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• W3039345425 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. 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. Traditionally, gene therapy relies on viral-based delivery of a protein-coding gene that either semi-randomly integrates into the genome (for retroviruses and lentiviruses) or remains as extrachromosomal DNA copy (for adeno-associated virus [AAV]).1Colella P. Ronzitti G. Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy.Mol. Ther. Methods Clin. Dev. 2017; 8: 87-104Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 2Naldini L. Gene therapy returns to centre stage.Nature. 2015; 526: 351-360Crossref PubMed Scopus (656) Google Scholar, 3Shirley J.L. de Jong Y.P. Terhorst C. Herzog R.W. Immune responses to viral gene therapy vectors.Mol. Ther. 2020; 28: 709-722Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar These forms of gene therapy usually use overexpression of a protein that is missing or mutated in human disease. Lentiviral gene therapy has the advantage of being highly efficient and causing long-term efficacy. A drawback of lentiviral gene therapy is the lack of control of the location at which the virus integrates into the host genome, with the risk of insertional mutagenesis. By optimizing the lentiviral backbone and by controlling the number of viral copies, it has been demonstrated in multiple clinical trials that lentiviral gene therapy is safe provided that it is used with the proper precautions.2Naldini L. Gene therapy returns to centre stage.Nature. 2015; 526: 351-360Crossref PubMed Scopus (656) Google Scholar,4Rainov N.G. Ren H. Clinical trials with retrovirus mediated gene therapy—what have we learned?.J. Neurooncol. 2003; 65: 227-236Crossref PubMed Scopus (84) Google Scholar AAV-mediated gene therapy does not rely on integration into the host genome but instead involves delivery of a DNA episome to the nucleus. It is therefore considered to have a lower risk of genotoxicity compared to lentiviral gene therapy. However, episomal copies of AAV DNA are lost upon cell division, resulting in loss of efficacy. This restricts AAV gene therapy to nondividing cells. In addition, pre-existing immunity to AAV capsid proteins occurs in a significant percentage of the human population and precludes eligibility for the treatment.5Ronzitti G. Gross D.A. Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors.Front. Immunol. 2020; 11: 670Crossref PubMed Scopus (18) Google Scholar Acquired immunity after a single AAV-mediated gene therapy treatment occurs invariably in patients and precludes eligibility for a second treatment. In both forms of gene therapy, cDNA overexpression can only be used when dosage effects of the transgene product do not apply. Although the desired average number of gene copies can be approached via the viral titer, it is not possible to precisely control this using viral-based overexpression. Developments in recent years have enabled the seamless engineering of the human genome using a variety of tools collectively termed gene editing. Precision gene editing strategies allow alteration of the genome of cells at specific loci to generate targeted genomic changes, which are being exploited for multiple applications in medicine. We first introduce the basics of gene editing and then summarize the major challenges for their clinical implementation. Gene editing tools that are currently under investigation in clinical trials include zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered interspaced short palindromic repeats (CRISPR) in combination with CRISPR-associated protein (Cas). For a detailed comparison between these tools, we refer to previously published reviews.6Gaj T. Gersbach C.A. Barbas 3rd, C.F. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering.Trends Biotechnol. 2013; 31: 397-405Abstract Full Text Full Text PDF PubMed Scopus (1987) Google Scholar,7Broeders M. Herrero-Hernandez P. Ernst M.P.T. van der Ploeg A.T. Pijnappel W.W.M.P. Sharpening the molecular scissors: advances in gene-editing technology.iScience. 