This project will test the central hypothesis that cellular transplants of Schwann cells genetically modified to produce augmented amounts of neuro-trophins will promote CNS repair. Schwann cells are readily obtainable by peripheral nerve biopsy, sustainable as purified primary cultures, and possess intrinsic properties that favor their use in CNS repair, including the ability to myelinate CNS or PNS axons and the ability to secrete extracellular matrix molecules to support and guide new axonal growth. In extensive preliminary experiments, the investigators have transduced Schwann cells to produce and secrete supraphysiological levels of human nerve growth factor (hNGF) and human neurotrophin-3 (hNT3). In proposed experiments, two in vivo models will be used to evaluate the ability of genetically modified Schwann cells to promote neural repair. A spinal cord injury model will examine the ability of genetically modified Schwann cells to promote axonal regrowth. A model of basal forebrain cholineric neuronal degeneration will examine whether genetically modified Schwann cells rescue degenerating neurons. The choice of neurotrophic factors is based upon published data from the principal investigator's laboratory demonstrating in vivo axonal regeneration and neuronal rescue using neurotrophin infusions or grafts of genetically modified fibroblasts. Preliminary in vivo Schwann cell data indicates the practicality and feasibility of addressing the proposal's central hypothesis in these models. The following Specific Aims will be addressed: 1) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human nerve growth factor (hNGF) will promote axonal repair after spinal cord injury. 2) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human neurotrophin-3 (hNT3) will promote axonal repair after spinal cord injury. 3) Determine whether primary Schwann cells genetically modified to express and secrete augmented amounts of human NGF will rescue degenerating host cholinergic neurons in the brain.
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