Targeting hepatic angiotensinogen with N-acetylgalactosamine-conjugated siRNA represents a novel approach to block the RAS pathway and manage hypertension with dosing 1 to 2 times per year.
Does targeting angiotensinogen with N-acetylgalactosamine-conjugated small interfering RNA reduce blood pressure compared to classical RAS blockade?
Targeting hepatic angiotensinogen with siRNA offers a novel, long-acting approach to hypertension management that may overcome poor adherence and the RAS escape phenomenon.
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.
Ye et al. (Thu,) conducted a review in Hypertension. N-acetylgalactosamine-conjugated small interfering RNA targeting AGT vs. Classical RAS blockade or antisense oligonucleotides was evaluated. Targeting hepatic angiotensinogen with N-acetylgalactosamine-conjugated siRNA represents a novel approach to block the RAS pathway and manage hypertension with dosing 1 to 2 times per year.