Angiotensinogen (AGT) / PCSK9 (dual)

Class

Dual-target GalNAc-conjugated siRNA (AGT + PCSK9 silencing)

Angiotensinogen (AGT) and PCSK9 are two liver-produced proteins that independently drive major cardiovascular risk factors. AGT is the sole precursor from which the renin-angiotensin-aldosterone system (RAAS) generates angiotensin II, a peptide that raises blood pressure by constricting blood vessels and promoting sodium retention. PCSK9 is a secreted protein that binds the LDL receptor on liver cells and marks it for degradation, reducing the liver's capacity to clear LDL cholesterol from blood and thereby raising circulating LDL levels. Because both proteins are synthesized in hepatocytes and both diseases they underlie—hypertension and hyperlipidemia—commonly coexist and compound cardiovascular risk, silencing their messenger RNAs together in a single molecule is a rational strategy to address multifactorial risk with one treatment course. This is achieved using small interfering RNA (siRNA), a technology that degrades the mRNA transcripts before they can be translated into protein, conjugated to N-acetylgalactosamine (GalNAc), a sugar ligand that is efficiently taken up by a receptor expressed almost exclusively on hepatocytes. This delivery approach concentrates drug action in the liver, where both target genes are expressed, while limiting exposure elsewhere. The broader relevance of this mechanism spans cardiovascular disease prevention, particularly in settings where a durable, infrequently dosed intervention addressing more than one risk factor is desirable.