2020; 23: 100789Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In short, target site recognition occurs by sequence-specific DNA-binding proteins (in the case of ZFNs and TALENs) or by a short stretch of RNA termed single guide RNA (sgRNA; in the case of CRISPR-Cas). Current clinical applications of gene editing rely on the introduction of double-strand DNA breaks (DSBs), mediated by Fok-1 (in the case of ZFNs or TALENs) or by Cas nucleases (in the case of CRISPR-Cas) and the introduction of desired genomic alterations through the cell’s endogenous DNA repair mechanisms. Two major DNA repair pathways are being exploited to conduct targeted genomic changes in clinical trials: (1) gene editing through homology-directed repair (HDR) used to replace a pathogenic variant or insert foreign DNA elements to restore the wild-type (WT) expression of a missing (or truncated) gene; and (2) non-homologous end joining (NHEJ) used to remove DNA elements leading to aberrant expression of genes or to gain a therapeutic function. In contrast to traditional strategies for gene therapy, gene editing provides more versatile tools for gene therapy, for example to precisely correct point variants,8Komor A.C. Kim Y.B. Packer M.S. Zuris J.A. Liu D.R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.Nature. 2016; 533: 420-424Crossref PubMed Scopus (1330) Google Scholar,9Gaudelli N.M. Komor A.C. Rees H.A. Packer M.S. Badran A.H. Bryson D.I. Liu D.R. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage.Nature. 2017; 551: 464-471Crossref PubMed Scopus (899) Google Scholar to place an extra, healthy gene copy at a safe genomic location of choice (a safe harbor: a location in the human genome at which integration of a gene is not harmful),10Sadelain M. Papapetrou E.P. Bushman F.D. Safe harbours for the integration of new DNA in the human genome.Nat. Rev. Cancer. 2011; 12: 51-58Crossref PubMed Scopus (249) Google Scholar,11van der Wal E. Herrero-Hernandez P. Wan R. Broeders M. In ’t Groen S.L.M. van Gestel T.J.M. van IJcken W.F.J. Cheung T.H. van der Ploeg A.T. Schaaf G.J. Pijnappel W.W.M.P. Large-scale expansion of human iPSC-derived skeletal muscle cells for disease modeling and cell-based therapeutic strategies.Stem Cell Reports. 2018; 10: 1975-1990Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar or to disrupt a gene. This would, for example, enable the restoration of endogenous expression levels following precise correction of the disease-associated variant within the natural locus, which would be especially important for gene products for which a correct dosage is required. It would also increase control of integration sites of a cDNA by choosing appropriate safe harbor locations. Such locations also should provide efficient transcription of the transgene by providing a favorable epigenetic environment consisting of euchromatin. Examples of safe harbor locations in the human genome are the albumin, AAVS1, and the CCR5 loci. Although the technology for gene editing is rapidly evolving, there are still important challenges for its clinical implementation. First, undesired editing of genomic regions can occur as a side effect of gene editing.7Broeders M. Herrero-Hernandez P. Ernst M.P.T. van der Ploeg A.T. Pijnappel W.W.M.P. Sharpening the molecular scissors: advances in gene-editing technology.iScience. 2020; 23: 100789Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar This can be off-target, i.e., the introduction of a DNA break outside the genomic region of choice due to the targeting of the gene editing machinery to a chromosomal location that carries sequence similarity to the region of interest. In this scenario, genes or regulatory regions other than the targeted gene can be modified, resulting in undesired downstream effects. Undesired events may include insertions, deletions, and chromosomal translocations.12Hsu P.D. Scott D.A. Weinstein J.A. Ran F.A. Konermann S. Agarwala V. Li Y. Fine E.J. Wu X. Shalem O. et al.DNA targeting specificity of RNA-guided Cas9 nucleases.Nat. Biotechnol. 2013; 31: 827-832Crossref PubMed Scopus (2369) Google Scholar,13Kosicki M. Tomberg K. Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements.Nat. Biotechnol. 