Targeting angiotensinogen with RNA-based therapeutics

Abstract

Purpose of review To summarize all available data on targeting angiotensinogen with RNA-based therapeutics as a new tool to combat cardiovascular diseases. Recent findings Liver-targeted, stable antisense oligonucleotides and small interfering RNA targeting angiotensinogen are now available, and may allow treatment with at most a few injections per year, thereby improving adherence. Promising results have been obtained in hypertensive animal models, as well as in rodent models of atherosclerosis, polycystic kidney disease and pulmonary fibrosis. The next step will be to evaluate the optimal degree of suppression, synergy with existing renin-angiotensin-aldosterone system blockers, and to determine harmful effects of suppressing angiotensinogen in the context of common comorbidities, such as heart failure and chronic kidney disease.

Assessing the efficacy and safety of angiotensinogen inhibition using human genetics

“…in GTEx, liver tissue only had 153 samples, vs. 491 samples for skeletal muscle, where we did find evidence of colocalisation). However, sensitivity analysis using a variant associated with circulating AGT protein concentration, which is mainly liver-derived, 8 yielded similar estimates to that of our instrument. In light of this and recent data showing that ALN-AGT01 lowers circulating AGT levels 68 , our findings are likely to be of relevance to these novel therapies.…”

“…At least two AGT-blocking biopharmaceutical agents are currently under development. 8 These agents, an RNA interference (RNAi)-based therapy (ALN-AGT01) and an antisense oligonucleotide (ASO)-based therapy (IONIS-AGT-LRx), act by blocking translation of AGT messenger RNA (mRNA), thereby reducing the amount AGT protein produced. These therapeutic approaches allow for less frequent administration, which may offer benefits in terms of adherence and cardiovascular risk reduction, when compared to existing orally-administered small molecule-based antihypertensives.…”

“…These therapeutic approaches allow for less frequent administration, which may offer benefits in terms of adherence and cardiovascular risk reduction, when compared to existing orally-administered small molecule-based antihypertensives. 8 By way of example, recent clinical trials of inclisiran, an RNA-based inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), have shown that six monthly injection of this agent leads to sustained reductions in LDL cholesterol, 9 which suggests that this approach may provide a means by which adherence is improved. Inhibition of AGT—the most proximal protein in the RAS pathway—may also avoid counterregulatory mechanisms that attenuate the BP-lowering effects of other RAS pathway targeting-drugs.…”

“…Inhibition of AGT—the most proximal protein in the RAS pathway—may also avoid counterregulatory mechanisms that attenuate the BP-lowering effects of other RAS pathway targeting-drugs. 8…”

The emerging role of angiotensinogen in cardiovascular diseases

“…However, the contribution of AGT to cardiovascular diseases gained less attention. Encouragingly, the development of many novel techniques including the creation of the cell‐specific genetic mice models, as well as antisense oligonucleotides (ASO; C. H. Wu et al, 2019) or RNA‐based therapeutics targeting specific organs (Ren, Colafella, Bovee, Uijl, & Danser, 2020) can provide new insights into understanding AGT and its contributions to cardiovascular diseases.…”