Verve Therapeutics: one base-editor dose cut ANGPTL3 protein by over 90% in primates for 3 years
Authors report that a CRISPR adenine base editor in a GalNAc–lipid nanoparticle inactivated liver ANGPTL3 in mice and primates; a first-in-human trial is ongoing.
Researchers at Verve Therapeutics, a wholly owned subsidiary of Eli Lilly and Company in Boston, together with colleagues from Mount Sinai and the University of Pennsylvania, describe in Nature a potential single-course approach to lowering blood lipids. An infusion of guide RNA and mRNA encoding a CRISPR adenine base editor, encapsulated in a GalNAc–lipid nanoparticle, leads to durable, liver-selective inactivation of the ANGPTL3 gene. In nonhuman primates, a single dose produced a mean reduction of more than 90% in circulating ANGPTL3 protein, with durability confirmed out to 3 years nature.com
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Target and delivery
Circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins are leading risk factors for atherosclerotic cardiovascular disease. The authors note that, despite several approved lipid-lowering medications, most patients fail to reach target lipid levels under the chronic care treatment model.
ANGPTL3 is a known driver of increased LDL-C and triglyceride concentrations. The base editor introduces a DNA base-pair change at the target ANGPTL3 locus, and the GalNAc–lipid nanoparticle is used to direct the editing to the liver.
Safety and lipid results
Analyses in human liver cells in vitro confirmed the intended base-pair change at the target locus. According to the authors, there was no detectable off-target editing at any of approximately 3000 candidate sites and no treatment-related structural variants nature.com
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Targeted ANGPTL3 inactivation in nonhuman primates was well tolerated. 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.
Stage of work
The results reported in the paper come from cell and animal studies. According to the authors, they provided the scientific foundation for starting an ongoing first-in-human clinical trial in patients with refractory hyperlipidemia syndromes.