2018; 36: 765-771Crossref PubMed Scopus (38) Google Scholar Undesired variants can also be generated on-target, i.e., unintended modification of the genomic region of interest. In this scenario, regulatory elements within the gene of interest may be unintentionally changed. This may include elements involved in promoter activity, splicing, mRNA stability, protein translation, or microRNA (miRNA) genes (that are often present in introns or untranslated regions). The CRISPR-Cas9 system is inherently more prone to off-target effects compared to ZFNs or TALENs, because target site recognition in CRISPR-Cas9 relies on RNA-DNA interaction of only short stretches, and the RNA-DNA interaction allows some mismatches. In contrast, ZFNs and TALENs depend on highly specific protein-DNA interactions that allow fewer mismatches.14Cornu T.I. Mussolino C. Cathomen T. Refining strategies to translate genome editing to the clinic.Nat. Med. 2017; 23: 415-423Crossref PubMed Scopus (129) Google Scholar This has promoted much research directed toward enhancing the performance of CRISPR-Cas-based gene editing with respect to specificity and nuclease activity (see below). Methods to detect undesired events in gene editing often rely on in silico predictions, followed by analyses of predicted off-target events. This is not necessarily sufficient for clinical application, and unbiased analysis based on next-generation sequencing is expected to become an important tool in the future. For a more extensive discussion on off-target effects, see Broeders et al.,7Broeders M. Herrero-Hernandez P. Ernst M.P.T. van der Ploeg A.T. Pijnappel W.W.M.P. Sharpening the molecular scissors: advances in gene-editing technology.iScience. 2020; 23: 100789Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Kim et al.,15Kim D. Luk K. Wolfe S.A. Kim J.S. Evaluating and enhancing target specificity of gene-editing nucleases and deaminases.Annu. Rev. Biochem. 2019; 88: 191-220Crossref PubMed Scopus (24) Google Scholar Manghwar et al.,16Manghwar H. Li B. Ding X. Hussain A. Lindsey K. Zhang X. Jin S. CRISPR/Cas systems in genome editing: methodologies and tools for sgRNA design, off-target evaluation, and strategies to mitigate off-target effects.Adv. Sci. (Weinh.). 2020; 7: 1902312PubMed Google Scholar and Pattanayak et al.17Pattanayak V. Guilinger J.P. Liu D.R. Determining the specificities of TALENs, Cas9, and other genome-editing enzymes.Methods Enzymol. 2014; 546: 47-78Crossref PubMed Scopus (44) Google Scholar The delivery of gene editing tools is a crucial aspect when it comes to clinical implementation. Two routes can be distinguished: ex vivo and in vivo delivery.18Yin H. Kauffman K.J. Anderson D.G. Delivery technologies for genome editing.Nat. Rev. Drug Discov. 2017; 16: 387-399Crossref PubMed Scopus (214) Google Scholar,19Lino C.A. Harper J.C. Carney J.P. Timlin J.A. Delivering CRISPR: a review of the challenges and approaches.Drug Deliv. 2018; 25: 1234-1257Crossref PubMed Scopus (203) Google Scholar In ex vivo delivery, autologous or allogeneic cells are modified by gene editing outside the patient, and gene-modified cells are transplanted into the patient. Any route of administration of gene editing machinery can be applied ex vivo, such as transfection, nucleofection, or (viral) transduction. Ex vivo gene editing allows quality control prior to treatment. In particular, undesired off-target and on-target events can be monitored. Note that quality control can be performed on bulk generations of cells. Rare undesired events that occur in only a few cells and that might cause cellular transformation will be difficult to detect. Alternatively, this method involves an extra complication: the engraftment of (stem) cells. For example, maintaining engraftment potential and viability of the cell of interest can be challenging. Clinically, the most advanced forms of ex vivo gene editing involve T cells and hematopoietic stem cells (HSCs). In in vivo gene editing, gene editing tools are applied directly to the organism. Vehicles for delivery include AAV, lipid nanoparticles (LNPs), gold nanoparticles (GNPs), or cell-penetrating peptides (CPPs). The delivery method in in vivo gene editing is crucial for its safety.20Tong S. Moyo B. Lee C.M. Leong K. Bao G. Engineered materials for in vivo delivery of genome-editing machinery.Nat. Rev. Mater. 2019; 4: 726-737Crossref Scopus (6) Google Scholar When gene editing components are delivered in vivo via vehicles that remain present for an extended period, for example via AAV, there is a cumulative risk of undesired genotoxic events that can last for the time that the AAV remains present, which has been estimated to last for a period of 10 years or longer.1Colella P. Ronzitti G. Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy.Mol. Ther. Methods Clin. Dev. 2017; 8: 87-104Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar In contrast, when delivered as RNA or protein, there is only short-term exposure and a reduced risk of genotoxicity. For in vivo gene editing, immunity against the delivery vehicle and the gene editing components are important considerations.21Li A. Tanner M.R. Lee C.M. Hurley A.E. De Giorgi M. Jarrett K.E. Davis T.H. Doerfler A.M. Bao G. Beeton C. Lagor W.R. AAV-CRISPR gene editing is negated by pre-existing immunity to Cas9.Mol. Ther. 2020; 28: 1432-1441Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Both pre-existing and acquired immunity should be considered. The AAV delivery vehicle is subject to pre-existing immunity in a significant proportion of the population.1Colella P. Ronzitti G. Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy.Mol. Ther. Methods Clin. Dev. 2017; 8: 87-104Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar In addition, preexisting immunity to Cas9 protein from several species has been reported in several studies. This may neutralize the therapy or induce adverse events.21Li A. Tanner M.R. Lee C.M. Hurley A.E. De Giorgi M. Jarrett K.E. Davis T.H. Doerfler A.M. Bao G. Beeton C. Lagor W.R. AAV-CRISPR gene editing is negated by pre-existing immunity to Cas9.Mol. Ther. 2020; 28: 1432-1441Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 22Charlesworth C.T. Deshpande P.S. Dever D.P. Camarena J. Lemgart V.T. Cromer M.K. Vakulskas C.A. Collingwood M.A. Zhang L. Bode N.M. et al.Identification of preexisting adaptive immunity to Cas9 proteins in humans.Nat. Med. 2019; 25: 249-254Crossref PubMed Scopus (189) Google Scholar, 23Crudele J.M. Chamberlain J.S. Cas9 immunity creates challenges for CRISPR gene editing therapies.Nat. Commun. 2018; 9: 3497Crossref PubMed Scopus (54) Google Scholar In summary, the safety and efficacy of gene editing technology for the treatment of human disease depend on multiple factors, including the choice of the gene editing method, being either ex vivo or in vivo, the gene editing technique, target site selection, delivery method, and target tissue. Technological developments are ongoing to improve gene editing tools with respect to specificity, efficiency, and versatility. These have been extensively described by us and others in recent reviews7Broeders M. Herrero-Hernandez P. Ernst M.P.T. van der Ploeg A.T. Pijnappel W.W.M.P. Sharpening the molecular scissors: advances in gene-editing technology.iScience. 2020; 23: 100789Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,24Pickar-Oliver A. Gersbach C.A. The next generation of CRISPR-Cas technologies and applications.Nat. Rev. Mol. Cell Biol. 2019; 20: 490-507Crossref PubMed Scopus (193) Google Scholar, 25Moon S.B. Kim D.Y. Ko J.H. Kim Y.S. Recent advances in the CRISPR genome editing tool set.Exp. Mol. Med. 2019; 51: 1-11Crossref Scopus (27) Google Scholar, 26Carroll D. Genome editing: past, present, and future.Yale J. Biol. Med. 2017; 90: 653-659PubMed Google Scholar and are only briefly mentioned here. First, variations of the original CRISPR-Cas9 method have been designed. These include the following: homology-independent targeted integration (HITI) for generating a knockin via NHEJ without involvement of HDR;27Suzuki K. Izpisua Belmonte J.C. In vivo genome editing via the HITI method as a tool for gene therapy.J. Hum. Genet. 2018; 63: 157-164Crossref PubMed Scopus (34) Google Scholar microhomology-mediated end joining (MMEJ)-dependent knockin, which is based on the presence of short stretches of homology that are utilized by the MMEJ DNA repair pathway;28Chang H.H.Y. Pannunzio N.R. Adachi N. Lieber M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair.Nat. Rev. Mol. Cell Biol. 2017; 18: 495-506Crossref PubMed Scopus (373) Google Scholar base editing,29Molla K.A. Yang Y. CRISPR/Cas-mediated base editing: technical considerations and practical applications.Trends Biotechnol. 