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Therapeutic application of the CRISPR system: current issues and new prospects

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A Correction to this article was published on 01 June 2019

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Abstract

Since its discovery, the Clustered Regularly Interspaced Short Palindromic Repeat (the CRISPR) system has been increasingly applied to therapeutic genome editing. Employment of several viral and non-viral vectors has enabled efficient delivery of the CRISPR system to target cells or tissues. In addition, the CRISPR system is able to modulate the target gene’s expression in various ways, such as mutagenesis, gene integration, epigenome regulation, chromosomal rearrangement, base editing and mRNA editing. However, there are still limitations hindering an ideal application of the system: inefficient delivery, dysregulation of the delivered gene, the immune response against the CRISPR system, the off-target effects or the unintended on-target mutations. In addition, there are recent discoveries that have not been yet applied to CRISPR-mediated therapeutic genome editing. Here, we review the overall principles related to the therapeutic application of the CRISPR system, along with new strategies for the further application and prospects to overcome the limitations.

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Change history

  • 01 June 2019

    In Original article publication, the Acknowledgment statement was not included. The acknowledgement of this article is given below:

References

  • Abbas A et al (2016) Basic immunology: functions and disorders of the immune system, 5th edn. Elsevier, Amsterdam, p 69

    Google Scholar 

  • Abudayyeh OO, Gootenberg JS, Essletzbichler P, Han S, Joung J, Belanto JJ, Verdine V, Cox DBT, Kellner MJ, Regev A, Lander ES, Voytas DF, Ting AY, Zhang F (2017) RNA targeting with CRISPR-Cas13. Nature 550(7675):280–284

    PubMed  PubMed Central  Google Scholar 

  • Aida T, Nakade S, Sakuma T, Izu Y, Oishi A, Mochida K, Ishikubo H, Usami T, Aizawa H, Yamamoto T, Tanaka K (2016) Gene cassette knock-in in mammalian cells and zygotes by enhanced MMEJ. BMC Genom 17(1):979

    Google Scholar 

  • Ali MM, Li F, Zhang Z, Zhang K, Kang DK, Ankrum JA, Le XC, Zhao W (2014) Rolling circle amplification: a versatile tool for chemical biology, materials science and medicine. Chem Soc Rev 43(10):3324–3341

    CAS  PubMed  Google Scholar 

  • Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272(5270):1955–1958

    CAS  PubMed  Google Scholar 

  • Allen TM, Cullis PR (2013) Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev 65(1):36–48

    CAS  PubMed  Google Scholar 

  • Allen F, Crepaldi L, Alsinet C, Strong AJ, Kleshchevnikov V, De Angeli P, Páleníková P, Khodak A, Kiselev V, Kosicki M, Bassett AR, Harding H, Galanty Y, Muñoz-Martínez F, Metzakopian E, Jackson SP, Parts L (2018) Predicting the mutations generated by repair of cas9-induced double-strand breaks. Nat Biotechnol 37:64–72

    Google Scholar 

  • Al-Zaidy SA, Sahenk Z, Rodino-Klapac LR, Kaspar B, Mendell JR (2015) Follistatin gene therapy improves ambulation in Becker muscular dystrophy. J Neuromuscul Dis 2(3):185–192

    PubMed  PubMed Central  Google Scholar 

  • Ames RS, Kost TA, Condreay JP (2007) BacMam technology and its application to drug discovery. Expert Opin Drug Discov 2:1669–1681

    CAS  PubMed  Google Scholar 

  • Anders C, Niewoehner O, Duerst A, Jinek M (2014) Structural basis of PAM-dependent target DNA recognition by the Cas9 endonuclease. Nature 513(7519):569–573

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aparicio T, Baer R, Gautier J (2014) DNA double-strand break repair pathway choice and cancer. DNA Repair (Amst) 19:169–175

    CAS  Google Scholar 

  • Aragao-Santiago L, Hillaireau H, Grabowski N, Mura S, Nascimento TL, Dufort S, Coll JL, Tsapis N, Fattal E (2016) Compared in vivo toxicity in mice of lung delivered biodegradable and non-biodegradable nanoparticles. Nanotoxicology 10(3):292–302

    CAS  PubMed  Google Scholar 

  • Asai T, Tsuzuku T, Takahashi S, Okamoto A, Dewa T, Nango M, Hyodo K, Ishihara H, Kikuchi H, Oku N (2014) Cell-penetrating peptide-conjugated lipid nanoparticles for siRNA delivery. Biochem Biophys Res Commun 444(4):599–604

    CAS  PubMed  Google Scholar 

  • Aschauer DF, Kreuz S, Rumpel S (2013) Analysis of transduction efficiency, tropism and axonal transport of AAV serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS One 8(9):e76310

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bae S, Kim J-S (2018) Machine learning finds Cas9-edited genotypes. Nat Biomed Eng 2:892–893

    PubMed  Google Scholar 

  • Bae KH et al (2003) Human zinc fingers as building blocks in the construction of artificial transcription factors. Nat Biotech 21:275–280

    CAS  Google Scholar 

  • Bao Z, Jain S, Jaroenpuntaruk V, Zhao H (2017) Orthogonal genetic regulation in human cells using chemically induced CRISPR/Cas9 activators. ACS Synth Biol 6:686–693

    CAS  PubMed  Google Scholar 

  • Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819):1709–1712

    CAS  PubMed  Google Scholar 

  • Bennardo N, Cheng A, Huang N, Stark JM (2008) Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4(6):e1000110

    PubMed  PubMed Central  Google Scholar 

  • Bisset DR, Stepniak-Konieczna EA, Zavaljevski M, Wei J, Carter GT, Weiss MD, Chamberlain JR (2015) Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy. Hum Mol Genet 24(17):4971–4983

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bitinaite J, Wah DA, Aggarwal AK, Schildkraut I (1998) FokI dimerization is required for DNA cleavage. Proc Natl Acad Sci USA 95:10570–10575

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blasco RB, Karaca E, Ambrogio C, Cheong TC, Karayol E, Minero VG, Voena C, Chiarle R (2014) Simple and rapid in vivo generation of chromosomal rearrangements using CRISPR/Cas9 technology. Cell Rep 9(4):1219–1227

    CAS  PubMed  Google Scholar 

  • Bondy-Denomy J, Garcia B, Strum S, Du M, Rollins MF, Hidalgo-Reyes Y, Wiedenheft B, Maxwell KL, Davidson AR (2015) Multiple mechanisms for CRISPR-Cas inhibition by anti-CRISPR proteins. Nature 526(7571):136–139

