Despite the peripheral nervous system's (PNS) intrinsic capability to regenerate following injury, permanent dysfunction of the PNS is common. Researchers have developed biodegradable conduits from diverse materials in an effort to find a new way to address the degeneration of PNS myelin and axons, and to bypass risks associated with current treatments for injury. Several conduits have entered clinical use, but regeneration with these devices is highly variable and none has been able to stimulate repair across large nerve gaps that exceed 3 cm in humans. There is a critical need for therapies that enhance peripheral nerve regeneration (PNR) after injury or the dysfunction that results from prolonged disease states, such as diabetes or polyneuropathies. It is widely accepted that in order for a conduit-based therapy to stimulate regeneration of large nerve gaps and to reproducibly stimulate regeneration of smaller nerve gaps, a biological enhancer is needed. Many enhancers, such as recombinant proteins, cells and cellular components, have proven effective in small animal models and have even been translated into larger animal models, but none has entered the clinic. A key reason is the lengthy and costly regulatory process needed to evaluate complex biologicals for human use. One compound tested in animal models with biodegradable conduits is polysialic acid (PSA), which promotes cell migration and axonal elongation. Following PN injury, PSA is greatly upregulated in motoneurons and Schwann cells. Exogenously supplied PSA has promoted regeneration after acute damage to the femoral nerve and spinal cord of adult mice. We have identified a small molecule, tegaserod, with the potential to act as a mimetic for PSA. This proposal focuses on testing a novel small molecule polysialic acid mimetic as a potential therapeutic for peripheral nerve injury. has been approved by the FDA for a different indication, acting via an entirely different mechanism of action. This project proposes to retask tegaserod for PNR. Our preliminary data indicates that tegaserod stimulates neuronal behavior in a manner and pathway consistent with PSA. Importantly, this stimulation appears to be independent of tegaserod's established mechanism of activity as a 5-HT receptor agonist. Supplementing our in vitro data is an in vivo study that showed mice receiving tegaserod within a conduit improved following femoral nerve injury significantly more than mice that received the vehicle control. Tegaserod, as a small molecule, does not carry the biological risks of transplanted cells and xenogeneic proteins and is likely to face a considerably smoother pathway for clinical entry. This proposal outlines the experiments necessary to determine the potential of tegaserod for PNR and clinical translation. In vitro experiments and in silico molecular modeling will further assess the mechanism by which tegaserod stimulates neural regeneration. Simultaneously, we will conduct experiments that determine the optimal treatment dose of tegaserod delivered to nerves in a more stringent animal model, as well as develop methods for a more sustained delivery that we hypothesize will be necessary for even larger gap sizes. Achieving these experimental goals will set the stage for future pre-clinical animal models, and clinical trials. PUBLIC HEALTH RELEVANCE: To address a need for improved devices for peripheral nerve regeneration after nerve injury, we have identified a compound, tegaserod, previously approved by the FDA that we have found to mimic the pro-repair molecule polysialic acid. Tegaserod will be tested in critical size defects in an animal model, both encapsulated in a hydrogel as well as gradually released from polymeric nerve conduits, to optimally regenerate peripheral nerve. !