{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:44:11Z","timestamp":1791243851944,"version":"4.1.0"},"reference-count":158,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Zilebesiran represents an innovative antihypertensive therapy employing small interfering RNA (siRNA) to inhibit hepatic angiotensinogen, a key regulator of the renin\u2013angiotensin\u2013aldosterone system. By directly targeting the source of angiotensin II production, zilebesiran offers a novel mechanism distinct from conventional antihypertensive treatments. In the clinical studies KARDIA-1 and KARDIA-2, zilebesiran demonstrated clinically significant reductions in systolic blood pressure, with effects lasting up to 24 weeks after a single subcutaneous injection. In KARDIA-1, doses of 300 mg and 600 mg administered every 6 months resulted in reductions of over 15 mmHg in systolic blood pressure at 3 months compared with placebo. KARDIA-2 further showed an additional reduction of up to 12.1 mmHg at 3 months when zilebesiran was used as an adjunct to standard antihypertensive therapy. KARDIA-3 is currently evaluating the therapy in a larger global population to assess its impact on major cardiovascular outcomes. Zilebesiran has demonstrated a favorable safety profile with minimal adverse events, offering potential advantages for patients with resistant or uncontrolled hypertension and those at high cardiovascular risk, especially where adherence to daily oral medications is challenging. Beyond blood pressure reduction, zilebesiran may protect target organs, including the heart, kidneys, and retina. In conclusion, zilebesiran represents a promising siRNA-based therapy that may redefine the management of difficult-to-control hypertension, offering durable, targeted, and patient-friendly treatment with broad cardiovascular benefits. Future studies will clarify its long-term safety, efficacy across diverse populations, and integration into personalized hypertension management strategies.<\/jats:p>","DOI":"10.3390\/ijms262110717","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T12:13:08Z","timestamp":1762258388000},"page":"10717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Zilebesiran as an Innovative siRNA-Based Therapeutic Approach for Hypertension: Emerging Perspectives in Cardiovascular Medicine"],"prefix":"10.3390","volume":"26","author":[{"given":"Petruta A.","family":"Morosan","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Grigore T. 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Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1093\/eurheartj\/ehae178","article-title":"2024 ESC Guidelines for the Management of Elevated Blood Pressure and Hypertension","volume":"45","author":"McEvoy","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1161\/HYPERTENSIONAHA.120.15026","article-title":"2020 International Society of Hypertension Global Hypertension Practice Guidelines","volume":"75","author":"Unger","year":"2020","journal-title":"Hypertension"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Writing Committee Members, Jones, D.W., Ferdinand, K.C., Taler, S.J., Johnson, H.M., Shimbo, D., Abdalla, M., Altieri, M.M., Bansal, N., and Bello, N.A. (2025). 2025 AHA\/ACC\/AANP\/AAPA\/ABC\/ACCP\/ACPM\/AGS\/AMA\/ASPC\/NMA\/PCNA\/SGIM Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 152, e114\u2013e218.","DOI":"10.1161\/CIR.0000000000001356"},{"key":"ref_5","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2021). Worldwide Trends in Hypertension Prevalence and Progress in Treatment and Control from 1990 to 2019: A Pooled Analysis of 1201 Population-Representative Studies with 104 Million Participants. Lancet, 398, 957\u2013980."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1055\/a-1577-8663","article-title":"Arterielle Hypertonie\u2014Eine \u00dcbersicht F\u00fcr Den \u00c4rztlichen Alltag","volume":"147","author":"Hengel","year":"2022","journal-title":"Dtsch. Med. Wochenschr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"262","DOI":"10.5830\/CVJA-2017-040","article-title":"Roadmap to Achieve 25% Hypertension Control in Africa by 2025","volume":"28","author":"Dzudie","year":"2017","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_8","first-page":"80","article-title":"Spotlight on Hypertension in the African Continent","volume":"39","author":"Khan","year":"2025","journal-title":"J. Hum. Hypertens."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1161\/HYPERTENSIONAHA.121.18884","article-title":"How to Improve Awareness, Treatment, and Control of Hypertension in Africa, and How to Reduce Its Consequences: A Call to Action from the World Hypertension League","volume":"79","author":"Parati","year":"2022","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1093\/ajh\/hpae141","article-title":"Trends in Blood Pressure Control among US Adults with Hypertension, 2013\u20132014 to 2021\u20132023","volume":"38","author":"Hardy","year":"2025","journal-title":"Am. J. Hypertens."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e70093","DOI":"10.1111\/jch.70093","article-title":"Hypertension Prevalence, Awareness, and Control in US Adults Before and After the COVID-19 Pandemic","volume":"27","author":"Essa","year":"2025","journal-title":"J. Clin. Hypertens."