LPA gene / apolipoprotein(a)

Class

siRNA (small interfering RNA) targeting LPA

Pathway

RNAi-mediated silencing of hepatic LPA gene expression, decreasing apo(a) production and reducing circulating Lp(a) levels (up to ~95% reduction reported in Phase 1 interim data)

The LPA gene encodes apolipoprotein(a), a protein that attaches to a low-density lipoprotein-like particle to form lipoprotein(a), or Lp(a). Lp(a) is synthesized almost entirely in the liver, and the amount of apolipoprotein(a) produced is largely fixed by genetics rather than diet, exercise, or lifestyle. Elevated Lp(a) is an independent, causal risk factor for atherosclerotic cardiovascular disease and for calcification of the aortic valve, and unlike LDL cholesterol, it is not meaningfully lowered by statins or most existing lipid-modifying therapies. This has created interest in directly reducing hepatic production of apolipoprotein(a) at the genetic level. Small interfering RNA (siRNA) achieves this by exploiting RNA interference, a natural cellular process that degrades specific messenger RNA before it can be translated into protein. By targeting the LPA transcript, an siRNA therapeutic can reduce synthesis of apolipoprotein(a) in liver cells, lowering circulating Lp(a). Because the intervention acts upstream, at the level of gene expression rather than particle clearance, its effects can be substantial and long-lasting per dose. This mechanism is relevant broadly to cardiovascular risk reduction strategies aimed at genetically elevated Lp(a), a population for whom few pharmacological options currently exist.