effective IV dose of B27- HYD that results in a minimum 40% reduction of 3 out of 5 pharmacodynamic TBI biomarkers (calpain-mediated proteolytic breakdown products of ?II-spectrin, GFAP, CRMPs, GAP-43, and TDP-43). Effects of B27-HYD on arterial blood pressure, heart rate, body and head temperature, and blood chemistry (blood gases, glucose) will be determined; and 2) Demonstrate that a safe and effective dose of B27-HYD administered in the correct timeframe protects brain cell and tissue, and improves recovery from cognitive and emotional dysfunction after severe TBI. Milestone: A minimum 35% brain cell and tissue protection, 35% reduction in the sensorimotor deficits (mNSS) and 40% overall improvement in cognitive and emotional deficits (Morris water maze, Elevated Plus Maze, Forced Swimming Test) will be criteria for success to move on to Phase II. As an outcome of the proposed SBIR Phase I investigations, we expect that a safe and effective IV dose of B27-HYD, that significantly reduces TBI biomarkers, will i) increase brain cell survival, ii) enhance brain repair and regeneration, and iii) lead to marked improvement in cognitive and emotional functions. After successful completion of our Phase I feasibility study, we plan to confirm the in vivo efficacy of B27-HYD in a swine model of severe TBI. We have assembled a team of neuroscientists, neurosurgeons, neuroprotective/neurorestorative drug development scientists and regulatory experts with expertise and experience in TBI pathology, preclinical drug development and regulatory experience to pursue the translational research outlined in this proposal.
The proposed studies are of an important and under-investigated area of neurotherapeutic drug development that has potential applicability to therapeutic research in traumatic brain injury and other neuropathological conditions involving deregulated protease activity. The proposed research has relevance to public health, because the knowledge obtained from the study is expected to form the basis for future preclinical and clinical studies of neuroprotective strategies. The positive impact on management of TBI and other acute brain injuries will be significant, therefore.