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41371-023-00879-x","article-title":"Prevalence and Determinants of Hypertension in South-Asian Urban Communities: Findings from Demographic and Health Surveys (DHS) Data of South Asian Countries","volume":"38","author":"Talukder","year":"2024","journal-title":"J. Hum. Hypertens."},{"key":"ref_13","unstructured":"(2025, September 21). Hypertension\u2014China, Available online: https:\/\/www.who.int\/china\/health-topics\/hypertension."},{"key":"ref_14","unstructured":"World Health Organization (2023). Global Report on Hypertension: The Race Against a Silent Killer."},{"key":"ref_15","unstructured":"(2025, June 16). Cardiovascular Diseases Kill 10 000 People in the WHO European Region Every Day, with Men Dying More Frequently than Women, Available online: https:\/\/www.who.int\/europe\/news\/item\/15-05-2024-cardiovascular-diseases-kill-10-000-people-in-the-who-european-region-every-day--with-men-dying-more-frequently-than-women."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2147\/VHRM.S337640","article-title":"Angiotensin Receptor Blockers in the Management of Hypertension: A Real-World Perspective and Current Recommendations","volume":"18","author":"Gallo","year":"2022","journal-title":"Vasc. Heal. Risk Manag."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1097\/HJH.0000000000003548","article-title":"The Latest Hypertension Guidelines: From Encryption to Decryption, Finally!","volume":"41","author":"Ram","year":"2023","journal-title":"J. Hypertens."},{"key":"ref_18","first-page":"53","article-title":"Current Approach to Resistant Hypertension","volume":"2","author":"Chaudhry","year":"2024","journal-title":"J. Cardiol. Cardiovasc. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e032197","DOI":"10.1161\/JAHA.123.032197","article-title":"Trends of Antihypertensive Prescription Among US Adults from 2010 to 2019 and Changes Following Treatment Guidelines: Analysis of Multicenter Electronic Health Records","volume":"13","author":"Lin","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1001\/jamaneurol.2020.2499","article-title":"Trends in Antihypertensive Medication Use Among Individuals with a History of Stroke and Hypertension, 2005 to 2016","volume":"77","author":"Santos","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/cpt.2934","article-title":"Genome-Wide Association Studies Categorized by Class of Antihypertensive Drugs Reveal Complex Pathogenesis of Hypertension with Drug Resistance","volume":"114","author":"Yamazaki","year":"2023","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hu, Y., Huerta, J., Cordella, N., Mishuris, R.G., and Paschalidis, I.C. (2023). Personalized Hypertension Treatment Recommendations by a Data-Driven Model. BMC Med. Inform. Decis. Mak., 23.","DOI":"10.1186\/s12911-023-02137-z"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1111\/bph.70063","article-title":"Advancing Antihypertensive Drug Development","volume":"182","author":"Pu","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s40292-024-00634-4","article-title":"Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach","volume":"31","author":"Nardoianni","year":"2024","journal-title":"High Blood Press. Cardiovasc. Prev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11827","DOI":"10.1093\/nar\/gkaa670","article-title":"Investigating the Pharmacodynamic Durability of GalNAc-siRNA Conjugates","volume":"48","author":"Brown","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Boutari, C., and Siskos, F. (2023). Novel Dual Endothelin Inhibitors in the Management of Resistant Hypertension. Life, 13.","DOI":"10.3390\/life13030806"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1161\/HYPERTENSIONAHA.122.19430","article-title":"Novel Pharmacological Approaches in the Treatment of Hypertension: A Focus on RNA-Based Therapeutics","volume":"80","author":"Addison","year":"2023","journal-title":"Hypertension"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1053\/j.ajkd.2023.09.009","article-title":"Entering a New Era of Antihypertensive Therapy","volume":"83","author":"Cohen","year":"2024","journal-title":"Am. J. Kidney Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Menezes Junior, A.d.S., Nogueira, T.H.M., de Lima, K.B.A., de Oliveira, H.L., and Botelho, S.M. (2025). Exploratory Studies on RNAi-Based Therapies Targeting Angiotensinogen in Hypertension: Scoping Review. J. Pers. Med., 15.","DOI":"10.3390\/jpm15010003"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"177110","DOI":"10.1016\/j.ejphar.2024.177110","article-title":"Innovative Hypertension Treatments: Transitioning from Conventional Therapies to siRNA-Based Solutions","volume":"985","author":"Parvan","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e22187","DOI":"10.1002\/ddr.22187","article-title":"Unveiling the Potential of Antisense Oligonucleotides: Mechanisms, Therapies, and Safety Insights","volume":"85","year":"2024","journal-title":"Drug Dev. