Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer.

AIMS/HYPOTHESIS: The aim of this study was to determine whether prolonged expression of neurotrophin-3 (NT-3) in mice, achieved by herpes simplex virus (HSV)-mediated gene transfer with gene expression under the control of an HSV latency promoter, can provide protection against the progression of diabetic neuropathy over a 6 month period. MATERIALS AND METHODS: Mice with diabetes induced by streptozotocin were inoculated s.c. into both hind feet with a non-replicating HSV vector containing the coding sequence for NT-3 under the control of the HSV latency-associated promoter 2 (LAP2) elements or with a control vector. Nerve function was evaluated by electrophysiological and behavioural measures over the course of 6 months after the onset of diabetes. RESULTS: Animals inoculated with the NT-3-expressing vector, but not animals inoculated with control vector, showed preservation of sensory and motor nerve amplitude and conduction velocity measured electrophysiologically, small fibre sensory function assessed by withdrawal from heat, autonomic function measured by pilocarpine-induced sweating, skin innervation assessed by protein gene product 9.5 staining of axons, and density of calcitonin gene-related peptide terminals in the spinal cord measured by immunohistochemistry 5.5 months after vector inoculation. CONCLUSIONS/INTERPRETATION: These results indicate that the continuous production of NT-3 by LAP2-driven expression of the transgene from an HSV vector over a 6 month period protects against progression of diabetic neuropathy in mice, and provide a proof-of-principle demonstration for the development of a novel therapy for preventing the progression of diabetic neuropathy.