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: Marija Tadin-Strapps, Michael Robinson, Lauretta Le Voci, Lori Andrews, Satya Yendluri, Stephanie Williams, Steve Bartz, Douglas G Johns
• Journal: Journal of cardiovascular translational research (J Cardiovasc Transl Res) Vol. 8 Issue 1 Pg. 44-53 (Feb 2015) ISSN: 1937-5395 [Electronic] United States
• PMID: 25604958 (Publication Type: Journal Article)

Chemical References

• Lipids
• Lipoprotein(a)
• RNA, Small Interfering

Topics

• Animals
• Atherosclerosis (blood, genetics, pathology, therapy)
• Cell Line
• Disease Models, Animal
• Female
• Gene Transfer Techniques
• Humans
• Lipids (chemistry)
• Lipoprotein(a) (blood, genetics)
• Liver (metabolism)
• Macaca mulatta
• Male
• Nanomedicine
• Nanoparticles
• RNA, Small Interfering (chemistry, genetics, metabolism)
• RNAi Therapeutics
• Time Factors
• Transfection