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.30574\/wjbphs.2024.19.3.0599","article-title":"Bioanalysis of Antisense Oligonucleotides: Techniques, Challenges, Regulatory Considerations, and Future Perspectives","volume":"19","author":"Gandhi","year":"2024","journal-title":"World J. Biol. Pharm. Health Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Collotta, D., Bertocchi, I., Chiapello, E., and Collino, M. (2023). Antisense Oligonucleotides: A Novel Frontier in Pharmacological Strategy. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1304342"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/35888","article-title":"Potent and Specific Genetic Interference by Double-Stranded RNA in Caenorhabditis Elegans","volume":"391","author":"Fire","year":"1998","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.cell.2006.12.001","article-title":"RNA Interference: Big Applause for Silencing in Stockholm","volume":"127","author":"Zamore","year":"2006","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1161\/HYPERTENSIONAHA.120.16876","article-title":"Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease","volume":"77","author":"Ren","year":"2021","journal-title":"Hypertension"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1161\/HYPERTENSIONAHA.124.22878","article-title":"Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects with REVERSIR","volume":"81","author":"Ye","year":"2024","journal-title":"Hypertension"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/ATVBAHA.124.318374","article-title":"Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases","volume":"44","author":"Daugherty","year":"2024","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.ymthe.2006.01.001","article-title":"Progress towards in Vivo Use of siRNAs","volume":"13","author":"Behlke","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1126\/science.1073827","article-title":"A microRNA in a Multiple-Turnover RNAi Enzyme Complex","volume":"297","author":"Zamore","year":"2002","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1136\/bmj.328.7450.1245","article-title":"RNA Interference","volume":"328","author":"Downward","year":"2004","journal-title":"BMJ"},{"key":"ref_42","first-page":"497","article-title":"Design, Mechanism, Delivery and Therapeutics of Canonical and Dicer-Substrate siRNA","volume":"14","author":"Raja","year":"2019","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41392-020-0207-x","article-title":"Therapeutic siRNA: State of the Art","volume":"5","author":"Hu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bonavida, B. (2008). Antisense Oligonucleotides and siRNA as Specific Inhibitors of Gene Expression: Mechanisms of Action and Therapeutic Potential. Sensitization of Cancer Cells for Chemo\/Immuno\/Radio-Therapy, Humana Press.","DOI":"10.1007\/978-1-59745-474-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7137","DOI":"10.1073\/pnas.0812317106","article-title":"Small Interfering RNA-Induced TLR3 Activation Inhibits Blood and Lymphatic Vessel Growth","volume":"106","author":"Cho","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.imlet.2017.03.019","article-title":"Activation of Cell Membrane-Localized Toll-like Receptor 3 by siRNA","volume":"189","author":"Pirher","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_47","first-page":"203","article-title":"Clinical Progress of Nanomedicine-Based RNA Therapies","volume":"12","author":"Lim","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1903637","DOI":"10.1002\/adma.201903637","article-title":"Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery","volume":"31","author":"Kim","year":"2019","journal-title":"Adv. Mater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41573-019-0017-4","article-title":"The Current State and Future Directions of RNAi-Based Therapeutics","volume":"18","author":"Setten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"176467","DOI":"10.1016\/j.ejphar.2024.176467","article-title":"siRNA as Potential Therapeutic Strategy for Hypertension","volume":"969","author":"Tanna","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7605","DOI":"10.2147\/IJN.S436038","article-title":"A Comprehensive Review of Small Interfering RNAs (siRNAs): Mechanism, Therapeutic Targets, and Delivery Strategies for Cancer Therapy","volume":"18","author":"Zhang","year":"2023","journal-title":"Int. J. Nanomed."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.tibs.2004.12.007","article-title":"siRNA and miRNA: An Insight into RISCs","volume":"30","author":"Tang","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2405524","DOI":"10.1002\/smll.202405524","article-title":"Elucidating siRNA Cellular Delivery Mechanism Mediated by Quaternized Starch Nanoparticles","volume":"20","author":"Cohen","year":"2024","journal-title":"Small"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ali Zaidi, S.S., Fatima, F., Ali Zaidi, S.A., Zhou, D., Deng, W., and Liu, S. (2023). Engineering siRNA Therapeutics: Challenges and Strategies. J. Nanobiotechnology, 21.","DOI":"10.1186\/s12951-023-02147-z"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/10611860400006257","article-title":"The Design and Exogenous Delivery of siRNA for Post-Transcriptional Gene Silencing","volume":"12","author":"Gilmore","year":"2004","journal-title":"J. Drug Target."