Abstract 428: Lipoprotein(a) Targeting With RNAi Delivery Platforms in Transgenic Mice and Cynomolgus Monkeys
| Autor: | Holly Hamilton, Christine Chapman, David B. Rozema, Jessica Grondolsky, Qili Chu, David L. Lewis, Almeida Lauren J, Julia Hegge, Darren H. Wakefield, Jane Hoover-Plow, Vladimir S. Trubetskoy, Steven Kanner, Stacey Melquist, Aaron Almeida |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 36 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.36.suppl_1.428 |
| Popis: | Background: Meta-analyses of clinical studies have demonstrated that high levels of lipoprotein(a), known as Lp(a), correlate with residual risk of cardiovascular disease (CVD) while Mendelian genetic studies indicate that Lp(a) is an independent cause of CVD. Lp(a) is a complex lipoprotein particle similar in structure to LDL (consisting of cholesterol, triglycerides, phospholipids and apoB-100), but contains the genetically variable liver-expressed protein apo(a). Lp(a) may contribute to atherosclerosis by targeting oxidized phospholipids to vascular injury sites, promoting both inflammation and accumulation of lipids. Methods: RNA interference (RNAi) based approaches for reducing liver apo(a) expression were developed using both a targeted intravenous platform called Dynamic Polyconjugates (DPC) TM and a subcutaneous (SQ) format. The DPC platform comprises an RNAi trigger conjugated to cholesterol, and a hepatocyte-targeted, membrane active peptide to promote endosomal release of the RNAi trigger. The SQ platform is an RNAi trigger targeted to liver by N-acetyl galactosamine in a proprietary format. RNAi activity was assessed in two different humanized transgenic mice and cynomolgus monkeys. Results: In Lp(a) transgenic mice expressing human apo(a) and apoB-100 genes, treatment with a single DPC dose reduced serum Lp(a) by >98% at nadir and >90% for >5 weeks. A single DPC injection in cynomolgus monkeys resulted in >95% reduction in endogenous Lp(a) particles at 5 weeks post injection, without significant changes in toxicity biomarkers. Treatment with a SQ RNAi trigger reduced serum apo(a) in transgenic mice by >90% at nadir, while that in monkeys reached 64% reduction of Lp(a). Additional modifications to the RNAi trigger improved both depth and duration of knockdown in transgenic mice. Conclusion: Long-duration reductions in circulating apo(a) and Lp(a) have been shown with hepatocyte-directed delivery of apo(a)-specific RNAi triggers in mice and monkeys. This represents an intriguing mechanism to evaluate in humans for reducing residual risk of CVD in LDL-controlled individuals with elevated Lp(a). |
| Databáze: | OpenAIRE |
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