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Gene therapy to repair the injured nerve
Eggers, R.
2020
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citation for published version (APA)
Eggers, R. (2020). Gene therapy to repair the injured nerve.
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This thesis shows that gene therapy after nerve damage can be a powerful tool to improve function recovery. We also show that control over location, dose and timing is essential. The most severe type of peripheral nerve damage in patients is a spinal root avulsion, in which spinal nerve roots innervating the arm are torn from the surface of the spinal cord. This can occur following a traffic accident, or following complicated child birth. Despite neurochirurgical repair, limited spontaneous recovery is observed following an extensive root avulsion lesion, resulting in a loss of function and pain for these frequently young patients. In experimental models, we show a rapid loss of spinal motoneurons following ventral root avulsion, and the number of axons that is able to regenerate towards the distal musculature is limited. During prolonged denervation time periods, the endogenous growth support from factors such as GDNF in the peripheral nerve is lost. Using gene therapy, we are able to locally express GDNF protein. We find that sustained high GDNF protein concentrations leads to local axonal trapping, limiting the long distance axonal outgrowth. To obtain control over gene expression, we developed an regulatable viral vector which has an immune-evasive transactivator (dox-i-GDNF). Using this system, we are able to show that up to one year after ventral root reimlantation, timed-GDNF expression enhanced motoneuron survival and increased the number of axons that was able to regenerate up to 10 cm distal twofold. Our results demonstrate that 1) the beneficial effects of timed GDNF-gene therapy are more robust following spinal nerve avulsion lesions that allow target reinnervation within a relatively short time window after the lesion, and 2) that long distance regeneration remains suboptimal.
