Continuous Real Time CSF Shunt Flow Monitor ShuntCheck

DESCRIPTION (provided by applicant): A large body of evidence indicates that the cognitive impairment and delayed neurodegeneration in traumatic brain injury (TBI) is caused by increased accumulation of tau, phosphorylated tau (p-tau) and other neurotoxic proteins including APP and alpha-synuclein (aSYN) which also cause neurodegeneration in Alzheimer's Disease (AD) and Parkinson's Disease (PD), respectively. We have developed the first small molecule drug, Posiphen, that selectively inhibits the synthesis of tau, p-tau, APP and aSYN in brain. It works by a unique mechanism to selectively block translation of mRNA for tau, APP and aSYN. Posiphen has undergone extensive preclinical development and is efficacious in animal models of AD, is orally available with excellent pharmacokinetics and is highly brain penetrant. We have completed three Phase 1 studies in 120 humans and shown that Posiphen is safe and well tolerated. Furthermore, in patients with mild cognitive impairment, oral Posiphen administrationreduces CSF levels of tau, p-tau, APP and Abeta back to the levels found in healthy normal volunteers. Since Posiphen effectively and safely reduces expression of these neurotoxic proteins in brain and these proteins are believed to have a central role inthe pathophysiology of TBI, we propose in this Phase 1 SBIR to test the efficacy of Posiphen in animal models of TBI to provide the justification for its rapid transition into testing for safety and efficacy in treating TBI patient. Studies proposed willtest Posiphen in the lateral fluid-percussion (LFP) injury model and the controlled cortical impact (CCI) injury model, two well established animal models of TBI. We will test whether Posiphen can prevent the rise in accumulation of tau, p- tau, APP and aSYN in brain, block the cognitive impairment and prevent neurodegeneration induced by TBI. Cognition will be tested in the Morris Water Maze task. Because LFP causes degeneration of nigrostriatal dopamine neurons, we will also assess the neuroprotective effects of Posiphen by measuring tyrosine hydrolyase positive neurons with stereological methods. These studies will be done in collaboration with two experts in neurodegeneration at UCLA, Dr. Marie-Francoise Chesselet, the Charles H. Markham Professor of Neurology and an expert in PD research and partnering PI of this grant and Dr. David Hovda, Director of the Brain Injury Center, and an NINDS funded TBI center and an expert on TBI research and recipient of the Army's highest civilian honor, the Strength ofthe Nation Award for work on developing treatment approaches for TBI. Because Posiphen has already been tested and shown to be safe in humans, if shown to be effective in TBI models, extensive preclinical development will not be necessary and we will be able to rapidly begin testing the drug for efficacy for TBI in human trials. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Project Narrative The goal of QR Pharma is to develop Posiphen to treat TBI and other neurodegenerative disorders including AD and PD. The drug has already undergone clinical development and has been shown to be safe and well tolerated in 120 humans. If Posiphen is found effective in the TBI animal models employed in this grant, then we will attempt to rapidly transition its development into clinical testing for safety and efficacy in treating TBI patients.