Advancement of Drugs for the Treatment of Repeated Mild Traumatic Brain Injury (mTBI)

Due to its increased prevalence in soldiers, as well as its inconspicuous nature of initial neurologic effects, mild traumatic brain injury (mTBI) has become an epidemic. Further, military personnel engaging in “at-risk” activities, such as breaching, are more likely to sustain multiple mTBIs. Although TBI-related deaths per year have steadily decreased due to policy changes and successful clinical management, there are no FDA-approved treatments for mTBI. Our group have shown that repeated mTBI (rmTBI) results in mitochondrial dysfunction as well as mitochondrial oxidative damage. It is well-known that mitochondrial dysfunction underlies many pathological processes and contributes to neurological deficits. To target mitochondrial impairment to improve function, our group has also demonstrated that mild mitochondrial uncoupling reduces oxidative stress and is neuroprotective after TBI. Indeed, using a prodrug for mitochondrial uncoupling, MP201 (Mitochon Pharmaceuticals, Inc.), can deliver low, sustained levels of 2,4 dinitrophenol (DNP) that works to reduce calcium burden and lower oxidative stress, which are two hallmarks of TBI pathophysiology. In a military-relevant model of rmTBI, we will directly assess alterations in mitochondrial function following treatment of MP201. Further, we will test the long-term response of MP201 treatment on neurological function. To advance MP201 towards clinical translation, IND enabling work will be performed as another major portion of this grant.