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/nbt1122","article-title":"Potent and Persistent in Vivo Anti-HBV Activity of Chemically Modified siRNAs","volume":"23","author":"Morrissey","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Subhan, M.A., and Torchilin, V. (2020). siRNA Based Drug Design, Quality, Delivery and Clinical Translation. Nanomed. Nanotechnol. Biol. Med., 29.","DOI":"10.1016\/j.nano.2020.102239"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Rosenberg, E. (2017). Chapter 4\u2014DNA in Three Dimensions: The Double-Helix. It\u2019s in Your DNA, Academic Press.","DOI":"10.1016\/B978-0-12-812502-1.00004-4"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.chembiol.2011.12.008","article-title":"RNA-Based Therapeutics: Current Progress and Future Prospects","volume":"19","author":"Burnett","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9840","DOI":"10.1093\/nar\/gkaa715","article-title":"Some ASOs That Bind in the Coding Region of mRNAs and Induce RNase H1 Cleavage Can Cause Increases in the Pre-mRNAs That May Blunt Total Activity","volume":"48","author":"Liang","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"102437","DOI":"10.1016\/j.omtn.2024.102437","article-title":"Development, Opportunities, and Challenges of siRNA Nucleic Acid Drugs","volume":"36","author":"Xiao","year":"2025","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, M., and Zhang, C. (2024). Preferential Cleavage of Upstream Targets in Concatenated miRNA\/siRNA Target Sites Support a 5\u2032-3\u2032 Scanning Model for RISC Target Recognition. Biochem. Biophys. Res. Commun., 703.","DOI":"10.1016\/j.bbrc.2024.149662"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Gareri, C., Polimeni, A., Giordano, S., Tamm\u00e8, L., Curcio, A., and Indolfi, C. (2022). Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias. J. Clin. Med., 11.","DOI":"10.3390\/jcm11133884"},{"key":"ref_64","first-page":"275","article-title":"Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics","volume":"2","author":"Mansoor","year":"2008","journal-title":"Gene Regul. Syst. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43856-023-00419-1","article-title":"Possibilities and Limitations of Antisense Oligonucleotide Therapies for the Treatment of Monogenic Disorders","volume":"4","author":"Lauffer","year":"2024","journal-title":"Commun. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/35078107","article-title":"Duplexes of 21-Nucleotide RNAs Mediate RNA Interference in Cultured Mammalian Cells","volume":"411","author":"Elbashir","year":"2001","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/anie.200802092","article-title":"RNA Interference: From Basic Research to Therapeutic Applications","volume":"48","author":"Kurreck","year":"2009","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1007\/s40265-018-0983-6","article-title":"Patisiran: First Global Approval","volume":"78","author":"Hoy","year":"2018","journal-title":"Drugs"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/jcph.1480","article-title":"Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis","volume":"60","author":"Zhang","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1358\/dot.2021.57.1.3230207","article-title":"Givosiran to Treat Acute Porphyria","volume":"57","author":"Honor","year":"2021","journal-title":"Drugs Today"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1056\/NEJMoa1913147","article-title":"Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria","volume":"382","author":"Balwani","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s40265-020-01463-0","article-title":"Lumasiran: First Approval","volume":"81","author":"Scott","year":"2021","journal-title":"Drugs"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1056\/NEJMoa2021712","article-title":"Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1","volume":"384","author":"Garrelfs","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Moya-Garzon, M.D., Gomez-Vidal, J.A., Alejo-Armijo, A., Altarejos, J., Rodriguez-Madoz, J.R., Fernandes, M.X., Salido, E., Salido, S., and Diaz-Gavilan, M. (2021). Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias. J. Pers. Med., 11.","DOI":"10.3390\/jpm11020074"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1609243","article-title":"A Highly Durable RNAi Therapeutic Inhibitor of PCSK9","volume":"376","author":"Fitzgerald","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Lee, S.-H., and Kang, M.K. (2021). PCSK9 Inhibiting siRNA. Stroke Revisited: Dyslipidemia in Stroke, Springer.","DOI":"10.1007\/978-981-16-3923-4"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Dec, A., Niemiec, A., Wojciechowska, E., Malig\u0142\u00f3wka, M., Bu\u0142dak, \u0141., Bo\u0142dys, A., and Okopie\u0144, B. (2023). Inclisiran\u2014A Revolutionary Addition to a Cholesterol-Lowering Therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076858"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Wo\u0142owiec, \u0141., Osiak, J., Wo\u0142owiec, A., Wijata, A., Grze\u015bk, E., Kozakiewicz, M., Banach, J., Nowaczyk, A., Nowaczyk, J., and Grze\u015bk, G. (2023). Inclisiran\u2014Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020323"},{"key":"ref_80","unstructured":"(2025, September 15). FDA Approves Fifth RNAi Drug\u2014Alnylam\u2019s Next-Gen hATTR Treatment. Available online: https:\/\/www.nature.com\/articles\/d41573-022-00118-x."