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bouard D, Alazard-Dany D, Cosset FL et al (2000) Viral vectors: from virology to transgene expression. Br J Pharmacol 157:153–165

    Google Scholar 

  • Boulton SJ, Jackson SP (1996) Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J 15(18):5093–5103

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braun CJ, Bruno PM, Horlbeck MA, Gilbert LA, Weissman JS, Hemann MT (2016) Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation. Proc Natl Acad Sci USA 113(27):E3892–E3900

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braun SMG, Kirkland JG, Chory EJ, Husmann D, Calarco JP, Crabtree GR (2017) Rapid and reversible epigenome editing by endogenous chromatin regulators. Nat Commun 8(1):560

    PubMed  PubMed Central  Google Scholar 

  • Broering R, Montag M, Jiang M, Lu M, Sowa JP, Kleinehr K, Gerken G, Schlaak JF (2011) Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state. Int Immunol 23(9):537–544

    CAS  PubMed  Google Scholar 

  • Brouns SJ, Jore MM, Lundgren M, Westra ER, Slijkhuis RJ, Snijders AP, Dickman MJ, Makarova KS, Koonin EV, van der Oost J (2008) Small CRISPR RNAs guide antiviral defense in prokaryotes. Science 321(5891):960–964

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bultmann S et al (2012) Targeted transcriptional activation of silent oct4 pluripotency gene by combining designer TALEs and inhibition of epigenetic modifiers. Nucl Acids Res 40:5368–5377

    CAS  PubMed  PubMed Central  Google Scholar 

  • Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM (2009) Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 199(3):381–390

    PubMed  Google Scholar 

  • Canny MD, Moatti N, Wan LCK, Fradet-Turcotte A, Krasner D, Mateos-Gomez PA, Zimmermann M, Orthwein A, Juang YC, Zhang W, Noordermeer SM, Seclen E, Wilson MD, Vorobyov A, Munro M, Ernst A, Ng TF, Cho T, Cannon PM, Sidhu SS, Sicheri F, Durocher D (2018) Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nat Biotechnol 36(1):95–102

    CAS  PubMed  Google Scholar 

  • Carlisle RC, Benjamin R, Briggs SS, Sumner-Jones S, McIntosh J, Gill D, Hyde S, Nathwani A, Subr V, Ulbrich K, Seymour LW, Fisher KD (2008) Coating of adeno-associated virus with reactive polymers can ablate virus tropism, enable retargeting and provide resistance to neutralising antisera. J Gene Med 10(4):400–411

    CAS  PubMed  Google Scholar 

  • Castanotto D, Rossi JJ (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426–433

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cencic R, Miura H, Malina A, Robert F, Ethier S, Schmeing TM, Dostie J, Pelletier J (2014) Protospacer adjacent motif (PAM)-distal sequences engage CRISPR Cas9 DNA target cleavage. PLoS One 9(10):e109213

    PubMed  PubMed Central  Google Scholar 

  • Chadwick AC, Wang X, Musunuru K (2017) In vivo base editing of PCSK9 as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol 37(9):1741–1747

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chandler RJ, LaFave MC, Varshney GK, Trivedi NS, Carrillo-Carrasco N, Senac JS, Wu W, Hoffmann V, Elkahloun AG, Burgess SM, Venditti CP (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J. Clin. Invest 125:870–880

    PubMed  PubMed Central  Google Scholar 

  • Charlesworth CT et al (2019) Identification of pre-existing adaptive immunity to Cas9 proteins in humans. Nat Med 25:249–254

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen C-Y, Hsiao-Hsuan W, Chen C-P, Chern S-R, Hwang S-M, Huang S-F, Lo W-H, Chen Guan-Yu, Yu-Chen H (2011) Biosafety assessment of human mesenchymal stem cells engineered by hybrid baculovirus vectors. Mol Pharm 8(5):1505–1514

    CAS  PubMed  Google Scholar 

  • Chen X, Gonçalves MA et al (2016) Engineered viruses as genome editing devices. Mol Ther 3:447–457

    Google Scholar 

  • Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, Sternberg SH, Keith Joung J, Yildiz A, Doudna JA (2017) Enhanced proofreading governs CRISPR-Cas9 targeting accuracy. Nature 550(7676):407–410

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng SL, Lai CF, Fausto A, Chellaiah M, Feng X, McHugh KP, Teitelbaum SL, Civitelli R, Hruska KA, Ross FP, Avioli LV (2000) Regulation of alphaVbeta3 and alphaVbeta5 integrins by dexamethasone in normal human osteoblastic cells. J Cell Biochem 77(2):265–276

    CAS  PubMed  Google Scholar 

  • Chew WL, Tabebordbar M, Cheng JKW, Mali P, Wu EY, Ng AHM, Zhu K, Wagers AJ, Church GM (2016) A multi-functional AAV-CRISPR-Cas9 and its host response. Nat Methods 13(10):868–874

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cho SW, Kim S, Kim Y, Kweon J, Kim HS, Bae S, Kim J-S (2014) Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases. Genome Res 24(1):132–141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choi PS, Meyerson M (2014) Targeted genomic rearrangements using CRISPR/Cas technology. Nat Commun 5:3728

    CAS  PubMed  Google Scholar 

  • Chrai SS, Murari R, Ahmad I (2002) Liposomes (a review) part two: drug delivery systems. BioPharm 17:40–43

    Google Scholar 

  • Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, Kühn R (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33(5):543–548

    CAS  PubMed  Google Scholar 

  • Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823

    CAS  PubMed  PubMed Central  Google Scholar 

  • Contreras-Galindo R, Fischer S, Saha AK, Lundy JD, Cervantes PW, Mourad M, Wang C, Qian B, Dai M, Meng F, Chinnaiyan A, Omenn GS, Kaplan MH, Markovitz DM (2017) Rapid molecular assays to study human centromere genomics. Genome Res 27(12):2040–2049

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cox DB, Platt RJ, Zhang F (2015) Therapeutic genome editing: prospects and challenges. Nat Med 21(2):121–131

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cox DBT, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F (2017) RNA editing with CRISPR-Cas13. Science 358(6366):1019–1027

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crudele JM, Chamberlain JS (2018) Cas9 immunity creates challenges for CRISPR gene editing therapies. Nat Commun 9:3497

