Enhanced regeneration and reinnervation following timed GDNF gene therapy in a cervical ventral root avulsion

Avulsion of spinal nerve roots is a severe proximal peripheral nerve lesion. Despite neurosurgical repair, recovery of function in human patients is disappointing, because spinal motor neurons degenerate progressively, axons grow slowly and the distal Schwann cells which are instrumental to supporting axon extension lose their pro-regenerative properties. We have recently shown that timed GDNF gene therapy (dox-i-GDNF) in a lumbar plexus injury model promotes axon regeneration and improves electrophysiological recovery but fails to stimulate voluntary hind paw function. Here we report that dox-i-GDNF treatment following avulsion and re-implantation of cervical ventral roots leads to sustained motoneuron survival and recovery of voluntary function. These improvements were associated with a twofold increase in motor axon regeneration and enhanced reinnervation of the hand musculature. In this cervical model the distal hand muscles are located 6,5 cm from the reimplantation site, whereas following a lumber lesion this distance is twice as long. Since the first signs of muscle reinnervation are observed 6 weeks after the lesion, this suggests that regenerating axons reached the hand musculature before a critical state of chronic denervation has developed. These results demonstrate that the beneficial effects of timed GDNF-gene therapy are more robust following spinal nerve avulsion lesions that allow reinnervation of target muscles within a relatively short time window after the lesion. This study is an important step in demonstrating the potential of timed GDNF-gene therapy to enhance axon regeneration after neurosurgical repair of a severe proximal nerve lesion.