2019; 37: 1121-1142Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar a mismatch repair- or base excision repair-dependent pathway in which a natural cytidine or adenosine deaminase (ADA) is coupled to a catalytically dead Cas9 (dCas9) to convert cytidine to uridine (which is replicated as thymidine), or to convert adenine to inosine, which is replicated as guanine; and prime editing,30Anzalone A.V. Randolph P.B. Davis J.R. Sousa A.A. Koblan L.W. Levy J.M. Chen P.J. Wilson C. Newby G.A. Raguram A. Liu D.R. Search-and-replace genome editing without double-strand breaks or donor DNA.Nature. 2019; 576: 149-157Crossref PubMed Scopus (454) Google Scholar in which a Cas9 nicking variant is used that introduces single stranded DNA breaks and that is coupled to reverse transcriptase to enable a wide variety of genomic changes. Second, other natural and engineered Cas9 variants have been identified and developed with distinct and/or enhanced targeting properties, including Cas12a (Cpf1), Cas12b (C2c1), FokI fused to dCas9,31Tsai S.Q. Wyvekens N. Khayter C. Foden J.A. Thapar V. Reyon D. Goodwin M.J. Aryee M.J. Joung J.K. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing.Nat. Biotechnol. 2014; 32: 569-576Crossref PubMed Scopus (617) Google Scholar Cas9-HF1,32Kleinstiver B.P. Pattanayak V. Prew M.S. Tsai S.Q. Nguyen N.T. Zheng Z. Joung J.K. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects.Nature. 2016; 529: 490-495Crossref PubMed Scopus (1166) Google Scholar eSpCs9,33Slaymaker I.M. Gao L. Zetsche B. Scott D.A. Yan W.X. Zhang F. Rationally engineered Cas9 nucleases with improved specificity.Science. 2016; 351: 84-88Crossref PubMed Scopus (1090) Google Scholar evoCas9,34Casini A. Olivieri M. Petris G. Montagna C. Reginato G. Maule G. Lorenzin F. 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Yeh J.R.J. et al.Engineered CRISPR-Cas9 nucleases with altered PAM specificities.Nature. 2015; 523: 481-485Crossref PubMed Scopus (798) Google Scholar And fourth, sgRNAs have been modified with respect to their length, structure, and chemistry to reduce off-target properties.37Fu Y. Sander J.D. Reyon D. Cascio V.M. Joung J.K. Improving CRISPR-Cas nuclease specificity using truncated guide RNAs.Nat. Biotechnol. 2014; 32: 279-284Crossref PubMed Scopus (1094) Google Scholar, 38Kocak D.D. Josephs E.A. Bhandarkar V. Adkar S.S. Kwon J.B. Gersbach C.A. Increasing the specificity of CRISPR systems with engineered RNA secondary structures.Nat. Biotechnol. 2019; 37: 657-666Crossref PubMed Scopus (78) Google Scholar, 39Yin H. Song C.Q. Suresh S. Kwan S.Y. Wu Q. Walsh S. Ding J. Bogorad R.L. Zhu L.J. Wolfe S.A. et al.Partial DNA-guided Cas9 enables genome editing with reduced off-target activity.Nat. Chem. Biol. 2018; 14: 311-316Crossref PubMed Scopus (82) Google Scholar These promising developments need future work to evaluate their suitability for clinical testing. Whereas there have been numerous applications of gene editing in preclinical studies, information on clinical applications of gene editing is scattered in the literature. In this review, we present a comprehensive overview of current clinical trials using gene editing strategies for the treatment of human disease, and include selected preclinical examples. For more extensive overviews of preclinical studies, we refer to excellent reviews.40Lee J. Bayarsaikhan D. Bayarsaikhan G. Kim J.S. Schwarzbach E. Lee B. Recent advances in genome editing of stem cells for drug discovery and therapeutic application.Pharmacol. Ther. 2020; 209: 107501Crossref PubMed Scopus (1) Google Scholar,41You L. Tong R. Li M. Liu Y. Xue J. Lu Y. Advancements and obstacles of CRISPR-Cas9 technology in translational research.Mol. Ther. Methods Clin. Dev. 2019; 13: 359-370Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition, in this review, we focus on gene editing in somatic cells, and we refer to other recent reviews and opinion articles for editing the germline.42Coller B.S. Ethics of human genome editing.Annu. Rev. Med. 2019; 70: 289-305Crossref PubMed Scopus (23) Google Scholar, 43Lea R.A. Niakan K.K. Human germline genome editing.Nat. Cell Biol. 2019; 21: 1479-1489Crossref PubMed Scopus (5) Google Scholar, 44Ormond K.E. Mortlock D.P. Scholes D.T. Bombard Y. Brody L.C. Faucett W.A. Garrison N.A. Hercher L. Isasi R. Middleton A. et al.Human germline genome editing.Am. J. Hum. Genet. 