Preclinical Evaluation of an ER- and Field-Ready Therapy for Spinal Cord Injury
Abstract
Cervical spinal cord injury is a common and frequently devastating injury that can result in a broad range of life- long walk-related disabilities. Although spinal cord injury involves a cascade of pathological events that evolve over time, research aimed at therapy development has failed to stop these events to decrease physical assistance required for locomotion. Spinal cord injury causes blood vessel shear injury, blood spinal cord barrier dysfunction, and bleeding. Iron deposited by diffuse bleeds fuels inflammation through multiple pathways, which further induce progressive disabilities. There is an urgent need to address bleed-induced risk factors for long-term progressive disabilities, and to develop effective therapies that have excellent potential for translation. This proposal will test the preclinical evaluation of the safety and efficacy of a new patented drug, SP-420, to remove excess bleed-induced free and toxic iron – a powerful catalyst of inflammation, and to enhance neural and vascular agents to protect and heal injured neural and vascular tissues at the injury site. Two Specific Aims will be tested in a clinically relevant rodent model of contusion cervical spinal cord injury using this new drug, which can safely eliminate excess bleed iron. Specific Aim 1 will conduct experiments related to optimize dose and timing of acute SP-420 therapy compared to normal saline in a rat model of cervical SCI. The dose response study will identify the most effective and safe dose of this new drug, SP-420 in acute setting. SP-420 will be administered using three fixed dosages and tested against saline control for 3 weeks in a clinically relevant rodent model of contusion cervical spinal cord injury. SP-420 therapy will be initiated at four post-injury periods: 30 minutes, 1 (24 hours after SCI) day, 3 days, and 7 days following SCI, and treatments will be for 3 weeks each. A cohort of treated animals will be followed up for 8 weeks following initiation of treatment. The comprehensive functional and safety outcome measures will be applied to all animals. Collectively, we will test 4 acute periods of interventions (30 minutes, 24 hours, 3 days, and 7 days after SCI). A list of comprehensive outcome measures will be applied using behavioral, physiological, MRIs, and molecular and cellular assays. These studies will address critical questions regarding acute therapeutic window using a safe dose and comparative analysis of results from these acute studies. The timing of initial intervention has been chosen because time to initial medic contact in theater of operation is approximately 30 minutes, with earliest evacuation possible at 20 minutes after injury. Our goal is to create a best case scenario, realizing that longer time periods are both possible and likely in military and civilian injuries, and that is why 24 hours, 3 days, and 7 days were also selected. We will also have opportunity to determine sex-related differences in functional motor impairment/recovery, MRI, histology, and biomarker data following SP-420 therapies. We propose that our new patented drug treatment will significantly decrease long-term spinal cord injury-induced disabilities, and these improvements will correspond with significant decreases in bleed iron, tissue damage, and inflammation. These studies will provide an innovative treatment for SCI. If our proposed treatment is determined to be safe and effective in the SCI setting, it is well positioned for immediate translation to clinical treatment and rehabilitation in Army and civilians. Although SP-420 has obtained an approval as an Investigational New Drug (IND) from Food and Drug Administration for use in human disease, Thalassemia, it has not been cleared for spinal cord injury trials due to the lack of comprehensive preclinical evaluation of efficacy and safety data. These studies will provide the needed safely and efficacy data for this potential new drug to r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210748
Entities
People
- Prodip Bose
Organizations
- United States Army
- University of Florida