    PubMed  PubMed Central  Google Scholar 

  • Cvetković DM, Živanović MN, Milutinović MG, Djukić TR, Radović MD, Cvetković AM, Filipović ND, Zdravković ND (2017) Real-time monitoring of cytotoxic effects of electroporation on breast and colon cancer cell lines. Bioelectrochemistry 113:85–94

    Google Scholar 

  • Cyranoski D (2016) Chinese scientists to pioneer first human CRISPR trial. Nat News. https://www.nature.com/news/chinese-scientists-to-pioneer-first-human-crispr-trial-1.20302. Accessed 10 Jan 2019

  • D’Astolfo DS et al (2015) Efficient intracellular delivery of native proteins. Cell 161:674–690

    PubMed  Google Scholar 

  • Dahlmann M, Stein U (2015) RNA interference for antimetastatic therapy. Methods Mol Biol 1317:153–165

    PubMed  Google Scholar 

  • Dakin RS, Parker AL, Delles C, Nicklin SA, Baker AH (2015) Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector. Hum Gene Ther 26(5):312–319

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davis KM, Pattanayak V, Thompson DB, Zuris JA, Liu DR (2015) Small molecule-triggered Cas9 protein with improved genome-editing specificity. Nat Chem Biol 11(5):316–318

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Solis CA, Ho A, Holehonnur R, Ploski JE (2016) The development of a viral mediated CRISPR/Cas9 system with doxycycline dependent gRNA expression for inducible in vitro and in vivo genome editing. Front Mol Neurosci 9:70

    PubMed  PubMed Central  Google Scholar 

  • Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, Eckert MR, Vogel J, Charpentier E (2011) CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471(7340):602–607

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381(6584):661–666

    CAS  PubMed  Google Scholar 

  • Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of singlestranded RNA. Science 303:1529–1531

    CAS  PubMed  Google Scholar 

  • Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA 108(7):2909–2914

    CAS  PubMed  PubMed Central  Google Scholar 

  • Doshi BS, Arruda VR (2018) Gene therapy for hemophilia: what does the future hold. Ther Adv Hematol 9(9):273–293

    CAS  PubMed  PubMed Central  Google Scholar 

  • East-Seletsky A, O’Connell MR, Knight SC, Burstein D, Cate JH, Tjian R, Doudna JA (2016) Two distinct RNase activities of CRISPR-C2c2 enable guide-RNA processing and RNA detection. Nature 538(7624):270–273

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eikenes L, Bruland ØS, Brekken C, Davies Cde L (2004) Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res 64(14):4768–4773

    CAS  PubMed  Google Scholar 

  • Elliott B, Richardson C, Jasin M (2005) Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Mol Cell 17(6):885–894

    CAS  PubMed  Google Scholar 

  • Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, Wilson JM (2013) CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest 123:2994–3001

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fazil MHUT, Ong ST, Chalasani MLS, Low JH, Kizhakeyil A, Mamii A, Lim CFH, Wright GD, Lakshminarayanan R, Kelleher D, Verma NK (2016) GapmeR cellular internalization by macropinocytosis induces sequence-specific gene silencing in human primary T-cells. Sci Rep 6:37721

    CAS  PubMed  PubMed Central  Google Scholar 

  • Finn JD, Smith AR, Patel MC, Shaw L, Youniss MR, van Heteren J, Dirstine T, Ciullo C, Lescarbeau R, Seitzer J, Shah RR, Shah A, Ling D, Growe J, Pink M, Rohde E, Wood KM, Salomon WE, Harrington WF, Dombrowski C, Strapps WR, Chang Y, Morrissey DV (2018) A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep 22(9):2227–2235

    CAS  PubMed  Google Scholar 

  • Fogarty Norah M E, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, Lea R, Elder K, Wamaitha SE, Kim D, Maciulyte V, Kleinjung J, Kim J-S, Wells D, Vallier L, Bertero A, Turner James M A, Niakan KK (2017) Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550(7674):67–73

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fominaya J, Bravo J, Decaudin D, Brossa JY, Nemati F, Rebollo A (2015) Enhanced serum proteolysis resistance of cell-penetrating peptides. Ther Deliv 6(2):139–147

    CAS  PubMed  Google Scholar 

  • Fu Y, Sander JD, Reyon D, Cascio VM, Joung JK (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32(3):279–284

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Xiong X, Wong S, Charles EJ, Lim WA, Qi LS (2016) Complex transcriptional modulation with orthogonal and inducible dCas9 regulators. Nat Methods 13(12):1043–1049

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garneau JE, Dupuis MÈ, Villion M, Romero DA, Barrangou R, Boyaval P, Fremaux C, Horvath P, Magadán AH, Moineau S (2010) The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature 468(7320):67–71

    CAS  PubMed  Google Scholar 

  • Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR (2017) Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551(7681):464–471

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrke JM, Cervantes O, Clement MK, Wu Y, Zeng J, Bauer DE, Pinello L, Joung JK (2018) An APOBEC3A-Cas9 base editor with minimized bystander and off-target activities. Nat Biotechnol 36(10):977–982

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gestin M, Dowaidar M, Langel Ü (2017) Uptake mechanism of cell-penetrating peptides. Adv Exp Med Biol 1030:255–264

    CAS  PubMed  Google Scholar 

  • Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginossar N, Brandman O, Whitehead EH, Doudna JA et al (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154:442–451

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gil-Farina I, Fronza R, Kaeppel C, Lopez-Franco E, Ferreira V, D’Avola D, Benito A, Prieto J, Petry H, Gonzalez-Aseguinolaza G, Schmidt M (2016) Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Ther 24:1100–1105

    CAS  PubMed  PubMed Central  Google Scholar 

  • Glover L, Jun J, Horn D (2011) Microhomology-mediated deletion and gene conversion in African trypanosomes. Nucl Acids Res 39(4):1372–1380

    CAS  PubMed  Google Scholar 

  • Gonzalez-Rodriguez A, Valverde AM (2015) RNA Interference as a therapeutic strategy for the treatment of liver diseases. Curr Pharm Des 21(31):4574–4586

    CAS  PubMed  Google Scholar 

  • Guilinger JP, Thompson DB, Liu DR (2014) Fusion of catalytically inactive Cas9 to Fokl nuclease improves the specificity of genome modification. Nat Biotechnol 32(6):577–582

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gulei D, Raduly L, Berindan-Neagoe I, Calin GA (2019) CRISPR-based RNA editing: diagnostic applications and therapeutic options. Expert Rev Mol Diagn. 19(2):83–88

