2544-P: INHBE-siRNA as a Promising Antiobesity Therapy: Preclinical Evaluation in Diet-Induced-Obesity Humanized INHBE Mice

Introduction and Objective: Studies have shown that heterozygous carriers of INHBE loss-of-function mutations have reduced abdominal fat and a lower risk of type 2 diabetes and coronary artery disease. Results from a Phase 1 clinical trial for treating obese patients indicated that a single dose of INHBE-siRNA effectively suppressed serum activin E for three months, improved body composition, and did not cause muscle loss. We investigated the impact of reducing Inhbe expression via INHBE-siRNA or Semaglutide on body weight and composition in a diet-induced obese (DIO) hINHBE mouse model. Methods: High-fat diet-induced obese (DIO) hINHBE mice were treated for 50 days with incretin agonists or INHBE-siRNA (weekly). Body weight, food intake, body composition (via EchoMRI or DEXA), fasting blood glucose (FBG), liver weight, adipose tissue (MAT, PRAT, eWAT, iWAT), muscle tissue (quadriceps), and INHBE mRNA levels were measured. Results: Following the administration of INHBE-siRNA (9 mg/kg, weekly) for 50 days, DIO hINHBE mice showed a 12.25% reduction in body weight compared to baseline. MRI data indicated that fat percentage decreased from 36.5% to 30.3%, while lean percentage increased from 50.1% to 55.4%, with DEXA results showing similar trends. Compared to DIO hINHBE control mice, weights of MAT, PRAT, eWAT, and iWAT were significantly reduced, and quadriceps muscle mass was preserved. FBG decreased by 18.7%. INHBE mRNA levels decreased by 93.8%. Similarly, after 50 days of Semaglutide treatment, DIO hINHBE mice showed a 13.6% reduction in body weight. Conclusion: INHBE expression was significantly reduced in DIO hINHBE mice treated with INHBE-siRNA, resulting in weight loss comparable to Semaglutide, with improved body composition and preserved muscle mass. These preclinical data support INHBE-siRNA treatment as a potential next-generation anti-obesity therapy for patients with obesity and other metabolic comorbidities. Disclosure H. Qi: Employee; Current; WuXi AppTex. Y. Li: None.