Novel Pharmacological Approaches in the Treatment of Hypertension: A Focus on RNA-Based Therapeutics.

Autor: Addison ML; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine & Veterinary Medicine, The University of Edinburgh, Scotland, United Kingdom (M.L.A., P.R., D.J.W.)., Ranasinghe P; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine & Veterinary Medicine, The University of Edinburgh, Scotland, United Kingdom (M.L.A., P.R., D.J.W.).; Department of Pharmacology, Faculty of Medicine, University of Colombo, Sri Lanka (P.R.)., Webb DJ; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine & Veterinary Medicine, The University of Edinburgh, Scotland, United Kingdom (M.L.A., P.R., D.J.W.).
Jazyk: angličtina
Zdroj: Hypertension (Dallas, Tex. : 1979) [Hypertension] 2023 Nov; Vol. 80 (11), pp. 2243-2254. Date of Electronic Publication: 2023 Sep 14.
DOI: 10.1161/HYPERTENSIONAHA.122.19430
Abstrakt: Hypertension remains the leading cause of cardiovascular disease and premature death globally, affecting half of US adults. A high proportion of hypertensive patients exhibit uncontrolled blood pressure (BP), associated with poor adherence, linked to pill burden and adverse effects. Novel pharmacological strategies are urgently needed to improve BP control. Dysregulation of the renin-angiotensin system increases BP through its primary effector, Ang II (angiotensin II), which results in tissue remodeling and end-organ damage. Silencing liver angiotensinogen (the sole source of Ang II) has been achieved using novel RNA therapeutics, including the antisense oligonucleotide, IONIS-AGT (angiotensinogen)-LR X , and the small-interfering RNA, zilebesiran. Conjugation to N-acetylgalactosamine enables targeted delivery to hepatocytes, where endosomal storage, slow leakage, and small-interfering RNA recycling (for zilebesiran) result in knockdown over several months. Indeed, zilebesiran has an impressive and durable effect on systolic BP, reduced by up to 20 mm Hg and sustained for 6 months after a single administration, likely due to its very effective knockdown of angiotensinogen, without causing acute kidney injury or hyperkalemia. By contrast, IONIS-AGT-LR X caused less knockdown and marginal effects on BP. Future studies should evaluate any loss of efficacy relating to antidrug antibodies, safety issues associated with long-term angiotensinogen suppression, and broader benefits, especially in the context of common comorbidities such as type 2 diabetes and chronic kidney disease.
Competing Interests: Disclosures Dr Webb has received nonpersonal support for research and consultancy from AbbVie, Actelion, AstraZeneca, Idorsia, Johnson & Johnson, and Novartis. Dr Webb has received funding for research in hypertension from the British Heart Foundation. University/British Heart Foundation Center for Cardiovascular Science received funding from Alnylam Pharmaceuticals for phase I trials with zilebesiran. The other authors report no conflicts.
Databáze: MEDLINE
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