title: Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension.
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.
authors: Department of Hypertension, Merck Sharp & Dohme Corp., Rahway, NJ, USA.
authors: Jeffrey
authors: J
authors: Olearczyk
authors: Department of Hypertension, Merck Sharp & Dohme Corp., Rahway, NJ, USA.
authors: Sheng
authors: S
authors: Gao
authors: Department of Hypertension, Merck Sharp & Dohme Corp., Rahway, NJ, USA.
authors: Marianne
authors: M
authors: Eybye
authors: Lead Development, Sirna Therapeutics Inc., a Wholly Owned Subsidiary of Merck Sharp & Dohme Corp., San Francisco, CA, USA.
authors: Satyasri
authors: S
authors: Yendluri
authors: Lead Development, Sirna Therapeutics Inc., a Wholly Owned Subsidiary of Merck Sharp & Dohme Corp., San Francisco, CA, USA.
authors: Lori
authors: L
authors: Andrews
authors: Extarnal Scientific Affairs, Merck Sharp & Dohme Corp., Palo Alto, CA, USA.
authors: Steven
authors: S
authors: Bartz
authors: Department of Hypertension, Merck Sharp & Dohme Corp., Rahway, NJ, USA.
authors: Doris
authors: D
authors: Cully
authors: Discovery Biology, RNA Therapeutics, Merck Sharp & Dohme Corp., West Point, PA, USA.
authors: Marija
authors: M
authors: Tadin-Strapps
mesh_terms: D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D053758:Nanoparticles; D034741:RNA, Small Interfering; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D000808:Angiotensinogen