    CAS  PubMed  Google Scholar 

  • Gutschner T, Haemmerle M, Genovese G, Draetta GF, Chin L (2016) Post-translational regulation of Cas9 during G1 enhances homology-directed repair. Cell Rep 14(6):1555–1566

    CAS  PubMed  Google Scholar 

  • Haeussler M, Schönig K, Eckert H, Eschstruth A, Mianné J, Renaud JB, Schneider-Maunoury S, Shkumatava A, Teboul L, Kent J, Joly JS, Concordet JP (2016) Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR. Genome Biol 17(1):148

    PubMed  PubMed Central  Google Scholar 

  • Halperin SO, Tou CJ, Wong EB, Modavi C, Schaffer DV, Dueber JE (2018) CRISPR-guided DNA polymerases enable diversification of all nucleotides in a tunable window. Nature 560(7717):248–252

    CAS  PubMed  Google Scholar 

  • Han X, Liu Z, Jo MC, Zhang K, Li Y, Zeng Z, Li N, Zu Y, Qin L (2015) CRISPR-Cas9 delivery to hard-to-transfect cells via membrane deformation. Sci Adv 1(7):e1500454

    PubMed  PubMed Central  Google Scholar 

  • Hartigan-O’Connor D, Kirk CJ, Crawford R, Mulé JJ, Chamberlain JS (2001) Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther 4(6):525–533

    PubMed  Google Scholar 

  • Hassan MO, Duarte R, Dix-Peek T, Vachiat A, Naidoo S, Dickens C, Grinter S, Manga P, Naicker S (2016) Correlation between volume overload, chronic inflammation, and left ventricular dysfunction in chronic kidney disease patients. Clin Nephrol 86(13):131–135

    PubMed  Google Scholar 

  • He XY, Liu BY, Peng Y, Zhuo RX, Cheng SX (2019) Multifunctional vector for delivery of genome editing plasmid targeting β-catenin to remodulate cancer cell properties. ACS Appl Mater Interfaces 11(1):226–237

    CAS  PubMed  Google Scholar 

  • Hendel A et al (2015) Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol 33:985–989

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heyer WD, Ehmsen KT, Liu J (2010) Regulation of homologous recombination in eukaryotes. Annu Rev Genet 44:113–139

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hickey DG, Edwards TL, Barnard AR, Singh MS, de Silva SR, McClements ME, Flannery JG, Hankins MW, MacLaren RE (2017) Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina. Gene Ther 24(12):787–800

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hindriksen S, Bramer AJ, Truong MA, Vromans Martijn J M, Post JB, Verlaan-Klink I, Snippert HJ, Lens Susanne M A, Hadders MA (2017) Baculoviral delivery of CRISPR/Cas9 facilitates efficient genome editing in human cells. PLoS One 12(6):e0179514

    PubMed  PubMed Central  Google Scholar 

  • Hoffman BE, Martino AT, Sack BK, Cao O, Liao G, Terhost C, Herzog RW (2011) Nonredundant roles of IL-10 and TGF-β in suppression of immune responses to hepatic AAV-factor IX gene transfer. Mol Ther 19(7):1263–1272

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hong SG, Yada RC, Choi K, Carpentier A, Liang TJ, Merling RK, Sweeney CL, Malech HL, Jung M, Corat MAF, AlJanahi AA, Lin Y, Liu H, Tunc I, Wang X, Palisoc M, Pittaluga S, Boehm M, Winkler T, Zou J, Dunbar CE (2017) Rhesus iPSC safe harbor gene-editing platform for stable expression of transgenes in differentiated cells of all germ layers. Mol Ther 25(1):44–53

    CAS  PubMed  PubMed Central  Google Scholar 

  • Horii T, Arai Y, Yamazaki M, Morita S, Kimura M, Itoh M, Abe Y, Hatada I (2014) Validation of microinjection methods for generating knockout mice by CRISPR/Cas-mediated genome engineering. Sci Rep 4:4513

    PubMed  PubMed Central  Google Scholar 

  • Howard DB, Harvey BK (2017) Assaying the stability and inactivation of AAV serotype 1 vectors. Hum Gene Ther Methods. 28(1):39–48

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hryhorowicz M, Grześkowiak B, Mazurkiewicz N, Śledziński P, Lipiński D, Słomski R (2019) Improved delivery of CRISPR/Cas9 system using magnetic nanoparticles into porcine fibroblast. Mol Biotechnol 61(3):173–180

    CAS  PubMed  Google Scholar 

  • Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, Li Y, Fine EJ, Wu X, Shalem O, Cradick TJ, Marraffini LA, Bao G, Zhang F (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31(9):827–832

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hung SS, Chrysostomou V, Li F et al (2016) AAV-Mediated CRISPR/Cas gene editing of retinal cells in vivo. Invest Ophthalmol Vis Sci 57(7):3470–3476

    CAS  PubMed  Google Scholar 

  • Jinek M et al (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jo A, Ham S, Lee GH, Lee YI, Kim S, Lee YS, Shin JH, Lee Y (2015) Efficient mitochondrial genome editing by CRISPR/Cas9. Biomed Res Int 2015:305716. https://doi.org/10.1155/2015/305716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johansen AK, Molenaar B, Versteeg D, Leitoguinho AR, Demkes C, Spanjaard B, de Ruiter H, Akbari Moqadam F, Kooijman L, Zentilin L, Giacca M, van Rooij E (2017) Postnatal cardiac gene editing using CRISPR/Cas9 with AAV9-mediated delivery of short guide RNAs results in mosaic gene disruption. Circ Res 121(10):1168–1181

    CAS  PubMed  Google Scholar 

  • Johnstone SA, Masin D, Mayer L, Bally MB (2001) Surface-associated serum proteins inhibit the uptake of phosphatidylserine and poly(ethylene glycol) liposomes by mouse macrophages. Biochim Biophys Acta 1513(1):25–37

    CAS  PubMed  Google Scholar 

  • Joshi S, Cooke JR, Chan DK, Ellis JA, Hossain SS, Singh-Moon RP, Wang M, Bigio IJ, Bruce JN, Straubinger RM (2016) Liposome size and charge optimization for intraarterial delivery to gliomas. Drug Deliv Transl Res 6(3):225–233

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jung I-Y, Lee J (2018) Unleashing the therapeutic potential of CAR-T cell therapy using gene-editing technologies. Mol Cells 41(8):717–723

