Development of Lipoprotein(a) siRNAs for Mechanism of Action Studies in Non-Human Primate Models of Atherosclerosis

被引：0
作者：
Marija Tadin-Strapps
Michael Robinson
Lauretta Le Voci
Lori Andrews
Satya Yendluri
Stephanie Williams
Steve Bartz
Douglas G. Johns
机构：
[1] Merck Sharp & Dohme Corp.,RNA Therapeutics
[2] Merck Sharp & Dohme Corp.,Division of Cardiovascular Diseases
[3] Sirna Therapeutics Inc.,External Scientific Affairs
[4] a Wholly Owned Subsidiary of Merck Sharp & Dohme Corp.,Department of Genetics and Pharmacogenomics
[5] Merck Research Labs,undefined
[6] Merck Sharp & Dohme Corp.,undefined
来源：
Journal of Cardiovascular Translational Research | 2015年 / 8卷
关键词：
Apo(a); Lp(a); NHP models; LDL-c lowering; Atherosclerosis; siRNA; LNP; RNAi;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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.
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页码：44 / 53
页数：9
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