Delivery of neurotrophic factors by ex vivo gene therapy has been shown to induce axonal growth from different neuronal populations after spinal cord injury. While growth factor gene delivery is a potent means of promoting the growth of several axonal populations into spinal cord lesion sites, existing reports have not succeeded in promoting axonal growth beyond injury sites and into the distal, denervated spinal cord. For the translation of these studies into realistic treatments for spinal cord injury, improved techniques for neurotrophin delivery are needed to establish long distance axonal growth beyond the lesion site. Furthermore, the safety and tolerability of neurotrophin gene delivery must be tested. This project will investigate regulatable expression systems for ex vivo and in vivo gene delivery of neurotrophic factors to promote anatomical axonal growth beyond spinal cord lesion sites, and potential functional recovery. Previous studies from the laboratory of the Principal Investigator and others have shown that the cellular delivery of neurotrophic factors to sites of spinal cord injury elicits extensive axonal growth but this growth is either restricted to the immediate injury site or for short distances beyond it. In the proposed experiments, we will sequentially turn on and off gene expression at various sites and times after spinal cord injury to determine whether extensive axonal growth beyond injury sites and to denervated distal segments can be achieved. The ability to regulate growth factor expression in vivo will also markedly enhance the safety of gene therapy for therapeutic applications. Adverse effects of neurotrophic factors could include hyperalgesia and pain. We will therefore investigate whether neurotrophin delivery to the injured spinal cord induces thermal and mechanical hyperalgesia, and if the regulation of neurotrophin expression can prevent or reverse this development. If successful, these studies will establish practical strategies for optimizing growth factor delivery to sites of spinal cord injury and can be extended to chronic models of spinal cord injury and larger animal studies in the future. Further, this could lead to the development of therapies for clinical translation.