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:196–200

    Google Scholar 

  • Kamimura K, Kanefuji T, Yokoo T, Abe H, Suda T, Kobayashi Y, Zhang G, Aoyagi Y, Liu D (2014) Safety assessment of liver-targeted hydrodynamic gene delivery in dogs. PLoS One 9(9):e107203

    PubMed  PubMed Central  Google Scholar 

  • Kearns NA, Pham H, Tabak B, Genga RM, Silverstein NJ, Garber M, Maehr R (2015) Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat Methods 12:401–403

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kemaladewi DU, Maino E, Hyatt E, Hou H, Ding M, Place KM, Zhu X, Bassi P, Baghestani Z, Deshwar AG, Merico D, Xiong HY, Frey BJ, Wilson MD, Ivakine EA, Cohn RD (2017) Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism. Nat Med 23(8):984–989

    CAS  PubMed  Google Scholar 

  • Kertzman P, Császár NBM, Furia JP, Schmitz C (2017) Radial extracorporeal shock wave therapy is efficient and safe in the treatment of fracture nonunions of superficial bones: a retrospective case series. J Orthop Surg Res. 12(1):164

    PubMed  PubMed Central  Google Scholar 

  • Khorsandi SE et al (2008) Minimally invasive and selective hydrodynamic gene therapy of liver segments in the pig and human. Cancer Gene Ther 15:225–230

    CAS  PubMed  Google Scholar 

  • Kim YG, Cha J, Chandrasegaran S (1996) Hybrid restriction enzymes: zinc finger fusions to FokI cleavage domain. Proc Natl Acad Sci USA 93:1156–1160

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim S, Kim D, Cho SW, Kim J, Kim JS (2014) Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res 24:1012–1019

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HK, Song M, Lee J, Menon AV, Jung S, Kang YM, Choi JW, Woo E, Koh HC, Nam JW, Kim H (2017a) In vivo high-throughput profiling of CRISPR-Cpf1 activity. Nat Methods 14(2):153–159

    CAS  PubMed  Google Scholar 

  • Kim YB, Komor AC, Levy JM, Packer MS, Zhao KT, Liu DR (2017b) Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions. Nat Biotechnol 35(4):371–376

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim D, Lim K, Kim ST, Yoon SH, Kim K, Ryu SM, Kim JS (2017c) Genome-wide target specificities of CRISPR RNA-guided programmable deaminases. Nat Biotechnol 35(5):475–480

    CAS  PubMed  Google Scholar 

  • Kim W, Lee S, Kim HS, Song M, Cha YH, Kim YH, Shin J, Lee ES, Joo Y, Song JJ, Choi EJ, Choi JW, Lee J, Kang M, Yook JI, Lee MG, Kim YS, Paik S, Kim HH (2018a) Targeting mutant KRAS with CRISPR-Cas9 controls tumor growth. Genome Res 28(3):374–382

    CAS  PubMed Central  Google Scholar 

  • Kim S, Koo T, Jee H-G, Cho H-Y, Lee G, Lim D-G, Shin HS, Kim J-S (2018b) CRISPR RNAs trigger innate immune responses in human cells. Genome Res 28(3):367–373

    CAS  PubMed Central  Google Scholar 

  • Kleinstiver BP, Prew MS, Tsai SQ, Topkar VV, Nguyen NT, Zheng Z, Gonzales AP, Li Z, Peterson RT, Yeh JR, Aryee MJ, Joung JK (2015) Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523(7561):481–485

    PubMed  PubMed Central  Google Scholar 

  • Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen N, Zheng Z, Keith Joung J (2016) High-fidelity CRISPR-Cas9 variants with undetectable genome-wide off-targets. Nature 529(7587):490–495

    CAS  PubMed  PubMed Central  Google Scholar 

  • Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR (2016) Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533(7603):420–424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Komor AC, Zhao KT, Packer MS, Gaudelli NM, Waterbury AL, Koblan LW, Kim YB, Badran AH, Liu DR (2017) Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T: a base editors with higher efficiency and product purity. Sci Adv 3(8):4774

    Google Scholar 

  • Koo T, Lee J, Kim J-S (2015) Measuring and reducing off-target activities of programmable nucleases including CRISPR-Cas9. Mol Cells 38(6):475–481

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kosicki M, Tomberg K, Bradley A (2018) Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol 36(8):765–771

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kost TA, Condreay JP, Jarvis DL (2005) Baculovirus as versatile vectors for protein expression in insect and mammalian cells. Nat Biotechnol 23:567–575

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo Y-C, Lee Y-J (2016) Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator-and apolipoprotein E-conjugated liposomes to the hippocampus. Int J Nanomed 11:6809–6824

    CAS  Google Scholar 

  • Kwon DY, Zhao YT, Lamonica JM, Zhou Z (2017) Locus-specific histone deacetylation using a synthetic CRISPR-Cas9-based HDAC. Nat Commun 8:15315

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lattanzi A, Meneghini V, Pavani G, Amor F, Ramadier S, Felix T, Antoniani C, Masson C, Alibeu O, Lee C, Porteus MH, Bao G, Amendola M, Mavilio F, Miccio A (2019) Optimization of CRISPR/Cas9 delivery to human hematopoietic stem and progenitor cells for therapeutic genomic rearrangements. Mol Ther 27(1):137–150

    CAS  PubMed  Google Scholar 

  • Lättig-Tünnemann G, Prinz M, Hoffmann D et al (2011) Backbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides. Nat Commun 2:453

    PubMed  Google Scholar 

  • Lau C-H, Zhu H, Tay JC-K, Li Z, Tay FC, Chen C, Tan W-K, Shouhui D, Sia V-K, Phang R-Z, Tang S-Y, Yang C, Chi Z, Liang C-C, Ning E, Wang S (2014) Genetic rearrangements of variable di-residue (RVD)-containing repeat arrays in a baculoviral TALEN system. Mol Ther Methods Clin Dev 1:14050

    PubMed  PubMed Central  Google Scholar 

  • Lee GK, Maheshri N, Kaspar B, Schaffer DV (2005) PEG conjugation moderately protects adeno-associated viral vectors against antibody neutralization. Biotechnol Bioeng 92(1):24–34

