LPA gene mRNA (apolipoprotein(a) / lipoprotein(a))

Class

GalNAc-conjugated small interfering RNA (siRNA) — Lp(a)-targeted RNAi therapeutic

Pathway

Silences hepatic LPA mRNA translation, lowering circulating lipoprotein(a) levels

Lipoprotein(a), or Lp(a), is a cholesterol-carrying particle in the blood that resembles LDL ("bad cholesterol") but carries an extra protein called apolipoprotein(a). Blood levels of Lp(a) are set almost entirely by genetics and inheritance, and are not meaningfully changed by diet, exercise, or standard cholesterol-lowering medicines such as statins. Elevated Lp(a) is an independent, causal risk factor for atherosclerotic cardiovascular disease and for calcific narrowing of the aortic heart valve. This mechanism uses small interfering RNA (siRNA), a molecule that triggers destruction of a specific messenger RNA (mRNA) before it can be used to build protein, to reduce the liver's production of apolipoprotein(a) directly at its genetic source, the LPA gene. The siRNA is chemically attached to a sugar molecule, GalNAc, which is recognized by a receptor found almost exclusively on liver cells, directing the drug to the liver and limiting exposure elsewhere. By lowering the liver's output of apolipoprotein(a) mRNA, this approach reduces circulating Lp(a) particle numbers, addressing a genetically driven cardiovascular risk factor that existing LDL- and triglyceride-focused therapies do not effectively lower.