The pathophysiology of traumatic spinal cord injury (SCI) involves the initial physical impact, which leads to secondary injury cascades of degenerative cellular and molecular events. The secondary injury spreads along the spinal cord over time, which adds new levels of disability and has devastating effects. Excess reactive oxygen species (ROS) formation at the impact site is an important component of these secondary injury cascades. Neupron is patented polymeric nanoparticle composition encapsulating antioxidant enzymes, superoxide dismutase and catalase, with high catalytic activity to neutralize ROS. The preliminary data demonstrated efficacy of Neupron following intravenous injection at 3 hrs after the injury in a rat contusion model of SCI. The treatment neutralized the excess ROS formed after the injury, 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 develop Neupron as an early therapeutic intervention to protect the spinal cord from secondary injury and promote regeneration. Such an effective early intervention can minimize severity of the post-injury disability and enhances the prospects of achieving better neurological and functional recovery. Through the R41 STTR Phase I grant, the main objective is to undertake critical formulation development of Neupron. The successful outcome of Phase-I would set the stage for Phase-II application to advance Neupron to the IND stage and ultimately to clinical development. Since there are ~17,000 cases of SCI per year in the US, Neupron will be considered 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 process that is reproducible for production of Neupron under GLP conditions and b) Evaluate Neupron for initial assessment of its biocompatibility in rat SCI model. Milestones: At least three consecutive production batches showing less than 5% variation in physical and biological (catalytic) characteristics of Neupron and without any toxicity concern. Aim 2: Characterize Neupron produced under cGMP conditions: Nebraska Nanomedicine Production Plant is a contract laboratory with cGMP nanoparticle production capacity. Neupron prepared under cGMP condition will be tested for physical and biological properties to ensure successful transfer of the protocol developed 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-IND meeting with the FDA.
Public Health Relevance Statement: Public Relevance: The project goal is to develop Neupron, 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. Terms: Antioxidants; anti-oxidant; Biomedical Engineering; bio-engineered; bio-engineers; bioengineering; catalase; Cattle; Bovine Species; bovid; bovine; cow; Clinical Trials; Contusions; Bruise; Orphan Drugs; Endotoxins; Enzymes; Enzyme Gene; Freeze Drying; Freeze Dryings; Lyophilization; Goals; Grant; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Recording of previous events; History; Human; Modern Man; Incidence; intravenous injection; Laboratories; Locomotion; Longitudinal Studies; long-term study; longitudinal outcome studies; longterm study; Mitochondria; mitochondrial; Nebraska; Legal patent; Patents; Plants; Polymers; Production; Rattus; Common Rat Strains; Rat; Rats Mammals; Natural regeneration; Regeneration; regenerate; Research; Saline; Saline Solution; Spinal Cord; Medulla Spinalis; Spinal cord injury; Spinal Cord Trauma; Spinal Trauma; Spinal cord injured; Traumatic Myelopathy; Superoxide Dismutase; Erythrocuprein; Hemocuprein; cytocuprein; Technology; Testing; Time; trauma centers; Vitamin E; Health Care Costs; Health Costs; Healthcare Costs; Injectable; Mediating; Schedule; Reactive Oxygen Species; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Guidelines; Secondary to; Injury; injuries; improved; Procedures; Site; Acute; Encapsulated; Phase; Variant; Variation; Biological; Ensure; Lesion; disability; Recovery; young adult; adult youth; young adulthood; Oxidative Stress; Early Intervention; Neuroprotective Agents; Neuroprotectants; Neuroprotective Drugs; Functional disorder; Dysfunction; Physiopathology; pathophysiology; Therapeutic; Attenuated; Contracting Opportunities; Contracts; Severities; Event; Clinic; Protocol; Protocols documentation; Source; Route; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; meetings; biocompatibility; biomaterial compatibility; 2-Phenyl-Benzopyrans; 2-Phenyl-Chromenes; Flavonoids; success; functional recovery; Recovery of Function; Toxicities; Toxic effect; intervention therapy; Therapeutic Intervention; Modeling; Property; Intervention Strategies; interventional strategy; Intervention; nano medicinal; nano medicine; nanomedicinal; nanomedicine; CAS2; CATB; Catalase B; GP75; Glycoprotein 75; TRP gene; TRP protein; TYRP; TYRP1; TYRP1 gene; Address; Dose; Data; Proliferating; Recombinants; Reproducibility; Apoptotic; Free Radical Scavenging; Small Business Technology Transfer Research; STTR; Characteristics; Molecular; Process; socioeconomics; socio-economic; socio-economically; socioeconomically; Development; developmental; cost; design; designing; nanoparticle; nano particle; nano-sized particle; nanosized particle; Outcome; scale up; Spinal cord injury patients; SCI Patients; Consumption; innovation; innovate; innovative; mitochondrial dysfunction; reconstitution; reconstitute; commercialization; neurological recovery; antioxidant enzyme; anti-oxidant enzyme; Formulation; clinical development; severe injury; critical injury; devastating injury; therapeutically effective