    CAS  PubMed  Google Scholar 

  • Lee K, Conboy M, Park HM, Jiang F, Kim HJ, Dewitt MA, Mackley VA, Chang K, Rao A, Skinner C, Shobha T, Mehdipour M, Liu H, Huang W-c, Lan F, Bray NL, Li S, Corn JE, Kataoka K, Doudna JA, Conboy I, Murthy N (2017) Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nat Biomed Eng 1:889–901

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee B, Lee K, Panda S, Gonzales-Rojas R, Chong A, Bugay V, Park HM, Brenner R, Murthy N, Lee HY (2018) Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nat Biomed Eng 2(7):497–507

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lekomtsev S, Aligianni S, Lapao A, Bürckstümmer T (2016) Efficient generation and reversion of chromosomal translocations using CRISPR/Cas technology. BMC Genom 17:739

    Google Scholar 

  • Li L, ten Hagen TL, Bolkestein M, Gasselhuber A, Yatvin J, van Rhoon GC, Eggermont AM, Haemmerich D, Koning GA (2013) Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia. J Control Release 167(2):130–137

    CAS  PubMed  Google Scholar 

  • Li Z, Kang H, Li Q, Che N, Liu Z, Li P, Zhang C, Liu R, Huang Y (2014) Ultrathin core-sheath fibers for liposome stabilization. Colloids Surf B Biointerfaces 122:630–637

    CAS  PubMed  Google Scholar 

  • Li J, Shou J, Guo Y, Tang Y, Wu Y, Jia Z, Zhai Y, Chen Z, Xu Q, Wu Q (2015a) Efficient inversions and duplications of mammalian regulatory DNA elements and gene clusters by CRISPR/Cas9. J Mol Cell Biol 7(4):284–298

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Park AI, Mou H, Colpan C, Bizhanova A, Akama-Garren E, Joshi N, Hendrickson EA, Feldser D, Yin H, Anderson DG, Jacks T, Weng Z, Xue W (2015b) A versatile reporter system for CRISPR-mediated chromosomal rearrangements. Genome Biol 16(1):111

    PubMed  PubMed Central  Google Scholar 

  • Li H, Chen Y, Deng Y, Wang Y, Ke X, Ci T (2017a) Effects of surface charge of low molecular weight heparin-modified cationic liposomes on drug efficacy and toxicity. Drug Dev Ind Pharm 43(7):1163–1172

    CAS  PubMed  Google Scholar 

  • Li G, Zhang X, Zhong C, Mo J, Quan R, Yang J, Liu D, Li Z, Yang H, Wu Z (2017b) Small molecules enhance CRISPR/Cas9-mediated homology-directed genome editing in primary cells. Sci Rep 7(1):8943

    PubMed  PubMed Central  Google Scholar 

  • Li X, Wang Y, Liu Y, Yang B, Wang X, Wei J, Lu Z, Zhang Y, Wu J, Huang X, Yang L, Chen J (2018) Base editing with a Cpf1-cytidine deaminase fusion. Nat Biotechnol 36(4):324–327

    CAS  PubMed  Google Scholar 

  • Li A, Lee CM, Hurley AE, Jarrett KE, De Giorgi M, Weiqi L, Balderrama KS, Doerfler AM, Deshmukh H, Ray A, Bao G, Lagor WR (2019) A self-deleting AAV-CRISPR system for in vivo genome editing. Mol Ther Methods Clin Dev 12:111–122

    CAS  PubMed  Google Scholar 

  • Lin J, Wong KC (2018) Off-target predictions in CRISPR-Cas9 gene editing using deep learning. Bioinformatics 34(17):i656–i663

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin FL, Sperle K, Sternberg N (1984) Model for homologous recombination during transfer of DNA into mouse L cells: role for DNA ends in the recombination process. Mol Cell Biol 4(6):1020–1034

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin S, Staahl BT, Alla RK, Doudna JA (2014a) Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. Elife 3:e04766

    PubMed  PubMed Central  Google Scholar 

  • Lin Y, Cradick TJ, Brown MT, Deshmukh H, Ranjan P, Sarode N, Wile BM, Vertino PM, Stewart FJ, Bao G (2014b) CRISPR/Cas9 systems have off-target activity with insertions or deletions between target DNA and guide RNA sequences. Nucl Acids Res 42(11):7473–7485

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin H, Hu H, Duan W et al (2018) Intramuscular delivery of scAAV9-hIGF1 prolongs survival in the hSOD1G93A ALS mouse model via upregulation of D-amino acid oxidase. Mol Neurobiol 55(1):682–695

    CAS  PubMed  Google Scholar 

  • Lisowski L, Tay SS, Alexander IE (2015) Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol 24:59–67

    CAS  PubMed  Google Scholar 

  • Liu F, Song Y, Liu D (1999) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther 6:1258–1266

    CAS  PubMed  Google Scholar 

  • Liu J, Gaj T, Patterson JT, Sirk SJ, Barbas CF (2014a) Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. PLoS One 9(1):e85755

    PubMed  PubMed Central  Google Scholar 

  • Liu M, Li W, Larregieu CA, Cheng M, Yan B, Chu T, Li H, Mao SJ (2014b) Development of synthetic peptide-modified liposomes with LDL receptor targeting capacity and improved anticancer activity. Mol Pharm 11(7):2305–2312

    CAS  PubMed  Google Scholar 

  • Liu Q, Chen X, Jia J, Zhang W, Yang T, Wang L, Ma G (2015) pH-responsive Poly(D, L-lactic-co-glycolic acid) nanoparticles with rapid antigen release behavior promote immune response. ACS Nano 9(5):4925–4938

    CAS  PubMed  Google Scholar 

  • Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, Shu J, Dadon D, Young RA, Jaenisch R (2016a) Editing DNA methylation in the mammalian genome. Cell 167(233–247):e217

    Google Scholar 

  • Liu Y, Zhan Y, Chen Z, He A, Li J, Wu H, Liu L, Zhuang C, Lin J, Guo X, Zhang Q, Huang W, Cai Z (2016b) Directing cellular information flow via crispr signal conductors. Nat Methods 13:938–944

    CAS  PubMed  Google Scholar 

  • Liu T, Hu Y, Guo S, Tan L, Zhan Y, Yang L, Liu W, Wang N, Li Y, Zhang Y, Liu C, Yang Y, Adelstein RS, Wang A (2018) Identification and characterization of MYH9 locus for high efficient gene knock-in and stable expression in mouse embryonic stem cells. PLoS One 13(2):e0192641

