Protective effect of HSV‐mediated gene transfer of nerve growth factor in pyridoxine neuropathy demonstrates functional activity of trkA receptors in large sensory neurons of adult animals

Abstract

The distinct distribution of trkA receptors on small neurons and trkC receptors on large neurons in the dorsal root ganglion correlates with the dependence of these two classes of neurons on nerve growth factor and neurotrophin-3, respectively, for survival during development. In adult animals, the distribution of high affinity neurotrophin (trk) is complex and overlapping; neurotrophins are not required for cell survival, but may influence cell phenotype and the response to injury. In order to test the functional activity of trkA receptors in the sensory ganglia of adult animals in vivo, we examined the ability of a nerve growth factor-expressing recombinant replication-defective herpes simplex virus-based vector to prevent the selective degeneration of large sensory fibres caused by intoxication with pyridoxine. Transduction of dorsal root ganglion neurons in vivo by subcutaneous inoculation of the nerve growth factor-expressing vector prevented the development of pyridoxine-induced neuropathy measured by electrophysiological, morphological and behavioural measures. These results demonstrate a functional activity of trkA receptors expressed on large neurons in the dorsal root ganglion in mature animals; this observation has important implications for the choice of neurotrophic factors for treatment of peripheral nerve disease.

Gene therapy: Novel treatments for polyneuropathy and chronic pain

“…Similar results have been reported using an HSV vector engineered to express nerve growth factor in the same model of neuropathy [11]. In a rodent model of type 1 diabetic neuropathy caused by the injection of streptozotocin (a pancreatic β cell toxin), subcutaneous inoculation of an HSV vector expressing nerve growth factor after the onset of diabetes prevents the development of neuropathy [12].…”

Herpes simplex virus vector-mediated delivery of glial cell line-derived neurotrophic factor rescues erectile dysfunction following cavernous nerve injury

“…Previous studies demonstrate the utility of replication-defective HSV vectors in the treatment of numerous neurodegenerative disorders of the PNS through the expression of trophic factors, such as nerve growth factor (NGF), neurotrophin 3 (NT-3) and GDNF, [37][38][39][40][41][42][43][44][45] and support their use as therapeutic agents in treating neurological complications of ED. In addition, we have recently demonstrated that replication-defective HSV vectors expressing NT-3 are effective in improving erectile function in rats with chemically induced diabetes mellitus (DM) when the vectors were injected around the cavernous nerve 4 weeks after the induction of DM, 39 although it is not known whether similar gene transfer techniques would be effective for the treatment of ED induced by nerve injury.…”

HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy

“…5 Expression of neurotrophic factors achieved by HSV-mediated gene transfer is also effective in preventing neuropathy in the pyridoxine and cisplatin models of polyneuropathy in rodents. [6][7][8] Other peptides not conventionally considered to be neurotrophic have been shown to have substantial neuroprotective effects in a variety of models. Vascular endothelial growth factor (VEGF), originally identified by its ability to induce the growth of new blood vessels, 9 can protect neurons from damage induced by ischemia 10,11 and trauma.…”