A cutaneous gene therapy approach to human leptin deficiencies: correctionof the murine ob/ob phenotype using leptin-targeted keratinocyte grafts

Leptin deficiency produces a phenotype of obesity, diabetes, and infertilit y in the ob/ob mouse. In humans, leptin deficiency occurs in some cases of congenital obesity and in lipodystrophic disorders characterized by reduced adipose tissue and insulin resistance. Cutaneous gene therapy is considere d an attractive potential method to correct circulating protein deficiencie s, since gene-transferred human keratinocytes can produce and secrete gene products with systemic action. However, no studies showing correction of a systemic defect have been reported. We report the successful correction of leptin deficiency using cutaneous gene therapy in the ob/ob mouse model. As a feasibility approach, skin explants from transgenic mice overexpressing leptin were grafted on immunodeficient ob/ob mice. One month later, recipie nt mice reached body weight values of lean animals. Other biochemical and c linical parameters were also normalized. In a second human gene therapy app roach, a retroviral vector encoding both leptin and EGFP cDNAs was used to transduce HK and, epithelial grafts enriched in high leptin-producing HK we re transplanted to immunosuppressed ob/ob mice. HK-derived leptin induced b ody weight reduction after a drop in blood glucose and food intake. Leptin replacement through genetically engineered HK grafts provides a valuable th erapeutic alternative for permanent treatment of human leptin deficiency co nditions.