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Editorial
. 2014 Aug;18(8):835-9.
doi: 10.1517/14728222.2014.913572. Epub 2014 Jun 11.

Activating Human Genes With Zinc Finger Proteins, Transcription Activator-Like Effectors and CRISPR/Cas9 for Gene Therapy and Regenerative Medicine

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Editorial

Activating Human Genes With Zinc Finger Proteins, Transcription Activator-Like Effectors and CRISPR/Cas9 for Gene Therapy and Regenerative Medicine

Charles A Gersbach et al. Expert Opin Ther Targets. .
Free PMC article

Abstract

New technologies have recently been developed to control the expression of human genes in their native genomic context by engineering synthetic transcription factors that can be targeted to any DNA sequence. The ability to precisely regulate any gene as it occurs naturally in the genome provides a means to address a variety of diseases and disorders. This approach also circumvents some of the traditional challenges of gene therapy. In this editorial, we review the technologies that have enabled targeted human gene activation, including the engineering of transcription factors based on zinc finger proteins, transcription activator-like effectors and the CRISPR/Cas9 system. Additionally, we highlight examples in which these methods have been developed for therapeutic applications and discuss challenges and opportunities.

Keywords: CRISPR; Cas9; gene editing; gene regulation; gene therapy; genetic reprogramming; protein engineering; transcription activator-like effector; transcription factor; zinc finger.

Figures

Figure 1
Figure 1
Technologies for engineering programmable DNA-binding proteins, including (A) zinc finger proteins, (B) TALEs, and (C) CRISPR/Cas9. (Top) Representative crystal structures of a (A) zinc finger protein (PDB 1P47) or (B) TALE (PDB UGM) fused to the p65 transcriptional activation domain (PDB 2RAM), or (C) Cas9 (green) bound to a gRNA (blue) and the corresponding DNA target site (brown) (PDB 4OO8). (Bottom) Zinc finger proteins and TALEs recognize their target sequences through non-covalent protein-DNA interactions between 3 bp or 1 bp per repeat domain, respectively. The CRISPR system consists of a complex of the gRNA and the Cas9 protein that recognizes its genomic target sequence by complementary base pairing of the gRNA (spheres) to the chromosomal DNA.

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