Sensory polyneuropathy can be a serious problem, but for the majority of clinically important neuropathies there are no available therapies. Neurotrophic and neuroprotective peptide factors have been identified that prevent or reverse neuropathy in rodent models of disease, but delivery of these highly pleiotropic peptides has posed an obstacle for translation into effective human therapies.
Targeted gene delivery to sensory neurons of the dorsal root ganglion using HSV-based vectors to provide local synthesis and continuous release of neurotrophic factors can be used to protect DRG neurons from degeneration while avoiding undesirable complications created by systemic administration.
In animal models of neuropathy caused by toxic exposure or diabetes we have demonstrated that HSV-mediated transfer of the genes coding for conventional (nerve growth factor, neurotrophin-3) or unconventional (vascular endothelial growth factor) neuroprotective peptides can prevent or reverse the progression of sensory neuropathy. Prolonged transgene expression would be required for effective treatment, and this can be achieved using the HSV latency associated promoter element to drive transgene expression.
Current work in the laboratory is focused on understanding the mechanisms through which vector-mediated neuropeptide expression prevents sensory nerve damage in diabetes, and refinement of an HSV vector from which transgene expression could be regulated.
A U01 grant from the NIH is funding the production of a human-grade HSV-based vector expressing neurotriphin-3 for a clinical trial in prevention of chemotherapy induced periheral neuropathy.