Abstract P605: Liver-specific Antisense Inhibition Of Angiotensinogen Reduced BP In A Hypertensive Rat Model Resistant To Standard RAS Inhibitors

Abstract

Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive therapeutics, there remains a need for a novel agent effective in individuals with treatment-resistant hypertension who cannot reach their target BP. Pharmacological agents targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS. Experiments were conducted to characterize a series of angiotensinogen (Agt) oligonucleotides (ASOs) and compare their efficacy in a model of malignant hypertension. Agt ASOs which targeted all systemic sites of Agt (e.g. liver, fat and kidney) versus LICA-conjugated Agt ASOs (Agt-LICA ASOs) that preferentially target the liver were evaluated in normotensive and hypertensive rats. Liver, adipose and kidney Agt RT-PCR were performed and revealed Agt ASO treatment reduced liver, adipose and kidney Agt expression by 93%, 96% and 82%, respectively. Agt-LICA ASO treatment resulted in 93%, 10% and 11% reductions of Agt mRNA in liver, adipose and kidney, respectively, thus demonstrating specific liver targeting with LICA. Plasma Agt, measured by ELISA, revealed no significant differences between the Agt and Agt-LICA ASO treatments. For example, after a single administration of the ASOs, plasma Agt was reduced 15-18%, 41-48%, 84-89% and 92% at 12, 24, 48 and 72 hours, respectively, after ASO administrations. Radiotelemetry was used to compare the BP lowering efficacy in spontaneously hypertensive rats (SHRs) fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors for BP control. Treatments of a control ASO or captopril or captopril plus losartan had a modest effect on BP whereas treatments with either the Agt or Agt-LICA ASOs resulted in similar MAP reductions of 30 - 40 mm Hg. These data demonstrate that the effects of global vs. liver-specific Agt inhibition result in similar reductions of plasma Agt or blood pressure. Additionally, ASO treatments produced superior BP efficacy relative to the standard of care in a model resistant to RAAS blockage. Such improvements could be desirable in individuals not at their BP goal with existing RAS therapeutics.