Lipoprotein(a) [Lp(a)] production pathway

Class

GalNAc-conjugated siRNA / gene-silencing therapy (Argo Biopharma; co-developed as DII235 with Novartis in later-stage trials)

Pathway

Liver-directed gene silencing to reduce Lp(a) production in patients with established atherosclerotic cardiovascular disease

Notes

original target text: Lipoprotein(a) [Lp(a)] production pathway (liver-directed; exact gene target not disclosed in available sources)

Lipoprotein(a), abbreviated Lp(a), is a particle in the blood similar to low-density lipoprotein (LDL, often called "bad cholesterol") but carrying an extra protein component, apolipoprotein(a). Blood levels of Lp(a) are set largely by inheritance and change little with diet or exercise. Elevated Lp(a) is now recognized as an independent, causal contributor to atherosclerotic cardiovascular disease and to calcification of the aortic valve, likely through effects that promote plaque buildup, inflammation, and clot formation. Because Lp(a) is produced almost entirely by the liver, one therapeutic strategy is to reduce hepatic production directly rather than to remove particles once they are already in circulation. Gene-silencing therapies use RNA interference (RNAi), delivered specifically to liver cells through a chemical tag called GalNAc that is recognized by a receptor found mainly on hepatocytes, to destroy the messenger RNA needed to manufacture the components of the Lp(a) particle before it can be assembled and released. This approach is being studied in people who already have established atherosclerotic cardiovascular disease and elevated Lp(a), with the goal of lowering a genetically driven risk factor that is not addressed by standard cholesterol-lowering treatments.