Targeting Angiotensinogen With N-Acetylgalactosamine-Conjugated Small Interfering RNA to Reduce Blood Pressure

Abstract

Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent N-acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.

Keywords: angiotensinogen; angiotensins; hepatocytes; hypertension; renin.

Figure.

Overview of the proposed mechanism of hepatocyte uptake of N-acetylgalactosamine (GalNAc) small interfering RNA (siRNA) and GalNAc antisense oligonucleotide (ASO) conjugates by ASGR (asialoglycoprotein receptor)-mediated endocytosis. Intracellular uptake by harnessing the ASGR results in the accumulation of the siRNAs and ASOs in the late endosomes, where they can reside for a prolonged period of time. Slow release of the siRNA from the late endosomes into the cytosol triggers loading of the siRNA in the RNA-induced silencing complex (RISC), which ensures hybridization to the target mRNA and subsequent mRNA cleavage and degradation. Slow release of the ASO from the late endosomes into the cytosol allows for further trafficking of the ASO inside the cell nucleus, which ensures hybridization to the target mRNA and recruitment of the RNase H nuclease for subsequent mRNA cleavage and degradation.