067 Electroporation-Enhanced Gene Therapy with KGF-1 Corrects Healing Impairment in Older Diabetic Mice

Abstract

Introduction: Diabetes is known to impair wound healing. We assessed the effect of aging on this impairment and further explored the possibility of repairing age-dependant impairment by replenishing levels of the growth factor KGF-1 using our system of electroporation enhanced gene therapy. Methods: Female BKS.Cg-m+/+Leprdb/J mice (diabetic) were obtained from the Jackson Laboratory (Bar Harbor, ME). Mice at time of study were 7, 27, and 84 weeks, respectively. Two wounds were created using a 5 mm punch biopsy. Plasmid DNA encoding KGF-1 was injected at 40 μg / wound. Electroporation was carried out with six square wave pulses, at 1800 volts for 100 μs; with aninterval of 125 ms. Wounds were assessed planometrically over a 14-day period. Results: We found that wound healing is severely impaired in older, but not young diabetic mice (7-week-old mice displayed a threefold smaller wound area than 84-week-old mice on day 9). Glucose levels were similar in old and young groups ruling out differences in intensity of the metabolic derangement to explain this disparity (old: 334 +/− 41 mg/dl vs. young: 290 +/− 33 mg/dl). Treatment with KGF-1 gene therapy increased wound closure in aged mice 5.9-fold as compared to untreated aged mice 5 days after wounding (treated: 3724 +/− 631 vs. untreated: 632 +/− 517, P = 0.002). Aged KGF-1 gene therapy-treated mice closed wounds 10-fold faster than treated young mice 5 days after wounding (old: 3724: +/− 631 vs. young 358 +/− 871, P = 0.004). Conclusions: We conclude that progressive damage to the tissues capability to heal occurs in individuals with diabetes. Treatment with KGF-1 gene therapy is more effective in aged mice than young mice. With an increasing geriatric diabetic population, gene therapy to replenish growth factors may be worth exploring.