    PubMed  PubMed Central  Google Scholar 

  • Liu Q, Zhao K, Wang C, Zhang Z, Chunxiong Zheng Yu, Zhao YZ, Liu C, An Y, Shi L, Kang C, Liu Y (2019) Multistage delivery nanoparticle facilitates efficient CRISPR/dCas9 activation and tumor growth suppression in vivo. Adv Sci (Weinh) 6(1):1801423

    Google Scholar 

  • Lo A, Qi L (2017) Genetic and epigenetic control of gene expression by CRISPR-Cas systems. F1000Research 6:747

    Google Scholar 

  • Long C, Amoasii L, Mireault AA et al (2016) Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351(6271):400–403

    CAS  PubMed  Google Scholar 

  • Lord J, Cruchaga C (2014) The epigenetic landscape of Alzheimer’s disease. Nat Neurosci 17(9):1138–1140

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luo Y, Xuehu X, An X, Sun X, Wang S, Zhu D (2016) Targeted inhibition of the miR-199a/214 cluster by CRISPR interference augments the tumor tropism of human induced pluripotent stem cell-derived neural stem cells under hypoxic condition. Stem Cells Int 2016:3598542

    PubMed  PubMed Central  Google Scholar 

  • Ma JL, Kim EM, Haber JE, Lee SE (2003) Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol Cell Biol 23(23):8820–8828

    CAS  PubMed  PubMed Central  Google Scholar 

  • Machitani M, Sakurai F, Wakabayashi K, Nakatani K, Takayama K, Tachibana M, Mizuguchi H (2017) Inhibition of CRISPR/Cas9-Mediated genome engineering by a Type I interferon-induced reduction in guide RNA expression. Biol Pharm Bull 40(3):272–277

    CAS  PubMed  Google Scholar 

  • Maddalo D, Manchado E, Concepcion CP, Bonetti C, Vidigal JA, Han Y-C, Ogrodowski P, Crippa A, Rekhtman N, de Stanchina E, Lowe SW, Ventura A (2014) In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 516(7531):423–427

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430–446

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maersch S, Huber A, Büning H, Hallek M, Perabo L (2010) Optimization of stealth adeno-associated virus vectors by randomization of immunogenic epitopes. Virology 397(1):167–175

    CAS  PubMed  Google Scholar 

  • Maheshri N, Koerber JT, Kaspar BK, Schaffer DV (2006) Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 24(2):198–204

    CAS  PubMed  Google Scholar 

  • Maier DA, Brennan AL, Jiang S, Binder-Scholl GK, Lee G, Plesa G, Zheng Z, Cotte J, Carpenito C, Wood T, Spratt SK, Ando D, Gregory P, Holmes MC, Perez EE, Riley JL, Carroll RG, June CH, Levine BL (2013) Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR22. Hum Gene Ther 24(3):245–258

    CAS  PubMed  PubMed Central  Google Scholar 

  • Majzoub RN, Chan C-L, Ewert KK, Silva Bruno F B, Liang KS, Jacovetty EL, Carragher B, Potter CS, Safinya CR (2014) Uptake and transfection efficiency of PEGylated cationic liposome–DNA complexes with and without RGD-tagging. Biomaterials 35(18):4996–5005

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mali P et al (2013) RNA-guided human genome engineering via Cas9. Science 339:823–826

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mandal PK et al (2014) Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell Stem Cell 15:643–652

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mangeot PE, Risson V, Fusil F, Marnef A, Laurent E, Blin J, Mournetas V, Massouridès E, Sohier TJM, Corbin A, Aubé F, Teixeira M, Pinset C, Schaeffer L, Legube G, Cosset FL, Verhoeyen E, Ohlmann T, Ricci EP (2019) Genome editing in primary cells and in vivo using viral-derived nanoblades loaded with Cas9-sgRNA ribonucleoproteins. Nat Commun 10(1):45

    PubMed  PubMed Central  Google Scholar 

  • Mansoor M, Melendez AJ (2008) Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics. Gene Regul Syst Biol 2:275–295

    CAS  Google Scholar 

  • Manthey GM, Bailis AM (2010) Rad51 inhibits translocation formation by non-conservative homologous recombination in Saccharomyces cerevisiae. PLoS ONE 5(7):e11889

    PubMed  PubMed Central  Google Scholar 

  • Marshall E (1999) Clinical trials: gene therapy death prompts review of adenovirus vector. Science 286(5448):2244–2245. https://doi.org/10.1126/science.286.5448.2244

    Article  CAS  PubMed  Google Scholar 

  • Mas-Moruno C, Rechenmacher F, Kessler H (2010) Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation. Anticancer Agents Med Chem 10(10):753–768

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mateos-Gomez P, Kent T, Deng S, McDevit S, Kashkina E, Hoang T, Pomerantz R, Sfeir A (2017) The helicase domain of Polθ counteracts RPA to promote alt-NHEJ. Nat Struct Mol Biol 24(12):1116–1123

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matharu N, Rattanasopha S, Tamura S, Maliskova L, Wang Y, Bernard A, Hardin A, Eckalbar WL, Vaisse C, Ahituv N (2019) CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363(6424):eaau0629

    CAS  PubMed  Google Scholar 

  • Matsoukas IG (2018) Commentary: RNA editing with CRISPR-Cas13. Front Genet 9:134

    PubMed  PubMed Central  Google Scholar 

  • Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S, Bowles D, Gray S, Li C, Galloway G, Malik V, Coley B, Clark KR, Li J, Xiao X, Samulski J, McPhee SW, Samulski RJ, Walker CM (2010a) Dystrophin immunity in Duchenne’s muscular dystrophy. N Engl J Med 363(15):1429–1437

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR (2010b) Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol 68(5):629–638

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK (2015) A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther 23(1):192–201

    CAS  PubMed  Google Scholar 

  • Mendez N, Herrera V, Zhang L, Hedjran F, Feuer R, Blair S, Trogler W, Reid T, Kummel A (2014) Encapsulation of adenovirus serotype 5 in anionic lecithin liposomes using a bead-based immunoprecipitation technique enhances transfection efficiency. Biomaterials 35(35):9554–9561

    CAS  PubMed  PubMed Central  Google Scholar 

  • Miao W, Roohi Ahangarani R, Carlier V, Vander Elst L, Saint-Remy JM (2016) Suppression of immune response to adenovirus serotype 5 vector by immunization with peptides containing an MHC class II Epitope and a thio-oxidoreductase motif. Hum Gene Ther 27(3):230–243

