Invited Speaker

Gene-transfer technology to combat metabolic disease cluster for lifetime
Satya P. Kalra, Pushpa S. Kalra
USA

Obesity, diabetes type 1 and 2, cardiovascular and skeletal ailments top the pandemic list of the disease cluster comprising the metabolic syndrome. Our research endeavors over a decade unraveling varied health benefits of gene therapy will be summarized. The adipocyte leptin is a mandatory peripheral feedback signal in integration of energy homeostasis and leptin insufficiency in the hypothalamus that engenders the pathophysiological sequalae of the metabolic syndrome. Leptin replenishment selectively in the hypothalamus by a single central injection of non-replicative, non-immunogenic and non-pathogenic recombinant adeno-associated virus vector encoding leptin gene in varied rodent models conferred the following health benefits for lifetime (Trends Pharmacol. Sci. 26:488, 2005; Peptides 29:127, 2008; Nutrition 24:820, 2008): Energy homeostasis: Age and high fat diet-induced obesity was suppressed in conjunction with decreased daily food intake and enhanced brown adipose tissue mediated non-shivering thermogenic energy expenditure. Diabetes: Basal and post-prandial insulin hypersecretion was suppressed along with improved insulin sensitivity, glucose tolerance and disposal, resulting in euglycemia in rodents inflicted with either diabetes type 1 or 2. Cardiovascular disease: The pro-inflammatory markers, CRP and IL-6 were reduced indicating suppression of obesity-dependent low grade systemic inflammation along with abrogation of hyperglycemia-induced cardiomyopathy. Skeletal health: Both osteoblast-specific osteocalcin secretion and long bone growth were promoted, while osteoporosis was reduced. Life-span: Early onset of mortality was blocked leading to normalization of life-span in leptin-deficient obese mice. In sum, these preclinical global health benefits set the stage for testing the efficacy of the one time central gene therapy in combating the chronic metabolic disease cluster in subhuman primates and humans.