LPA gene / apolipoprotein(a) mRNA

Class

GalNAc-conjugated siRNA (Lp(a)-lowering RNAi therapeutic)

Pathway

Hepatocyte uptake via asialoglycoprotein receptor; antisense strand loaded into RISC degrades LPA mRNA, preventing apo(a) synthesis and reducing circulating Lp(a)

Lipoprotein(a), or Lp(a), is a low-density-lipoprotein-like particle that carries a distinctive protein, apolipoprotein(a), attached to apolipoprotein B-100. Elevated plasma Lp(a) is an independent, largely genetically determined risk factor for atherosclerotic cardiovascular disease and aortic valve calcification, and unlike LDL cholesterol, its concentration is minimally responsive to diet, exercise, or most existing lipid-lowering drugs, being set predominantly by the LPA gene. This mechanism targets the root cause: the LPA gene transcript that encodes apolipoprotein(a) in liver cells (hepatocytes). Using RNA interference, a synthetic small interfering RNA is chemically linked to a GalNAc (N-acetylgalactosamine) sugar cluster, which binds the asialoglycoprotein receptor expressed almost exclusively on liver cells, driving selective hepatocyte uptake. Inside the cell, one strand of the siRNA loads into the RNA-induced silencing complex (RISC), guiding it to cleave LPA mRNA before it can be translated into protein. With less apolipoprotein(a) produced, assembly and secretion of new Lp(a) particles decline, lowering circulating levels. Because the approach acts upstream of protein synthesis and is confined to a single gene's message, it offers a route to durable Lp(a) reduction that is largely independent of cholesterol-lowering pathways, relevant to residual cardiovascular risk not addressed by statins or other lipid therapies.