In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering.

A single-course GalNAc-lipid nanoparticle infusion delivering a CRISPR adenine base editor mRNA and guide RNA achieves durable, liver-selective ANGPTL3 inactivation with >90% ANGPTL3 protein reduction lasting up to 3 years in nonhuman primates.

• Why it matters: Chronic lipid-lowering therapy often fails to reach LDL-C and triglyceride targets, so a durable, single-treatment approach targeting a key lipid driver like ANGPTL3 is needed.
• What they did: The authors tested base editing in human liver cells for on-target DNA base-pair change at the ANGPTL3 locus and assessed safety by checking ~3000 candidate off-target sites and treatment-related structural variants; they then dosed nonhuman primates and evaluated lipid outcomes in mouse and nonhuman primate hyperlipidemia models.
• The result: ANGPTL3 inactivation was well-tolerated and reduced circulating ANGPTL3 protein by >90% with durability to 3 years; in hyperlipidemia models it was linked to ~40–50% LDL-C and 50–70% triglyceride reductions, supporting a first-in-human trial.

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