Meganuclease Targeting of PCSK9 in Macaque Liver Leads to Stable Reduction in Serum Cholesterol

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2018 Jul 10

PMID 29985478

Citations 65

Authors

Lili Wang

Jeff Smith

Camilo Breton

Peter Clark

Jia Zhang

Lei Ying

Yan Che

Janel Lape

Peter Bell

Roberto Calcedo

Elizabeth L Buza

Alexei Saveliev

Victor V Bartsevich

Zhenning He

John White

Mingyao Li

Derek Jantz

James M Wilson

Affiliations

Soon will be listed here.

Abstract

Clinical translation of in vivo genome editing to treat human genetic diseases requires thorough preclinical studies in relevant animal models to assess safety and efficacy. A promising approach to treat hypercholesterolemia is inactivating the secreted protein PCSK9, an antagonist of the LDL receptor. Here we show that single infusions in six non-human primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. Animals experienced transient, asymptomatic elevations of serum transaminases owing to the formation of T cells against the transgene product. Vector DNA and meganuclease expression declined rapidly, leaving stable populations of genome-edited hepatocytes. A second-generation PCSK9-specific meganuclease showed reduced off-target cleavage. These studies demonstrate efficient, physiologically relevant in vivo editing in non-human primates, and highlight safety considerations for clinical translation.

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