Research Project
2797647
Optimization of cell-based delivery of neurotrophic factors for treatment of spinal cord injuries is the long-term objective. Allogeneic rat cells will be genetically modified with recombinant adeno-associated virus (rAAV) to produce human neurotrophin-3 (hNT-3), and grafted to spinal cord lesion cavities in rats with short term immunosuppression if needed. Development of this approach is attractive because it should obviate the need for patient specific genetic manipulation for autologous grafts, and will be amenable to industrial scale and quality control. The specific aims of the Phase I research can be summarized as follows: l. Transfect freshly isolated cells and cells from established cultures with rAAV/Bgalactosidase, and compare the relative viability in allogeneic rats. 2. Prepare rAAV/hNT-3 and transduce cells to secrete hNT-3; determine extent and duration of secretion in vitro. 3. Perform bilateral lesion surgery of the dorsal spinal cord with extensive resections to remove corticospinal, rubrospinal, and cemlospinal projections. Graft allogeneic cells secreting hNT-3 to acute lesion cavities, and analyze functional recovery and corticospinal axon growth. In Phase II, therapy of spinal cord injury with both NT-3 and BDNF secreting cells will be compared with therapy with cells secreting each factor alone in adult rats. Genetically-modified primary cultures of human cells will be developed. PROPOSED COMMERCIAL APPLICATION: Spinal cord injuries are often devastating medically, socially, and economically to individuals and their families. The occurrence of spinal cord injuries is approximately 12-40 per million people annually. Development of universal cell lines for in vivo delivery of neurotrophic factors that could stimulate functional recovery would have commercial potential in treatment of spinal cord injury and many other neurodegenerative conditions.
