Targeting Apolipoprotein(a) With a Novel RNAi Delivery Platform as a Prophylactic Treatment to Reduce Risk of Cardiovascular Events in Individuals With Elevated Lipoprotein (a)

Introduction: Mendelian randomization studies and meta-analyses have demonstrated that elevated circulating lipoprotein(a), known as Lp(a), is an independent risk factor for cardiovascular diseases (CVD). Lp(a) is a complex lipoprotein particle similar in structure to LDL, but contains the genetically variable liver-expressed protein apolipoprotein(a) (apo(a)). Lp(a) may contribute to atherosclerosis by targeting oxidized phospholipids to vascular injury sites, while promoting both inflammation and lipid accumulation. Methods: Hepatocyte-targeted RNA interference (RNAi) triggers for reducing liver apo(a) expression were developed that can be administered subcutaneously (SQ). Highly specific human/non-human primate (NHP) cross-reactive RNAi triggers were designed in silico and screened for knockdown activity in vitro and in two humanized transgenic mouse lines. Structure activity relationship (SAR) studies of the most active RNAi triggers identified optimal modifications resulting in lead identification. L...