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Review
. 2020 Jan 3;5(1):1.
doi: 10.1038/s41392-019-0089-y.

Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects

Hongyi Li  1 , Yang Yang  1 , Weiqi Hong  2 , Mengyuan Huang  2 , Min Wu  3 , Xia Zhao  4
Affiliations
Review

Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects

Hongyi Li et al. Signal Transduct Target Ther. .

Abstract

Based on engineered or bacterial nucleases, the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells. Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields, ranging from basic research to applied biotechnology and biomedical research. Recent progress in developing programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases, has greatly expedited the progress of gene editing from concept to clinical practice. Here, we review recent advances of the three major genome editing technologies (ZFNs, TALENs, and CRISPR/Cas9) and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies, focusing on eukaryotic cells and animal models. Finally, we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Genome editing platforms and mechanisms for DSB repair with endogenous DNA. Genome editing nucleases (ZFNs, TALENs and CRISPR/Cas9) induce DSBs at targeted sites. DSBs can be repaired by NHEJ or, in the presence of donor template, by HDR. Gene disruption by targeting the locus with NHEJ leads to the formation of indels. When two DSBs target both sides of a pathogenic amplification or insertion, a therapeutic deletion of the intervening sequences can be created, leading to NHEJ gene correction. In the presence of a donor-corrected HDR template, HDR gene correction or gene addition induces a DSB at the desired locus. DSB double-stranded break, ZFN zinc-finger nuclease, TALEN transcription activator-like effector nuclease, CRISPR/Cas9 clustered regularly interspaced short palindromic repeat associated 9 nuclease, NHEJ nonhomologous end-joining, HDR homology-directed repair.
Fig. 2
Fig. 2
Ex vivo and in vivo genome editing for clinical therapy. Right: For in ex vivo editing therapy, cells are isolated from a patient to be treated, edited and then re-engrafted back to the patient. To achieve therapeutic success, the target cells must be able to survive in vitro and return to the target tissue after transplantation. Left: For in vivo editing therapy, engineered nucleases are delivered by viral or nonviral approaches and directly injected into the patient for systemic or targeted tissue (such as the eye, brain, or muscle) effect.
Fig. 3
Fig. 3
Production of CAR T cell products with genome editing technology.
Fig. 4
Fig. 4
Viral and nonviral delivery systems for genome editing technology. The most commonly used viral vectors include adeno-associated viruses (AAVs), lentiviruses and adenoviruses (AdVs). Nonviral physical methods can be used for genome editing to deliver biomacromolecules intracellularly without the use of nanoparticles. Nonviral delivery may be microinjections in vitro, direct injection into the embryo or zygote ex vivo, or hydrodynamic injection in vivo. Alternatively, electroporation or mechanical deformation realize delivery by creating transient pores in the cellular membrane, making entry points for genome editing biomacromolecules.
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