Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models

• DOI: 10.1161/circulationaha.122.062132
• Publication Date: 2022-10-31T09:00:31Z
• Authors: Richard G. Lee; Anne Marie Mazzola; Maurine C. Braun; Colin Platt; Scott B. Vafai; Sekar Kathiresan; Ellen Rohde; Andrew M. Bellinger; Amit V. Khera
• Keywords: PCSK9; Tolerability

VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test efficacy, durability, tolerability, potential for germline editing of studies nonhuman primates murine F1 progeny study.Cynomolgus monkeys were given intravenous infusion vehicle control (n=10) or at dose 0.75 mg/kg (n=4) 1.5 (n=22) with subsequent follow-up up 476 days. Two assessed editing, including sequencing sperm samples from sexually mature male treated genotyping offspring female mice surrogate (VERVE-101mu).Liver biopsies 14 days after dosing noted mean 46% 70% mg/kg, respectively. This translated into reductions blood (proprotein convertase subtilisin/kexin type 9) 67% 83% cholesterol 49% 69% doses, respectively, as time-weighted average change baseline between day 28 dosing. Liver safety monitoring transient rise alanine aminotransferase aspartate concentrations that fully resolved by no accompanying total bilirubin. In subset necropsied 1 year dosing, findings related identified on macroscopic histopathologic assessment liver other organs. study assess primates, collected showed evidence editing. Among 436 saturating VERVE-101mu, edit was transmitted 0 animals.VERVE-101 well tolerated led durable effects These results have supported initiation first-in-human clinical trial patients heterozygous familial hypercholesterolemia atherosclerotic cardiovascular disease.