RNA DE INTERFERÊNCIA DIRECIONADO AO ANGIOTENSINOGÊNIO PARA TRATAMENTO DE HIPERTENSÃO: UMA REVISÃO DE ESCOPO

Abstract

Introduction: Systemic Arterial Hypertension (SAH) remains the leading cause of cardiovascular diseases and premature death worldwide. The control rate of hypertension is very low, with 4 out of 5 adults living with uncontrolled AH. Given the important role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of AH and the current antihypertensive drugs' lack of efficiency, there is a growing demand for research to provide a solution. In this context, therapeutic approaches aimed at the genetic silencing of angiotensinogen (AGT) production have attracted attention, as they promise administration every 3 or 6 months without significant adverse events. Methodology: This is a scoping review that gathered 16 articles to evaluate new RNA interference-based therapies aiming to improve hypertension treatment. Results: There is preclinical and clinical evidence that RNA interference (RNAi) therapy promotes blood pressure (BP) reduction, consisting of three main approaches capable of efficiently suppressing plasma AGT concentration and reducing BP: antisense oligonucleotide (ASO) with the clinical model IONIS-AGT-LRx, small interfering RNA (siRNA) with zilebesiran, and adeno-associated virus carrying short hairpin RNA (AAV-shRNA). Among the promising clinical results, ASO and siRNA stand out. Conjugation to N-acetylgalactosamine allows targeted delivery to hepatocytes, and thus endosomal storage, slow leakage, and recycling of siRNA result in several months of knockdown. While zilebesiran provides a 20 mmHg reduction in systolic BP maintained for 6 months after a single dose without significant adverse events, IONIS-AGT-LRx promoted a smaller knockdown and less pronounced effects on BP. Conclusion: RNA interference therapy shows promising preclinical and clinical evidence in reducing blood pressure, with two approaches standing out: ASOs and siRNAs. Targeted delivery to hepatocytes with N-acetylgalactosamine conjugation allows for durable and effective knockdown, with siRNAs demonstrating more consistent results.