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

Class

RNAi / siRNA (GalNAc-conjugated, extended-duration)

Pathway

Silences hepatic LPA mRNA, durably lowering lipoprotein(a) production

The LPA gene encodes apolipoprotein(a), the distinctive protein component of lipoprotein(a), or Lp(a), a cholesterol-carrying particle related to low-density lipoprotein (LDL). Lp(a) levels are determined almost entirely by genetics rather than diet, exercise, or standard cholesterol-lowering drugs, and elevated levels are an independent, causal contributor to atherosclerotic cardiovascular disease and to calcific narrowing of the aortic valve. Because apolipoprotein(a) carries pro-inflammatory and pro-thrombotic oxidized lipid cargo and structurally resembles plasminogen, high circulating amounts are thought to promote plaque formation and interfere with normal clot-dissolving processes. Since existing therapies do not meaningfully lower Lp(a), interest has grown in directly suppressing its hepatic production. This mechanism uses small interfering RNA (siRNA) chemically linked to a sugar molecule (GalNAc) that directs the drug to liver cells, where it degrades the messenger RNA transcribed from the LPA gene before it can be translated into apolipoprotein(a) protein. Lowering apolipoprotein(a) synthesis reduces assembly and secretion of complete Lp(a) particles. Because the modified siRNA persists within liver cells, its effect on Lp(a) production can last for months after a single dose, distinguishing it from therapies requiring frequent administration.