Low dose systemic AAV-exendin-4 gene therapy for Prader-Willi syndrome and dietary obesity

Prader-Willi syndrome (PWS) patients display developmental delays, endocrine dysfunction, excessive eating, central obesity, and various behavioral abnormalities. Effective and sustained treatments are limited, highlighting the need for new therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have revolutionized obesity treatment while their efficacy in PWS population remains inconsistent and data in PWS animal models are lacking. Here, we assessed the efficacy of a newly developed AAV platform to deliver a GLP-1RA exendin-4 via an engineered hybrid capsid Rec2. Intraperitoneal administration of Rec2-exendin-4 at the dose of 2 × 10¹⁰ viral genome per mouse normalized metabolic dysfunction in the Magel2-null mouse model of PWS. Systemic Rec2-exendin-4 treatment reversed genotype-driven excessive adiposity, impaired glycemic control, hyperleptinemia, and adipose gene expression signatures. Moreover, intraperitoneal injection of Rec2-exendin-4 (4 × 10¹⁰ viral genome/mouse) exerted high levels of efficacy in diet-induced obesity model-decreasing food intake; preventing excessive weight gain and obesity; improving glucose metabolism and insulin sensitivity; and reversing fatty liver. Metabolic improvements were maintained at least 5 months. These data demonstrate the therapeutic potential of a systemic AAV-mediated exendin-4 gene therapy for PWS-related metabolic abnormalities in Magel2-null model and dietary obesity.