671. Nerve Growth Factor and Neurotrophin-3 Delivered by HSV Gene Transfer Reverses Diabetic Neuropathy

Abstract

Top of pageAbstract Peripheral neuropathy, involving motor, sensory, and autonomic nerves, is a common and debilitating complication of diabetes. Many features of human diabetic neuropathy can be modeled in the mouse using streptozotocin (STZ) to selectively destroy pancreatic beta cells resulting in sustained hyperglycemia but not requiring insulin replacement. We have previously demonstrated that recombinant replication defective herpes simplex virus (HSV)-based vectors expressing the neurotrophic proteins NGF (vector SHN) or NT3 (vector QL2HNT3) delivered by subcutaneous inoculation to transduce dorsal root ganglia prevents the development of neuropathy in the STZ mouse. Using a double-blind experiment, we have extended these findings by examining if these vectors could reverse STZ-induced neuropathy once it has been established. Male Swiss-Webster mice were injected with streptozotocin (STZ) and six weeks later the presence of peripheral neuropathy was confirmed by electrophysiological measurements of a foot sensory nerve response to an evoked potential and the foot withdrawal latency from a heat source. STZ-treated mice were then randomized to four treatment groups: 1) No vector; 2) vector SHZ (control vector); 3) vector SHN; or, 4) vector QL2HNT3. Mice injected with STZ developed a peripheral neuropathy characterized by a decrease in the foot nerve sensory amplitude, an increase in the foot withdrawal latency from a heat source, and a decrease in the number of nerve fibers innervating the skin of the hind foot. These indices of neuropathy were reversed 5 weeks after mice were inoculated with either SHN or QL2HNT3 into the hind foot; mice inoculated with a control vector (SHZ) demonstrated no improvement. This data suggests that neurotrophic factor gene transfer using HSV-based vectors was able to reverse functional measures of established peripheral neuropathy in diabetic rodents and provides further evidence for the potential of HSV-based gene therapy to treat human diabetic neuropathy.