In Vivo Base Editing of PCSK9 With VERVE-102 for Hypercholesterolemia

In this article, the authors report interim results of Heart 2, a phase 1, open label, single ascending dose study of VERVE 102, a GalNAc lipid nanoparticle delivering mRNA for an adenine base editor and guide RNA targeting a proprotein convertase subtilisin–kexin type 9 (PCSK9) intron 1 splice site. Thirty-five adults with heterozygous familial hypercholesterolemia or premature coronary artery disease received 0.3 to 1.0 mg/kg intravenously. The median follow–up was approximately nine months, with 15 patients followed for at least one year. No dose–limiting toxicity, deaths, or withdrawals occurred. Infusion reactions were grade 1 to 2, and alanine aminotransferase (ALT) elevations were transient. At 1.0 mg/kg, PCSK9 and low-density lipoprotein (LDL) cholesterol fell by 88 percent and 62 percent, respectively, corresponding to a 78 mg/dL LDL reduction.