Abstract
Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.
Original language | English |
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Pages (from-to) | 295-311 |
Number of pages | 17 |
Journal | Brain |
Volume | 142 |
Issue number | 2 |
Early online date | 15 Jan 2019 |
DOIs | |
Publication status | Published - Feb 2019 |
Funding
This work was supported by grants from the Wings for Life Spinal Cord Research Foundation (WFL-NL-17/16 to J.V.), International Spinal Research Trust (TRI004_03 to J.V.) and a gift from the Dwarslaesiefonds (to J.V.).
Keywords
- chronic denervation
- GDNF
- gene therapy
- long distance regeneration
- ventral root avulsion