Oxidase-deficient Neutrophils from X-linked Chronic Granulomatous Disease IPS Cells: Functional Correction by Zinc Finger Nuclease-mediated Safe Harbor Targeting

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2011 Mar 18

PMID 21411759

Citations 129

Authors

Jizhong Zou

Colin L Sweeney

Bin-Kuan Chou

Uimook Choi

Jason Pan

Hongmei Wang

Sarah N Dowey

Linzhao Cheng

Harry L Malech

Affiliations

Soon will be listed here.

Abstract

We have developed induced pluripotent stem cells (iPSCs) from a patient with X-linked chronic granulomatous disease (X-CGD), a defect of neutrophil microbicidal reactive oxygen species (ROS) generation resulting from gp91(phox) deficiency. We demonstrated that mature neutrophils differentiated from X-CGD iPSCs lack ROS production, reproducing the pathognomonic CGD cellular phenotype. Targeted gene transfer into iPSCs, with subsequent selection and full characterization to ensure no off-target changes, holds promise for correction of monogenic diseases without the insertional mutagenesis caused by multisite integration of viral or plasmid vectors. Zinc finger nuclease-mediated gene targeting of a single-copy gp91(phox) therapeutic minigene into one allele of the "safe harbor" AAVS1 locus in X-CGD iPSCs without off-target inserts resulted in sustained expression of gp91(phox) and substantially restored neutrophil ROS production. Our findings demonstrate how precise gene targeting may be applied to correction of X-CGD using zinc finger nuclease and patient iPSCs.

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