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Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease.

Abstract：

:We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger nucleases (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, gene editing is applied ex vivo in T cells, transgenic T cell receptor (tTCR)-T cells, or chimeric antigen receptor (CAR)-T cells to improve adoptive cell therapy for multiple cancer types. This involves knockouts of immune checkpoint regulators such as PD-1, components of the endogenous TCR and histocompatibility leukocyte antigen (HLA) complex to generate universal allogeneic CAR-T cells, and CD7 to prevent self-destruction in adoptive cell therapy. In cervix carcinoma caused by human papillomavirus (HPV), E6 and E7 genes are disrupted using topically applied gene editing machinery. In HIV infection, the CCR5 co-receptor is disrupted ex vivo to generate HIV-resistant T cells, CAR-T cells, or hematopoietic stem cells. In β-thalassemia and sickle cell disease, hematopoietic stem cells are engineered ex vivo to induce the production of fetal hemoglobin. AAV-mediated in vivo gene editing is applied to exploit the liver for systemic production of therapeutic proteins in hemophilia and mucopolysaccharidoses, and in the eye to restore splicing of the CEP920 gene in Leber's congenital amaurosis. Close consideration of safety aspects and education of stakeholders will be essential for a successful implementation of gene editing technology in the clinic.

journal_name

Mol Ther Methods Clin Dev

journal_title

Molecular therapy. Methods & clinical development

authors

Ernst MPT,Broeders M,Herrero-Hernandez P,Oussoren E,van der Ploeg AT,Pijnappel WWMP

doi

10.1016/j.omtm.2020.06.022

subject

Has Abstract

pub_date

2020-07-03 00:00:00

pages

532-557

issn

2329-0501

pii

S2329-0501(20)30146-7

journal_volume

18

pub_type

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