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Shevelev, A., Pozdniakova, N., Generalov, E., and Tarasova, O. (2025). siRNA Therapeutics for the Treatment of Hereditary Diseases and Other Conditions: A Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178651"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1007\/s40265-023-01976-4","article-title":"Nedosiran: First Approval","volume":"83","author":"Syed","year":"2023","journal-title":"Drugs"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1021\/acsptsci.2c00110","article-title":"Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies","volume":"5","author":"Liu","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/j.ekir.2025.03.031","article-title":"PHYOX3: Nedosiran Long-Term Safety and Efficacy in Patients with Primary Hyperoxaluria Type 1","volume":"10","author":"Lieske","year":"2025","journal-title":"Kidney Int. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Soroka, A.B., Feoktistova, S.G., Mityaeva, O.N., and Volchkov, P.Y. (2023). Gene Therapy Approaches for the Treatment of Hemophilia B. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310766"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1182\/blood.2023021864","article-title":"Fitusiran Prophylaxis in People with Hemophilia A or B Who Switched from Prior BPA\/CFC Prophylaxis: The ATLAS-PPX Trial","volume":"143","author":"Kenet","year":"2024","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1161\/CIRCULATIONAHA.120.053029","article-title":"Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Study","volume":"144","author":"Thielmann","year":"2021","journal-title":"Circulation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1007\/s00134-022-06859-y","article-title":"New Drugs for Acute Kidney Injury","volume":"48","author":"Pickkers","year":"2022","journal-title":"Intensive Care Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/cbin.11841","article-title":"siRNA-based Nanotherapeutics as Emerging Modalities for Immune-mediated Diseases: A Preliminary Review","volume":"46","author":"Sargazi","year":"2022","journal-title":"Cell Biol. Int."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/s12276-023-00998-y","article-title":"Where Should siRNAs Go: Applicable Organs for siRNA Drugs","volume":"55","author":"Ahn","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/13543784.2018.1457647","article-title":"Tivanisiran, a Novel siRNA for the Treatment of Dry Eye Disease","volume":"27","author":"Bleau","year":"2018","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/CRD.0000000000000645","article-title":"Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis","volume":"33","author":"Khan","year":"2025","journal-title":"Cardiol. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5603\/ah.98623","article-title":"Zilebesiran\u2014The First siRNA-Based Drug in Hypertensiology: Why Is It Needed, and Will It Change the Treatment Approach of Hypertension?","volume":"28","author":"Surma","year":"2024","journal-title":"Arter. Hypertens."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1161\/ATVBAHA.123.319897","article-title":"Targeting Angiotensinogen with N-Acetylgalactosamine\u2013Conjugated Small Interfering RNA to Reduce Blood Pressure","volume":"43","author":"Ye","year":"2023","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Xiao, X., Nie, Y., and Leng, Y. (2025). Asialoglycoprotein Receptor 1: A Multifaceted Receptor in the Liver and Cardiovascular System. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1653452"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1093\/nar\/gkx060","article-title":"Characterizing the Effect of GalNAc and Phosphorothioate Backbone on Binding of Antisense Oligonucleotides to the Asialoglycoprotein Receptor","volume":"45","author":"Schmidt","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1246\/bcsj.72.1313","article-title":"Iron(II)-Assisted Assembly of Trivalent GalNAc Clusters and Their Interactions with GalNAc-Specific Lectins","volume":"72","author":"Sakai","year":"1999","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1089\/nat.2018.0736","article-title":"GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics","volume":"28","author":"Springer","year":"2018","journal-title":"Nucleic Acid Ther."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Cedillo, I., Chreng, D., Engle, E., Chen, L., McPherson, A.K., and Rodriguez, A.A. (2017). Synthesis of 5\u2032-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies. Molecules, 22.","DOI":"10.3390\/molecules22081356"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"(2025, September 16). Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy. Available online: https:\/\/www.mdpi.com\/1999-4923\/16\/7\/938.","DOI":"10.3390\/pharmaceutics16070938"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nrm.2017.132","article-title":"Mechanisms of Clathrin-Mediated Endocytosis","volume":"19","author":"Kaksonen","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1097\/MS9.0000000000002696","article-title":"Advancing Hypertension Management: The Role of Zilebesiran as an siRNA Therapeutic Agent","volume":"87","author":"Siddiqui","year":"2025","journal-title":"Ann. Med. Surg."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/hr.2009.74","article-title":"Devil and Angel in the Renin\u2013Angiotensin System: ACE\u2013Angiotensin II\u2013AT1 Receptor Axis vs. ACE2\u2013Angiotensin-(1\u20137)\u2013Mas Receptor Axis","volume":"32","author":"Iwai","year":"2009","journal-title":"Hypertens. Res."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Baranowska, I., Gawrys, O., Roszkowska-Chojecka, M.M., Badzynska, B., Tymecka, D., Olszynski, K.H., and Kompanowska-Jezierska, E. (2021). Chymase Dependent Pathway of Angiotensin II Generation and Rapeseed Derived Peptides for Antihypertensive Treatment of Spontaneously Hypertensive Rats. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.658805"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Maheta, D., Shah, F., Biba, V., Ngardig, N.N., Agrawal, S.P., Rajput, J., Sager, A.R., Frishman, W.H., and Aronow, W.S. (2025). Zilebesiran: A Novel RNA Interference Therapeutic for Hypertension. Cardiol. Rev.","DOI":"10.1097\/CRD.0000000000000962"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1056\/NEJMoa2208391","article-title":"Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension","volume":"389","author":"Desai","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1161\/HYPERTENSIONAHA.119.12703","article-title":"Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen","volume":"73","author":"Uijl","year":"2019","journal-title":"Hypertension"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1161\/HYPERTENSIONAHA.122.18731","article-title":"Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease","volume":"79","author":"Ye","year":"2022","journal-title":"Hypertension"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1161\/ATVBAHA.121.316590","article-title":"Renal Angiotensinogen Is Predominantly Liver Derived in Nonhuman Primates","volume":"41","author":"Kukida","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Smolinska, S., Antol\u00edn-Am\u00e9rigo, D., and Popescu, F.-D. (2023). Bradykinin Metabolism and Drug-Induced Angioedema. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411649"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/jcph.2337","article-title":"Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs","volume":"64","author":"An","year":"2024","journal-title":"J. Clin. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"102","DOI":"10.36011\/cpp.2025.7.e12","article-title":"Zilebesiran: An RNA Therapeutic Agent Interfering with Angiotensinogen Synthesis","volume":"7","author":"Choi","year":"2025","journal-title":"Cardiovasc. Prev. Pharmacother."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e027694","DOI":"10.1161\/JAHA.122.027694","article-title":"Small Interfering RNA Therapeutics in Hypertension: A Viewpoint on Vasopressor and Vasopressor-Sparing Strategies for Counteracting Blood Pressure Lowering by Angiotensinogen\u2013Targeting Small Interfering RNA","volume":"11","author":"Ranasinghe","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"A116","DOI":"10.1161\/hyp.80.suppl_1.116","article-title":"Abstract 116: Safety and Tolerability of Zilebesiran, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Obese Patients with Hypertension","volume":"80","author":"Taubel","year":"2023","journal-title":"Hypertension"},{"key":"ref_115","unstructured":"(2025, September 20). A Study to Evaluate ALN-AGT01 in Patients with Hypertension, v1.0. Available online: https:\/\/www.hra.nhs.uk\/planning-and-improving-research\/application-summaries\/research-summaries\/a-study-to-evaluate-aln-agt01-in-patients-with-hypertension-v10\/."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e026426","DOI":"10.1161\/JAHA.122.026426","article-title":"Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen","volume":"11","author":"Uijl","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11906-025-01325-8","article-title":"Small Interfering RNA Therapy for the Management and Prevention of Hypertension","volume":"27","author":"Ren","year":"2025","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/hr.2013.155","article-title":"Targeting of Hepatic Angiotensinogen Using Chemically Modified siRNAs Results in Significant and Sustained Blood Pressure Lowering in a Rat Model of Hypertension","volume":"37","author":"Olearczyk","year":"2014","journal-title":"Hypertens. