STTR Phase I: Novel Bio-Intervention to Attenuate Neurological Damage Following Traumatic Brain Injury

The broader impacts of this Small Business Innovation Research (SBIR) Phase I project hold global consequences in healthcare and scientific advancement. Foremost, it addresses an unmet medical need. Traumatic brain injury (TBI) is a leading cause of injury-related death and disability with an estimated annual world-wide incidence of 69M people. Project success will improve the quality of life of millions and lessen TBI’s social and economic burden. This intervention will stem TBI’s progression to follow-on neurodegenerative diseases such as Parkinson’s and other forms of dementia which, in turn, will broaden our scientific understanding of neurodegenerative pathways and reveal potential other novel drug targets. This technology also offers a mechanism that provides a drug agnostic delivery system across the blood-brain barrier (BBB). It has direct implications for US military combat readiness and veterans, noting 19% of deployed troops (Iraq & Afghanistan) suffered TBI. This project’s success will be most beneficial for Black and Hispanic patients, who are more susceptible to the after-effects of TBI. Importantly, this construct may hold therapeutic utility in myriad other disorders, including Alzheimer’s, Parkinson’s, ALS, stroke, myocardial infarction, insulin resistance, etc. As a first-to-market product, the commercial potential to treat TBI is considerable. The proposed project will test a novel fusion protein construct (NFP), which can cross the BBB and deliver a biologically active, targeted therapeutic payload to repair mitochondrial DNA (mtDNA) damage in neurons. Significantly, restoring neuronal mtDNA integrity enables proper encoding of proteins required for cellular energy production and reestablishes bioenergetic levels to avert programmed cell death pathways and ensuing neurodegeneration. The project will advance understanding of the extent of bioenergetic dysfunction and its role in neurodegenerative progression. To achieve technical success in the setting of TBI, NFP must be able to maintain structural integrity within the circulatory system, traverse brain capillary endothelial cells, penetrate neuronal cells, and then target and enter mitochondria to deliver the protein payload at the site of mtDNA damage. The goals of the proposed R&D program will verify NFP’s technical capability for such complex navigation and demonstrate its ability to attenuate neurological damage following TBI – to be confirmed through in vivo animal evaluation of TBI biomarker assays and analysis of behavioral changes. Program objectives will also achieve optimization of the protein’s component structure, quantify target site bioavailability, and identify a time-related dosing profile, with intervention occurring at differing time points from initial insult. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.