Emerging insights and future prospects for therapeutic application of siRNA targeting angiotensinogen in hypertension

Introduction
Hypertension is the main global risk factor for cardiovascular disease. Despite this, less than half of treated hypertensive patients are controlled. One reason for this is nonadherence, a major unmet need in hypertension pharmacotherapy. Small interfering RNA therapies inhibit protein translation, and, when linked to N-acetylgalactosamine, allow liver-specific targeting, durability over several months. Targeted knockdown of hepatic angiotensinogen, the source of all angiotensins, offers a precision medicine approach.

Areas covered
This article describes the molecular basis for durability over months and the 24h tonic target inhibition observed after one administration. We present an analysis of the published phase I trials using zilebesiran, a small interfering RNA targeting hepatic angiotensinogen, which reduces blood pressure by up to 20mmHg, lasting 24 weeks. Finally, we examine data evaluating reversibility of angiotensinogen knockdown and its relevance to the future clinical utility of zilebesiran.


Expert Opinion
Further studies should assess safety, efficacy, and outcomes in larger, more broadly representative groups. An advantage of zilebesiran is the potential for bi-annual dosing, thereby reducing nonadherence and improving control rates. It may also reduce nighttime blood pressure due to 24h tonic control. The provision of adherence assessment services will maximize the clinical value of zilebesiran.

Keywords (5-8):
Angiotensinogen
Angiotensin II
Drug adherence
GalNAc
Hypertension therapy
Nonadherence
Renin-angiotensin system
siRNA