1796-P: An Integrated Service Platform to Support the Discovery of Dual-Targeting Oligonucleotide Drugs to Treat Elevated ASCVD Risk in Diabetes

Introduction and Objective: Diabetes is often accompanied by atherogenic dyslipidemia, with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides serving as major drivers of atherosclerotic cardiovascular disease (ASCVD). This underscores the need for durable, liver-targeted therapies that can modulate multiple lipid metabolism pathways. Methods: Small interfering RNAs (siRNAs) enable potent and sustained suppression of hepatic gene expression and represents an attractive modality for next-generation lipid-lowering treatments. Target 1 regulates circulating LDL-C levels, whereas Target 2 governs triglyceride-rich lipoprotein metabolism. Targeting both pathways together may enhance lipid lowering effects. Results: Using our integrated oligonucleotide drug discovery platform in WuXi AppTec, which supports end-to-end drug discovery and development, we developed a dual-targeting siRNA designed to simultaneously silence Target 1 and Target 2, and evaluated the impact of linker chemistry on dual target knockdown efficiency. In mouse models, the dual-targeting siRNA achieved robust and sustained suppression of both targets, resulting in additive reductions in LDL-C and triglycerides. Conclusion: These findings support dual Target 1 /Target 2 silencing via siRNA as a promising therapeutic strategy for mixed hyperlipidemia and ASCVD risk in diabetes patients, and demonstrates the utility of our service platform to support the rapid discovery of multi-targeting oligonucleotide therapeutics.