PCSK9 gene (hepatocyte genomic DNA)

Class

In vivo CRISPR adenine base-editing therapeutic (lipid nanoparticle-delivered)

Pathway

Base-edits and permanently disrupts the PCSK9 gene in hepatocytes, lowering circulating PCSK9 and durably reducing LDL-C

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a liver protein that binds the LDL receptor on hepatocyte surfaces and marks it for degradation, reducing the liver's capacity to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream. People with naturally occurring loss-of-function variants in PCSK9 have lifelong low LDL-C and markedly reduced rates of atherosclerotic cardiovascular disease, which established PCSK9 loss as a validated strategy for cholesterol lowering. This mechanism pursues that same biological outcome through in vivo gene editing rather than a drug that transiently blocks the protein. A lipid nanoparticle carries an adenine base editor and guide RNA into hepatocytes, where it chemically converts a single DNA base pair within the PCSK9 gene, permanently disrupting its ability to produce functional protein. Because the edit is made directly in genomic DNA, the resulting reduction in circulating PCSK9 and LDL-C is intended to be durable after a single administration, in contrast to antibody or RNA-based therapies that require repeated dosing to sustain their effect. This approach is relevant to cardiovascular disease prevention, particularly for lifelong LDL-C reduction in people at elevated risk of atherosclerotic events.