A multifunctional neurotrophin with reduced affinity to p75NTR enhances transplanted Schwann cell survival and axon growth after spinal cord injury.

The lack of regeneration of axonal pathways after SCI is associated with the presence of inhibitory molecules within the glial scar, the loss of the neuron's intrinsic capacity to grow and the absence of growth factors. The NGF family of neurotrophins is a potent growth factor for several types of supraspinal and sensory axons. It is unclear, however, whether the neurotrophin's axon growth-promoting activities after central nervous system (CNS) injuries are mediated through the Trk receptors or p75 neurotrophin receptor (p75(NTR)) or both. To investigate the role of these receptors in the re-growth of specific fiber tracts after SCI, we created a series of neurotrophins that preferentially bind to either TrkB/C or p75(NTR) receptors. All the mutations were made on the NT-3/D15A backbone, a multifunctional neurotrophin that can bind TrkB, TrkC and p75(NTR). To test the mutants' axon growth-promoting activity after rat contusion SCI, we examined several spinal cord fiber projections after transplanting Schwann cells (SCs) expressing the different multi-neurotrophins. Grafts expressing the NT-3/D15A with reduced binding affinity to p75(NTR) contained more surviving SCs, and sensory as well as supra-spinal fibers, within the transplant than the NT-3/D15A neurotrophin-SC grafts. These data support the idea that neurotrophins lacking p75 activity can be more effective in promoting axon growth after CNS injury.