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"ehad655.2830","DOI":"10.1093\/eurheartj\/ehad655.2830","article-title":"Targeting Liver Angiotensinogen Using a GalNAc-siRNA Improves Cardiac Remodeling in Spontaneously Hypertensive Rats","volume":"44","author":"Liang","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1172\/JCI99417","article-title":"RNA Interference Therapeutics Targeting Angiotensinogen Ameliorate Preeclamptic Phenotype in Rodent Models","volume":"130","author":"Haase","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1161\/HYPERTENSIONAHA.118.11064","article-title":"Hypertension in Blacks: Individualized Therapy Based on Renin\/Aldosterone Phenotyping","volume":"72","author":"Spence","year":"2018","journal-title":"Hypertension"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/sj.ijo.0801217","article-title":"The Association of Human Adipose Angiotensinogen Gene Expression with Abdominal Fat Distribution in Obesity","volume":"24","author":"Elizalde","year":"2000","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/jhh.2009.48","article-title":"Angiotensinogen Promoter Variants Influence Gene Expression in Human Kidney and Visceral Adipose Tissue","volume":"24","author":"Sarzani","year":"2010","journal-title":"J. Hum. Hypertens."},{"key":"ref_124","unstructured":"Briana, D.D., and Malamitsi-Puchner, A. (2011). Apelin as an Adipokine. Adipokines, CRC Press."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"100875","DOI":"10.1016\/j.preteyeres.2020.100875","article-title":"Discovery and Clinical Translation of Novel Glaucoma Biomarkers","volume":"80","author":"Beykin","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S2213-8587(14)70256-6","article-title":"Effects of RAS Inhibitors on Diabetic Retinopathy: A Systematic Review and Meta-Analysis","volume":"3","author":"Wang","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"e626","DOI":"10.1111\/aos.13715","article-title":"Effects of microRNA-133b on Retinal Vascular Endothelial Cell Proliferation and Apoptosis through Angiotensinogen-Mediated Angiotensin II- Extracellular Signal-Regulated Kinase 1\/2 Signalling Pathway in Rats with Diabetic Retinopathy","volume":"96","author":"Liu","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_128","first-page":"61","article-title":"Study of kini-kallikrein and renin--angiotensin systems in patients with primary open angle glaucoma","volume":"53","author":"Borovic","year":"2009","journal-title":"Oftalmologia"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pharmthera.2013.11.002","article-title":"The Ocular Renin\u2013Angiotensin System: A Therapeutic Target for the Treatment of Ocular Disease","volume":"142","author":"Giese","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_130","unstructured":"(2025, September 20). Angiotensin AT1 Receptor Antagonism Normalizes Retinal Blood Flow and Acetylcholine-Induced Vasodiliation in Normotensive Diabetic Rats | Diabetologia. Available online: https:\/\/link.springer.com\/article\/10.1007\/s00125-003-1262-x."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/eye.2009.189","article-title":"Diabetic Retinopathy and Blockade of the Renin\u2013Angiotensin System: New Data from the DIRECT Study Programme","volume":"24","author":"Wright","year":"2010","journal-title":"Eye"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1161\/01.ATV.0000149377.90852.d8","article-title":"Dual Effect of Angiotensin-Converting Enzyme Inhibition on Angiogenesis in Type 1 Diabetic Mice","volume":"25","author":"Ebrahimian","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"(2025, June 30). Update on New Aspects of the Renin\u2013Angiotensin System in Liver Disease: Clinical Implications and New Therapeutic Options|Clinical Science|Portland Press. Available online: https:\/\/portlandpress.com\/clinsci\/article-abstract\/123\/4\/225\/69083\/Update-on-new-aspects-of-the-renin-angiotensin?redirectedFrom=fulltext.","DOI":"10.1042\/CS20120030"},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"(2025, June 30). The Renin\u2013Angiotensin System in Liver Disease. Available online: https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5807.","DOI":"10.3390\/ijms25115807"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"(2024). Abstract P104: Kidney Arteriolar Responses to Liver-Targeted Small Interference RNA (siRNA) Targeting Angiotensinogen in Diabetic Rats: Comparison with Other Renin-Angiotensin System Blockers. Hypertension, 81, AP104.","DOI":"10.1161\/hyp.81.suppl_1.P104"},{"key":"ref_136","unstructured":"(2025, June 30). Journal of Hypertension. Available online: https:\/\/journals.lww.com\/jhypertension\/abstract\/2022\/06001\/blood_pressure_independent_renoprotection_in.527.aspx."},{"key":"ref_137","first-page":"1450","article-title":"Tratamento Com Interfer\u00eancia de RNA: Zilebesiran o Medicamento Do Futuro","volume":"4","author":"Souza","year":"2023","journal-title":"Stud. Health Sci."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/s41581-023-00765-2","article-title":"RNA Interference for Treatment of Hypertension","volume":"19","author":"Carney","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1001\/jama.2024.0728","article-title":"RNA Interference with Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial","volume":"331","author":"Bakris","year":"2024","journal-title":"JAMA"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"A4138847","DOI":"10.1161\/circ.150.suppl_1.4138847","article-title":"Abstract 4138847: Home Blood Pressure Reductions with Zilebesiran in Patients with Mild-To-Moderate Hypertension Are Consistent with Ambulatory and Office Blood Pressure Reductions in the KARDIA-1 Study","volume":"150","author":"Zappe","year":"2024","journal-title":"Circulation"},{"key":"ref_141","unstructured":"(2025, June 26). Uncontrolled and Apparent Treatment Resistant Hypertension in the United States, 1988 to 2008 | Circulation. Available online: https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.111.030189."