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Hypertens Res. 2014 May;37(5):405-12. doi: 10.1038/hr.2013.155. Epub 2013 Dec 12.

Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension.

Author information

1
Department of Hypertension, Merck Sharp & Dohme Corp., Rahway, NJ, USA.
2
Lead Development, Sirna Therapeutics Inc., a Wholly Owned Subsidiary of Merck Sharp & Dohme Corp., San Francisco, CA, USA.
3
Extarnal Scientific Affairs, Merck Sharp & Dohme Corp., Palo Alto, CA, USA.
4
Discovery Biology, RNA Therapeutics, Merck Sharp & Dohme Corp., West Point, PA, USA.

Abstract

Angiotensinogen (AGT) is the precursor of active vasoconstrictive octapeptide angiotensin II (Ang II) in the renin-angiotensin-aldosterone system. Blocking the AGT-converting enzymes in the pathway and the Ang II receptor through pharmacological agents has been proven to be effective in lowering blood pressure (BP) in hypertensive patients. In this study, we developed chemically modified small interfering RNAs (siRNA) to target hepatic AGT mRNA in rats. Lipid nanoparticle encapsulated siRNAs were efficiently delivered to rat liver and resulted in significant reduction in hepatic Agt mRNA levels and plasma AGT concentration without impairing liver function. Single intravenous injection of Agt siRNA led to significant and sustained BP lowering in spontaneous hypertensive rats and in Sprague-Dawley rats, and the effect was maintained by weekly siRNA dosing. Data presented here provide proof-of-feasibility for the use of siRNA technology for inhibition of peripheral AGT levels via hepatic mRNA silencing with beneficial effects on BP in preclinical rat models. Similar approach could be used for validation of novel hypertension hepatic and extrahepatic targets.

PMID:
24335718
DOI:
10.1038/hr.2013.155
[Indexed for MEDLINE]
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