The pathophysiology of traumatic spinal cord injury (SCI) involves the initial physicalimpact, which leads to secondary injury cascades of degenerative cellular and molecular events. Thesecondary injury spreads along the spinal cord over time, which adds new levels of disability and hasdevastating effects. Excess reactive oxygen species (ROS) formation at the impact site is an importantcomponent of these secondary injury cascades. Neupron⢠is patented polymeric nanoparticle compositionencapsulating antioxidant enzymes, superoxide dismutase and catalase, with high catalytic activity toneutralize ROS. The preliminary data demonstrated efficacy of Neupron following intravenous injection at 3 hrsafter the injury in a rat contusion model of SCI. The treatment neutralized the excess ROS formed after theinjury, significantly inhibited the progression of secondary injury, and regained locomotive functions.AxoNeural Therapeutics, Inc., is a new spin off company of Cleveland Clinic Innovation. The goal is to developNeupron as an early therapeutic intervention to protect the spinal cord from secondary injury and promoteregeneration. Such an effective early intervention can minimize severity of the post-injury disability andenhances the prospects of achieving better neurological and functional recovery. Through the R41 STTRPhase I grant, the main objective is to undertake critical formulation development of Neupron. The successfuloutcome of Phase-I would set the stage for Phase-II application to advance Neupron to the IND stage andultimately to clinical development. Since there are ~17,000 cases of SCI per year in the US, Neupron will beconsidered as an orphan drug. Our aims for this proposal are:Aim 1: Establish parameters for pilot-scale production of Neupron: a) Establish a scale-up processthat is reproducible for production of Neupron under GLP conditions and b) Evaluate Neupron for initialassessment of its biocompatibility in rat SCI model. Milestones: At least three consecutive production batchesshowing less than 5% variation in physical and biological (catalytic) characteristics of Neupron and without anytoxicity concern. Aim 2: Characterize Neupron produced under cGMP conditions: Nebraska Nanomedicine ProductionPlant is a contract laboratory with cGMP nanoparticle production capacity. Neupron prepared under cGMPcondition will be tested for physical and biological properties to ensure successful transfer of the protocoldeveloped under GLP conditions. Neupron will be evaluated for bioburden and endotoxin levels. Milestones:Neupron meets the FDA guidelines for parenteral products (2l CFR parts 210 and 211). Arrange Pre-INDmeeting with the FDA. Public Relevance: The project goal is to develop Neupronâ¢, a neuroprotective agent as an early therapeutic intervention to protect the injured spinal cord from progressive degeneration, promote regeneration, and regain neurological and functional recovery. Thereby, improving the lives of people who suffer this devastating injury. 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