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1001\/jama.2025.6681","article-title":"Add-On Treatment with Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial","volume":"334","author":"Desai","year":"2025","journal-title":"JAMA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"ehae666.2593","DOI":"10.1093\/eurheartj\/ehae666.2593","article-title":"Subgroup Results from KARDIA-2: Impact of Demographic and Baseline Disease Characteristics on Zilebesiran Response in Patients with Hypertension Uncontrolled by a Standard Oral Antihypertensive","volume":"45","author":"Saxena","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"I122","DOI":"10.1161\/01.HYP.17.1_Suppl.I122","article-title":"Biohistory of Slavery and Blood Pressure Differences in Blacks Today. A Hypothesis","volume":"17","author":"Wilson","year":"1991","journal-title":"Hypertension"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Zilbermint, M., Hannah-Shmouni, F., and Stratakis, C.A. (2019). Genetics of Hypertension in African Americans and Others of African Descent. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051081"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1161\/HYPERTENSIONAHA.113.02989","article-title":"Racial Differences in Sensitivity of Blood Pressure to Aldosterone","volume":"63","author":"Tu","year":"2014","journal-title":"Hypertension"},{"key":"ref_147","first-page":"e77607","article-title":"Safety and Efficacy of Novel RNA Interference Therapeutic Agent Zilebesiran in People with Hypertension: A Systematic Review and Meta-Analysis","volume":"17","author":"Singh","year":"2025","journal-title":"Cureus"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1","DOI":"10.11648\/j.ejpm.20221001.11","article-title":"Factors of Uncontrolled Blood Pressure in Hypertensive Patients with Chronic Kidney Disease in the City of Boma","volume":"10","author":"Nimi","year":"2022","journal-title":"Eur. J. Prev. Med."},{"key":"ref_149","unstructured":"Alnylam Pharmaceuticals (2025, October 30). A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Adult Patients with High Cardiovascular Risk and Hypertension Not Adequately Controlled by Standard of Care Antihypertensive Medications, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06272487."},{"key":"ref_150","unstructured":"(2025, September 20). Alnylam to Advance Zilebesiran into Global Phase 3 Cardiovascular Outcomes Trial | AFP. Available online: https:\/\/www.afp.com\/pt\/node\/3792013."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.amjms.2016.10.005","article-title":"Effects of Amlodipine and Valsartan on Blood Pressure Variability and Pulse Wave Velocity in Hypertensive Patients","volume":"353","author":"Shi","year":"2017","journal-title":"Am. J. Med. Sci."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ymgme.2022.01.002","article-title":"Givosiran in Acute Intermittent Porphyria: A Personalized Medicine Approach","volume":"135","author":"Poli","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_153","unstructured":"(2012). Lumasiran. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, National Institute of Diabetes and Digestive and Kidney Diseases."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1474-4422(20)30368-9","article-title":"Long-Term Safety and Efficacy of Patisiran for Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy: 12-Month Results of an Open-Label Extension Study","volume":"20","author":"Adams","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1038\/s44161-023-00347-2","article-title":"Current and Future Strategies for Targeting the Endothelin Pathway in Cardiovascular Disease","volume":"2","author":"Abraham","year":"2023","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s40119-021-00233-7","article-title":"Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension","volume":"10","author":"Angeli","year":"2021","journal-title":"Cardiol. Ther."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1124\/jpet.118.253864","article-title":"Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension","volume":"368","author":"Trensz","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s11886-025-02262-3","article-title":"Endothelin Receptor Antagonists for the Treatment of Hypertension: Recent Data from Clinical Trials and Implementation Approach","volume":"27","author":"Manickavasagar","year":"2025","journal-title":"Curr. Cardiol. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10717\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T12:19:13Z","timestamp":1762258753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":158,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110717"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110717","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]}}}