R44NS120397

PROJECT SUMMARY/ABSTRACTSpinal cord injury (SCI) is estimated to affect between 249,000 and 363,000 Americans, with about 17,730 new injuries occurring each year. There are around 42000 SCI patients that are veterans in the United States. Nearly half of all SCIs occur in patients between the ages of 16 and 36, which results in individuals living with SCI for decades. The lifetime costs of living with spinal cord injury can average up to $5.1M per patient for individuals with high tetraplegia. So far, there are no FDA approved drug therapeutics for SCI, which highlights a huge unmet medical need for those patients. Most spinal cord injuries are anatomically incomplete, which means by reestablishing neural circuits in the spinal cord, those patients would have functional recovery potential. To initiate the recovery process, injured axons from the remaining neurons above or near the injury level need to regenerative growth to bypass the lesion site, reconnect to the neurons below the injury level, and then reestablish the neural circuits. The major obstruction that prevents axon regrowth is the chemical and physical barriers that accumulated at the lesion site quickly after injury, which blocks the axonal regenerative growth. For instance, when axons regrowth to the lesion site, the Wnts protein reinduced there will interact with Ryk receptor that reinduced on the axons, and then stop axon regeneration. To remove this obstruction, the interactions between Ryk receptor and Wnts protein must be blocked.Advanced from the first-in-class research conducted in a world-famous research group in the University of California, San Diego (UCSD), we developed a novel humanized monoclonal antibody drug candidate, VersaMab-101, which could block the interaction between Wnt and the Ryk receptor. After injection into rats with spinal cord injury, this antibody promoted axons regenerative growth and bypass the lesion site by stopping the toxic interaction between Ryk and Wnts. The re-established neural circuits would then promote functional recovery in rats.This novel therapeutic will benefits the patients with acute spinal cord injury by promoting axon regeneration and improving their behavior recovery. This therapeutic will also benefit the whole community by reducing the cost of long-term care. According to FDA recommendations in our pre-IND meeting, we propose to conduct GLP-complaint toxicity study in rats in this grant application to evaluate the VersaMab-101 safety profiles. We will also investigate the minimal required efficacy dose for rats with spinal cord contusion injuries.