Dose-finding and in vivo safety study of an adipose targeted leptin gene therapy for congenital leptin deficiency

Congenital leptin deficiency is a monogenic disease originated from adipose tissue, causing hyperphagia, severe obesity, and hyperinsulinemia. Moreover, most forms of lipodystrophy syndromes exhibit leptin deficiency. Leptin replacement therapy with leptin protein analog requires frequent injection for life and is extremely expensive. We previously reported that a single intraperitoneal injection of an adipose-targeting Rec2-leptin adeno-associated virus (AAV) vector normalized metabolic syndromes in the leptin deficient <i>ob/ob</i> mice. Here, we conducted a dose-deescalating study with four doses (2E10, 1E10, 5E9, and 1E9 viral genome per mouse) in <i>ob/ob</i> mice and extended <i>in vivo</i> monitoring to 27 weeks post dosing. Rec2-leptin at all doses normalized excessive weight gain, hyperphagia, obesity, low core temperature, glucose intolerance, and hyperinsulinemia in the <i>ob/ob</i> mice. Transgene expression was restricted in the targeting visceral adipose tissues and sustained throughout the 27-weeks study. Rec2-leptin at the lowest dose 1E9 viral genome (vg)/mouse restored the circulating leptin level to 18% of the normal level of wild-type (WT) mice. Rec2-leptin at all doses reversed liver steatosis and pancreatic islet hyperplasia. Behavioral assessment, serum chemistry, and histopathology noted no significant adverse effects attributed to Rec2-leptin. This study demonstrates that Rec2-leptin is safe and highly efficacious, supporting further development for genetic or acquired leptin deficiency.