1102-OR: Adipose-Targeted ALK7 siRNA Synergizes with Tirzepatide to Reduce Fat Mass while Preserving Lean Mass in Diet-Induced Obese Mice

Introduction and Objective: Current weight-loss therapies often induce lean mass loss and weight regain. ALK7 (ACVR1C) negatively regulates adipocyte lipolysis. We developed an adipose-targeted siRNA delivery platform with high tissue selectivity. This study evaluates whether our adipose-targeted ALK7 siRNA, alone or combined with Tirzepatide (TZP), promotes high-quality weight loss by reducing fat mass while preserving lean mass in diet-induced obese (DIO) mice. Methods: Two studies were conducted in DIO mice. Study 1 evaluated ALK7 siRNA monotherapy (3 & 5 mg/kg, SC, QW×22). Study 2 evaluated ALK7 siRNA (6 mg/kg, QW×7), TZP (3 nmol/kg, Q3D×6), or their combination. Assessments included body weight, food intake, body composition (DEXA), histopathology, metabolic biomarkers, ALK7 knockdown and gene expression (qPCR). Results: ALK7 siRNA monotherapy achieved >70% ALK7 knockdown in adipose depots (p<0.001), reducing body weight (-17.5%, p<0.01) without affecting food intake. Combination with TZP yielded synergistic reductions in body weight (-23% vs. -15% TZP alone) and fat mass (-47% vs. -26%), while fully preserving lean mass. The regimen upregulated adipose lipolysis and energy expenditure genes, alleviated hepatic steatosis/fibrosis, and did not alter serum free fatty acids, ketones, or liver enzymes/lipids. Toxicology profiles were favorable; no significant off-target risks were identified. Conclusion: Adipose-targeted ALK7 inhibition via ALK7 siRNA enhances fat-specific catabolism and synergizes with TZP to drive superior fat loss while preserving lean mass in DIO mice. The combination demonstrates a promising efficacy and safety profile, supporting its development as a potential therapy for sustainable obesity management.