Rational Design and Selection of Angiotensinogen-Targeting siRNA Candidates for the Treatment of Hypertension

Advances in antisense technology for cardiovascular drug discovery: from gene silencing to therapeutics.

The principles that shape cardiovascular ASO candidate development are discussed, with emphasis on mechanism selection, chemical design, and exposure feasibility, and sequence optimization with exposure-informed target qualification and therapeutic-index engineering throughout ASO candidate selection.

Zilebesiran, a Small Interfering RNA Therapeutic Targeting Angiotensinogen: Mechanism, Clinical Evidence, Safety, and Implementation Considerations

Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway.

Emerging Nucleic Acid-Based Therapies for Hypercholesterolemia with Focus on a New Modality, Liver-Directed miR-30c Analog C2

Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3′UTR (“del2.5”) that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease.

Multitarget Regulatory Mechanisms and Research Advances of Plant-Derived Bioactive Ingredients in Hypertension Prevention and Management.

Hypertension remains a major global risk factor for cardiovascular diseases, yet current treatments face challenges such as suboptimal blood pressure control and inadequate organ protection. Plant-derived bioactive ingredients (PDBIs), with their multi-target and multi-pathway properties, offer novel strategies for hypertension management. This review systematically examines the mechanisms of major PDBIs (flavonoids, terpenoids, alkaloids) in hypertension, focusing on their regulation of vascular function, renin-angiotensin-aldosterone system and sympathetic nervous system, water-salt homeostasis, and target organ protection. Key signaling pathways involved (NF-κB, TGF-β, MAPK, PI3K/Akt) are analyzed. Clinical translation challenges, including low bioavailability and response heterogeneity, are discussed. Future research should integrate systems pharmacology, smart delivery systems, and precision medicine to advance PDBIs from traditional use to evidence-based therapy, providing a theoretical basis for developing novel antihypertensive and organ-protective strategies.

Advances in nucleotide-based P2Y₁ antagonism: implications for cardiovascular therapeutics.

Targeting RNA-Binding Oncofetal Protein IGF2BP3: Discovery of Potent and Selective Inhibitors

Beyond enabling the discovery of several new potent and selective small molecules, these studies have allowed us to elucidate key parameters for potency, selectivity, and metabolic stability that should aid future efforts in RBP drug discovery.