LEPTIN GENE-THERAPY AND DAILY PROTEIN ADMINISTRATION - A COMPARATIVE-STUDY IN THE OB OB MOUSE/

We have compared the efficacy of daily injection of recombinant leptin protein (rh-leptin) with adenovirus-mediated delivery of the murine o r human leptin gene (Ad-leptin) for treatment of obesity in the obese (ob/ob) mouse model. We demonstrate an improved correction profile for obesity and associated surrogate markers using the adenovirus deliver y method. Rate of weight loss and percentage satiety were significantl y greater in the mice treated with Ad-leptin. These findings were asso ciated with lower peak serum leptin levels with Ad-leptin (22.9 +/- 2. 6 ng/ml for the human gene, and 43.9 +/- 11.5 ng/ml for the murine gen e) compared to rh-leptin (385.2 +/- 36.0 ng/ml). (Values are given as mean +/- standard error of the mean.) importantly rh-leptin and ex viv o-expressed Ad-leptin were equivalently active in a functional cell-ba sed assay. The primary difference in the two therapeutic approaches is the continuous chronic secretion of leptin mediated by gene delivery, versus the intermittent bolus delivery and rapid clearance of the dai ly injection of rh-leptin protein. Thus in vivo findings suggest that leptin effects are better achieved at lower steady-state levels, a pha rmacological feature attained here by gene therapy, These findings may have implications for the potential use of leptin in the treatment of obesity.