Approximately 18 million Americans have diabetes, of which 60-70% suffer from mild to severe nervous system damage making it the leading cause of neuropathy in the United States. Substantial evidence suggests that increased oxidative stress, defined as the inability of endogenous antioxidant mechanisms to neutralize reactive oxygen species (ROS), plays a critical role in the development of diabetes and diabetes-related complications such as neuropathy. For example, it has been reported that glutathione levels and superoxide dismutase (SOD) activity is reduced in diabetic animals. It has been suggested that antioxidant treatment might diminish the severity of diabetic complications but clinical trials with antioxidants, such as vitamins C and E have to date proven disappointing, most likely due to the inability to achieve sufficient concentrations in target tissues. Gene transfer offers a potential solution to the problem inherent in attempting to deliver an adequate dose of short-lived peptide factors to cells in the peripheral nervous system, and because of their inherent biological properties, herpes simplex virus (HSV)-based vectors are uniquely suited for this purpose. We have developed recombinant, replication- incompetent, genomic HSV-based vectors for gene transfer to the nervous system and have shown that these vectors can be used to deliver and express neurotrophic factors in dorsal root ganglia (DRG) neurons, which can prevent, and reverse, the progression of diabetic neuropathy. Here we hypothesize that antioxidant gene delivery to the DRG with HSV-based vectors can be used to prevent the progression of diabetic neuropathy. We will use a combination of physiology, anatomy, and biochemistry to assess the effectiveness of HSV-based genomic vectors expressing the antioxidant enzymes manganese SOD or glutathione peroxidase or the uncoupling protein-1 (UCP-1) gene, delivered to the DRG by peripheral inoculation, in preventing or reversing diabetic neuropathy in the streptozotocin-induced diabetic mouse and the B6-Akita diabetic mouse. Lay language summary: Nerve damage (neuropathy) is one of the most debilitating complications associated with diabetes. It affects 12 million Americans, a number that is expected to drastically rise as the number of people with diabetes increases over the next 20 years. It can lead to numbness of the legs and arms, chronic pain, bladder control problems, intestinal troubles, erectile dysfunction, and result! in amputation or other severe disability. Unfortunately there is no treatment. This grant proposes to examine a novel method to prevent this neuropathy by placing specific genes within the nerves themselves making them less susceptible to damage. We will test this idea in diabetic mice, if successful; this research could lead to a possible treatment for diabetic neuropathy in humans.