Low dose systemic AAV-exendin-4 gene therapy for Prader-Willi syndrome and dietary obesity.
This study suggests that AAV-exendin-4 gene therapy may normalize metabolic dysfunction in a mouse model of Prader-Willi syndrome, but further research is needed to assess its safety and efficacy in humans.
Where it sits
this study against the rest of the melanotan ii corpusSummary and findings
This study evaluated the efficacy of a low dose systemic AAV-exendin-4 gene therapy in mouse models of Prader-Willi syndrome (PWS) and dietary obesity. The treatment involved intraperitoneal administration of Rec2-exendin-4 at doses of 2 × 10^10 and 4 × 10^10 viral genomes per mouse. The results indicated normalization of metabolic dysfunction and improvements in various metabolic parameters.
Abstract
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 × 10<sup>10</sup> viral genome per mouse normalized metabolic dysfunction in the <i>Magel2</i>-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 × 10<sup>10</sup> 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 <i>Magel2</i>-null model and dietary obesity.