# Zilebesiran—Small Interfering RNAs as Prospective New Drug in the Treatment of Hypertension

## TL;DR

Zilebesiran is a new hypertension drug that uses siRNA to silence the angiotensinogen gene, leading to long-term blood pressure reduction.

## Contribution

Zilebesiran is the first antihypertensive drug based on siRNA gene silencing of angiotensinogen.

## Key findings

- Zilebesiran reduces blood pressure by more than 10 mmHg for months after a single dose.
- The drug's effect is prolonged due to siRNA storage in hepatocyte endosomes.

## Abstract

The inhibition of renin–angiotensin–aldosterone system (RAAS) activity is one of the key mechanisms in the treatment of arterial hypertension. Non-adherence to therapeutic recommendations is considered to be the main cause of failure to achieve therapeutic goals in patients with arterial hypertension. Zilebesiran is the first antihypertensive drug using expression genes modified by siRNA action. The mechanism of action is based on silencing the angiotensinogen gene by activating the RNA-induced silencing complex (RISC). The decreased production of angiotensinogen and storage of siRNA in hepatocyte endosomes makes the drug’s effect prolonged; it may last up to several months after drug administration. In hypertensive patients, a long-term reduction in blood pressure by more than 10 mmHg compared to placebo has been observed after a single dose of zilebesiran. Despite the promising results of the previous studies, further observations are still necessary regarding side effects and long-term effectiveness, as well as the possibility of developing resistance to treatment.