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A New Avenue for the Long-Term Upstream Inhibition of the Renin-Angiotensin-Aldosterone System by Inhibiting
Giovanna Gallo1,2, Giuliano Tocci1,2, Marta Ricci1,3
1Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189, Rome, Italy.
Abstract:
The renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of several conditions such as hypertension, heart failure and chronic kidney disease. In the last fifty years different therapeutic strategies, including angiotensin converting enzyme inhibitors (ACEi), type 1 angiotensin II receptor blockers (ARBs) and angiotensin receptor neprilysin inhibitors (ARNi), have been developed to counteract this neurohormonal dysregulation. However, all these therapeutic strategies have a relatively short-term action and they need to be administered orally once or more times every day to achieve the therapeutic purposes with a risk of poor therapeutic adherence.More recently, the search for a new effective strategy to provide a long-term control of hypertension was recently boosted by the availability of novel technologies, such as the angiotensinogen suppression in the liver realized through the silencing of RNA with zilebesiran, a small interfering RNA (siRNA) agent.The purpose of this article is to review the available data on Zilebesiran and to discuss in detail potential advantages in the clinical use as well as the still unresolved potential risks.
Insights
Zilebesiran, a novel RNA interference therapeutic, offers a new approach to long-term hypertension management by suppressing angiotensinogen. This review examines its potential benefits and risks compared to existing renin-angiotensin system (RAS) inhibitors.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- The renin-angiotensin system (RAS) is crucial in hypertension, heart failure, and kidney disease.
- Current RAS-targeting therapies (ACEi, ARBs, ARNi) require frequent oral administration, risking poor adherence.
- There is a need for novel, long-term hypertension management strategies.
Purpose of the Study:
- To review existing data on Zilebesiran, a small interfering RNA (siRNA) agent.
- To discuss the potential clinical advantages of Zilebesiran for hypertension control.
- To identify and discuss unresolved risks associated with Zilebesiran therapy.
Main Methods:
- Literature review of Zilebesiran studies.
- Analysis of Zilebesiran's mechanism of action (angiotensinogen suppression via RNA silencing).
- Comparative assessment of Zilebesiran against current RAS-modulating drugs.
Main Results:
- Zilebesiran targets angiotensinogen production in the liver using siRNA technology.
- Potential for infrequent dosing offers improved therapeutic adherence.
- Clinical data is emerging, highlighting both promise and areas needing further investigation.
Conclusions:
- Zilebesiran represents a promising advancement in long-term hypertension management.
- Its novel mechanism offers potential advantages over traditional RAS inhibitors.
- Further research is necessary to fully elucidate Zilebesiran's safety and efficacy profile.
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