Abstract 15574: A Subcutaneous Platform for RNAi Therapeutics Targeting ANGPTL3
RNAi therapeutics have gone from an idea in 2002 to positive clinical trial results in phase 1 and 2 by 2013, remarkable progress for a novel technology. Our initial clinical delivery systems consisted of siRNA formulated in lipid nanoparticles (LNPs) dosed via an intravenous route. Utilizing this system we were able to demonstrate proof of concept in humans with ALN-PCS, an RNAi therapeutic targeting PCSK9, which reduced both plasma PCSK9 as well as the clinically validated endpoint of LDL-C. For many metabolic diseases, however, a subcutaneous route of administration is much preferred. We have recently demonstrated that subcutaneous delivery of siRNA conjugated to a triantennary N-acetylgalactosamine ligand enables robust and sustained target silencing with siRNA uptake mediated by the hepatocyte-specific asiologlycoprotein receptor (ASGPR). Angiopoietin-like 3 (ANGPTL3) was recently implicated via human genetic studies in the regulation of lipoprotein levels. We have identified active siRNA molecules targeting ANGPTL3 and have demonstrated their ability to lower circulating ANGPTL3 protein, resulting in the reduction of Total-cholesterol, Low Density Lipoprotein Cholesterol and Triglycerides in various animal models of metabolic disease. In addition, we have identified several potent siRNA-GalNAc conjugates capable of lowering ANGPLT3 via subcutaneous dosing. Results from pre-clinical studies on ANGPTL3 and the application of a subcutaneous platform for RNAi therapeutics targeting genes implicated in metabolic disease will be presented
- © 2013 by American Heart Association, Inc.