Zinc-Finger Nucleases for Somatic Gene Therapy by Rahman
HUMAN GENE THERAPY 22:1–10 (August 2011) ª Mary Ann Liebert, Inc. DOI: 10.1089/hum.2011.087
Review
Zinc-Finger Nucleases for Somatic Gene Therapy: The Next Frontier
1 Shamim H. Rahman, Morgan L. Maeder,2,3 J. Keith Joung,2,3,4 and Toni Cathomen1
Abstract
Zinc-finger nucleases (ZFNs) are a powerful tool that can be used to edit the human genome ad libitum. The technology has experienced remarkable development in the last few years with regard to both the target site specificity and the engineering platforms used to generate zinc-finger proteins. As a result, two phase I clinical trials aimed at knocking out the CCR5 receptor in T cells isolated from HIV patients to protect these lymphocytes from infection with the virus have been initiated. Moreover, ZFNs have been successfully employed to knockout or correct disease-related genes in human stem cells, including hematopoietic precursor cells and induced pluripotent stem cells. Targeted genome engineering approaches in multipotent and pluripotent stem cells hold great promise for future strategies geared toward correcting inborn mutations for personalized cell replacement therapies. This review describes how ZFNs have been applied to models of gene therapy, discusses the opportunities and the risks associated with this novel technology, and suggests future directions for their safe application in therapeutic genome engineering.
Introduction
S
ince Rogers’s proposal in the 1970s to use ‘‘exogenous ‘good’ DNA to replace the defective DNA in those who suffer from genetic defects’’ (Friedmann and Roblin, 1972), a wide variety of technologies enabling gene transfer have emerged from different fields of science, including chemistry, physics, biology, and virology. The first successful gene therapy clinical trial aimed at the phenotypic correction of X-linked severe combined immunodeficiency (SCID-X1) was published in 2000 (Cavazzana-Calvo et al., 2000). This study was based on retroviral transfer of a
Review
Zinc-Finger Nucleases for Somatic Gene Therapy: The Next Frontier
1 Shamim H. Rahman, Morgan L. Maeder,2,3 J. Keith Joung,2,3,4 and Toni Cathomen1
Abstract
Zinc-finger nucleases (ZFNs) are a powerful tool that can be used to edit the human genome ad libitum. The technology has experienced remarkable development in the last few years with regard to both the target site specificity and the engineering platforms used to generate zinc-finger proteins. As a result, two phase I clinical trials aimed at knocking out the CCR5 receptor in T cells isolated from HIV patients to protect these lymphocytes from infection with the virus have been initiated. Moreover, ZFNs have been successfully employed to knockout or correct disease-related genes in human stem cells, including hematopoietic precursor cells and induced pluripotent stem cells. Targeted genome engineering approaches in multipotent and pluripotent stem cells hold great promise for future strategies geared toward correcting inborn mutations for personalized cell replacement therapies. This review describes how ZFNs have been applied to models of gene therapy, discusses the opportunities and the risks associated with this novel technology, and suggests future directions for their safe application in therapeutic genome engineering.
Introduction
S
ince Rogers’s proposal in the 1970s to use ‘‘exogenous ‘good’ DNA to replace the defective DNA in those who suffer from genetic defects’’ (Friedmann and Roblin, 1972), a wide variety of technologies enabling gene transfer have emerged from different fields of science, including chemistry, physics, biology, and virology. The first successful gene therapy clinical trial aimed at the phenotypic correction of X-linked severe combined immunodeficiency (SCID-X1) was published in 2000 (Cavazzana-Calvo et al., 2000). This study was based on retroviral transfer of a