In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering

Circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins are leading risk factors for atherosclerotic cardiovascular disease 1 . Despite several approved lipid-lowering medications, most patients fail to achieve target lipid levels under the chronic care treatment model 2,3 . Here, we describe a potential single-course treatment in which an infusion of guide RNA and mRNA encoding a CRISPR adenine base editor-encapsulated within a GalNAc-lipid nanoparticle-leads to durable, liver-selective inactivation of angiopoietin-like 3 (ANGPTL3), a known driver of increased LDL-C and triglyceride concentrations. Analyses in human liver cells in vitro confirmed that the base editor introduces a DNA base-pair change at the target ANGPTL3 locus with no detectable off-target editing at any of approximately 3000 candidate sites or treatment-related structural variants. Targeted ANGPTL3 inactivation in nonhuman primates was well-tolerated and led to a > 90% mean reduction in circulating ANGPTL3 protein, with durability confirmed out to 3 years following a single dose. In mouse and nonhuman primate models of hyperlipidemia, gene inactivation was associated with reductions of approximately 40 to 50% in LDL-C and 50 to 70% in triglycerides. These results provided the scientific foundation for initiation of an ongoing first-in-human clinical trial in patients with refractory hyperlipidemia syndromes.

Abstract from PubMed (PMID 42994815). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.