2017; 101: 167-176Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Thus far, precision gene editing has entered the clinic for the treatment of cancer immunotherapy, viral infections, and inherited hematologic, metabolic, and eye disorders (Table 1). These trials along with the underlying strategies are described in more detail below.Table 1Current Clinical Trials Involving Gene EditingTitleToolStatusCountryDeliveryIDRef.Cancer ImmunotherapyPD-1 knockout engineered T cells for advanced esophageal cancerCRISPR-Cas9completedChinaex vivoNCT0308171561Wu, S.; Hangzhou Cancer Hospital, Ltd.; Anhui Kedgene Biotechnology Co., Ltd. (2017). PD-1 knockout engineered T cells for advanced esophageal cancer. https://clinicaltrials.gov/ct2/show/NCT03081715.Google ScholarPD-1 knockout engineered t cells for metastatic non-small cell lung cancerCRISPR-Cas9active, not recruitingChinaex vivoNCT0279385662Lu, Y.; Sichuan University; Chengdu MedGenCell, Co., Ltd. (2016). PD-1 knockout engineered T cells for metastatic non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02793856.Google ScholarTherapeutic vaccine plus PD-1 knockout in prostate cancer treatmentCRISPR-Cas9recruitingChinaex vivoNCT0352565263Chen, S.; Guangzhou Anjie Biomedical Technology Co., Ltd.; University of Technology, Sydney (2018). Therapeutic vaccine plus PD-1 knockout in prostate cancer treatment. https://clinicaltrials.gov/ct2/show/NCT03525652.Google ScholarPD-1 knockout EBV-CTLs for advanced stage Epstein-Barr virus (EBV) associated malignanciesCRISPR-Cas9recruitingChinaex vivoNCT0304474364Yang, Y.; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School (2017). PD-1 knockout EBV-CTLs for advanced stage Epstein-Barr virus (EBV) associated malignancies. https://clinicaltrials.gov/ct2/show/NCT03044743.Google ScholarCD19 CAR and PD-1 knockout engineered T cells for CD19 positive malignant B cell derived leukemia and lymphomaN.S.not yet recruitingChinaex vivoNCT0329882882Shang, X.; Third Military Medical University (2017). CD19 CAR and PD-1 knockout engineered T cells for CD19 positive malignant B-cell derived leukemia and lymphoma. https://clinicaltrials.gov/ct2/show/NCT03298828.Google ScholarStudy of PD-1 gene-knocked out mesothelin-directed CAR-T cells with the conditioning of PC in mesothelin positive multiple solid tumorsCRISPR-Cas9recruitingChinaex vivoNCT0374796583Weidong, H.; Chinese PLA General Hospital (2018). Study of PD-1 gene-knocked out mesothelin-directed CAR-T cells with the conditioning of PC in mesothelin positive multiple solid tumors. https://clinicaltrials.gov/ct2/show/NCT03747965.Google ScholarCAR T and PD-1 knockout engineered T cells for esophageal cancerN.S.recruitingChinaex vivoNCT0370632684Chen, S.; Guangzhou Anjie Biomedical Technology Co., Ltd. (2018). CAR T and PD-1 knockout engineered T cells for esophageal cancer. https://clinicaltrials.gov/ct2/show/NCT03706326.Google ScholarAnti-MUC1 CAR T cells and PD-1 knockout engineered T cells for NSCLCN.S.recruitingChinaex vivoNCT0352578285Chen, S.; Guangzhou Anjie Biomedical Technology Co., Ltd.; University of Technology, Sydney (2018). Anti-MUC1 CAR T cells and PD-1 knockout engineered T cells for NSCLC. https://clinicaltrials.gov/ct2/show/NCT03525782.Google ScholarCRISPR (HPK1) edited CD19-specific CAR-T cells (XYF19 CAR-T Cells) for CD19+ leukemia or lymphomaCRISPR-Cas9recruitingChinaex vivoNCT0403756686Guangxun, G.; Xi’An Yufan Biotechnology Co., Ltd. (2019). CRISPR (HPK1) edited CD19-specific CAR-T cells (XYF19 CAR-T cells) for CD19+ leukemia or lymphoma. https://www.clinicaltrials.gov/ct2/show/NCT04037566.Google ScholarStudy of UCART19 in pediatric patients with relapsed/refractory B acute lymphoblastic leukemia (PALL)TALENactive, not recruitingUS/EU/UKex vivoNCT02808442103Servier (Institut de Recherches Internationales Servier); ADIR, a Servier Group company (2016). Study of UCART19 in pediatric patients with relapsed/refractory b acute lymphoblastic leukemia. https://clinicaltrials.gov/ct2/show/NCT02808442.Google ScholarDose escalation study of UCART19 in adult patients with relapsed/refractory B cell acute lymphoblastic leukaemia (CALM)TALENactive, not recruitingUS/EU/UK/Japanex vivoNCT02746952104Servier (Institut de Recherches Internationales Servier); ADIR, a" @default.
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• W3039345425 title "Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease" @default.
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