title: Development of lipoprotein(a) siRNAs for mechanism of action studies in non-human primate models of atherosclerosis.
abstract: Lipoprotein(a) [Lp(a)] has recently been recognized as an independent risk factor for coronary heart disease. While plasma Lp(a) levels are correlated with cardiovascular risk, the mechanism by which this particle contributes to atherosclerosis is largely unknown. Although humanized transgenic mouse model has recently been described to study Lp(a) biology, non-human primates (NHP) are the only preclinical model available that allow study of the role of Lp(a) in atherosclerosis in an innate setting. We describe targeting of LPA using lipid nanoparticle formulated short interfering RNAs (siRNAs) in lean rhesus macaque monkeys. We show >90 % LPA mRNA lowering in the liver and >95 % Lp(a) plasma reduction for over 3 weeks after a single siRNA dose. Given the potency of LPA siRNAs, siRNA approach may enable chronic reduction of Lp(a) in atherosclerotic NHP and help to unmask the role for Lp(a) in the genesis and progression of atherosclerosis in man.
authors.affiliation: RNA Therapeutics, Merck Sharp & Dohme Corp., West Point, 19486, PA, USA, marija_tadin-strapps@merck.com.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.forename: Michael
authors.initials: M
authors.lastname: Robinson
authors.forename: Lauretta
authors.initials: L
authors.lastname: Le Voci
authors.forename: Lori
authors.initials: L
authors.lastname: Andrews
authors.forename: Satya
authors.initials: S
authors.lastname: Yendluri
authors.forename: Stephanie
authors.initials: S
authors.lastname: Williams
authors.forename: Steve
authors.initials: S
authors.lastname: Bartz
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008055:Lipids / Q000737:chemistry; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D050997:Nanomedicine; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000067492:RNAi Therapeutics; D013997:Time Factors; D014162:Transfection
chemical_list: D008055:Lipids; D017270:Lipoprotein(a); D034741:RNA, Small Interfering