    CAS  PubMed  Google Scholar 

  • Miller DG, Wang PR, Petek LM, Hirata RK, Sands MS, Russell DW (2006) Gene targeting in vivo by adeno-associated virus vectors. Nat Biotechnol 24(8):1022–1026

    CAS  PubMed  Google Scholar 

  • Miller JC et al (2011) A TALE nuclease architecture for efficient genome editing. Nat Biotech 29:143–148

    CAS  Google Scholar 

  • Miller JB, Zhang S, Kos P, Xiong H, Zhou K, Perelman SS, Zhu H, Siegwart DJ (2017) Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA. Angew Chem Int Ed Engl 56(4):1059–1063

    CAS  PubMed  Google Scholar 

  • Min YL, Li H, Rodriguez-Caycedo C, Mireault AA, Huang J, Shelton JM, McAnally JR, Amoasii L, Mammen PPA, Bassel-Duby R, Olson EN (2019) CRISPR-Cas9 corrects duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Sci Adv 5(3):eaav4324

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, Ragni MV, Manno CS, Sommer J, Jiang H, Pierce GF, Ertl HC, High KA (2007a) CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 13(4):419–422

    CAS  PubMed  Google Scholar 

  • Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE, Zhou S, Wright JF, Jiang H, Pierce GF, Arruda VR, High KA (2007b) Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110(7):2334–2341

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, High KA, Vervoordeldonk MJ (2013a) Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther 20(4):417–424

    CAS  PubMed  Google Scholar 

  • Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, Basner-Tschakarjan E, Wright JF, High KA (2013b) Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5(194):194ra92

    PubMed  PubMed Central  Google Scholar 

  • Monteilhet V, Saheb S, Boutin S, Leborgne C, Veron P, Montus MF, Moullier P, Benveniste O, Masurier C (2011) A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol Ther 19(11):2084–2091

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morales ME, White TB, Streva VA, DeFreece CB, Hedges DJ, Deininger PL (2015) The contribution of alu elements to mutagenic DNA double-strand break repair. PLoS Genet 11(3):e1005016

    PubMed  PubMed Central  Google Scholar 

  • Mout R, Ray M, Lee Y-W, Scaletti F, Rotello VM (2017) In Vivo delivery of CRISPR/Cas9 for therapeutic gene editing: progress and challenges. Bioconjug Chem 28(4):880–884

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamae K, Nishimura Y, Takenaga M, Nakade S, Sakamoto N, Ide H, Sakuma T, Yamamoto T (2017) Establishment of expanded and streamlined pipeline of PITCh knock-in—a web-based design tool for MMEJ-mediated gene knock-in, PITCh designer, and the variations of PITCh, PITCh-TG and PITCh-KIKO. Bioengineered 8(3):302–308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakatochi M, Ichihara S, Yamamoto K, Naruse K, Yokota S, Asano H, Matsubara T, Yokota M (2017) Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease. Clin Epigenetics. 9:54

    PubMed  PubMed Central  Google Scholar 

  • Nanou A, Higginbottom A, Valori CF, Wyles M, Ning K, Shaw P, Azzouz M (2013) Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis. Mol Ther 21(8):1486–1496

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, Madhavan S, Pan X, Ran FA, Yan WX, Asokan A, Zhang F, Duan D, Gersbach CA (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351(6271):403–407

    CAS  PubMed  Google Scholar 

  • Nelson CE, Wu Y, Gemberling MP, Oliver ML, Waller MA, Bohning JD, Robinson-Hamm JN, Bulaklak K, Castellanos Rivera RM, Collier JH, Asokan A, Gersbach CA (2019) Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med 25(3):427–432

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neves Luís F F, Duan J, Voelker A, Khanal A, McNally L, Steinbach-Rankins JM, Ceresa BP (2016) Preparation and optimization of anionic liposomes for delivery of small peptides and cDNA to human corneal epithelial cells. J Microencapsul 33(4):391–399

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen R, Christensen EI, Birn H (2016) Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int 89(1):58–67

    CAS  PubMed  Google Scholar 

  • Niemeyer GP, Herzog RW, Mount J, Arruda VR, Tillson DM, Hathcock J, van Ginkel FW, High KA, Lothrop CD Jr (2009) Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 113:797–806

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nihongaki Y, Kawano F, Nakajima T, Sato M (2015) Photoactivatable CRISPR-Cas9 for optogenetic genome editing. Nat Biotechnol 33(7):755–760

    CAS  PubMed  Google Scholar 

  • Niu Y et al (2014) Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156:836–843

    CAS  PubMed  Google Scholar 

  • Oakes BL, Fellmann C, Rishi H, Taylor KL, Ren SM, Nadler DC, Yokoo R, Arkin AP, Doudna JA, Savage DF (2019) CRISPR-Cas9 circular permutants as programmable scaffolds for genome modification. Cell 176(1–2):254–267.e16

    PubMed  PubMed Central  Google Scholar 

  • Ogawa K, Kamimura K, Kobayashi Y, Abe H, Yokoo T, Sakai N, Nagoya T, Sakamaki A, Abe S, Hayashi K, Ikarashi S, Kohisa J, Tsuchida M, Aoyagi Y, Zhang G, Liu D, Terai S (2017) Efficacy and safety of pancreas-targeted hydrodynamic gene delivery in rats. Mol Ther Nucl Acids 9:80–88

    CAS  Google Scholar 

  • O’Riordan CR, Lachapelle A, Delgado C, Parkes V, Wadsworth SC, Smith AE, Francis GE (1999) PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 10(8):1349–1358

    PubMed  Google Scholar 

  • Ortinski PI, O’Donovan B, Dong X, Kantor B (2017) Integrase-deficient lentiviral vector as an all-in-one platform for highly efficient CRISPR/Cas9-mediated gene editing. Mol Ther Methods Clin Dev 5:153–164

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ousterout DG, Kabadi AM, Thakore PI, Majoros WH, Reddy TE, Gersbach CA (2015) Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause duchenne muscular dystrophy. Nat Commun 6:6244

    CAS  PubMed  Google Scholar 

  • Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, Kim JH, Kim DW, Kim JS (2015) Functional correction of large factor VIII gene chromosomal inversions in hemophilia A patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell 17(2):213–220

    CAS  PubMed  Google Scholar 

  • Pellenz S, Phelps M, Tang W, Hovde BT, Sinit RB, Fu W, Li H, Chen E, Monnat RJ Jr (2019) New human chromosomal sites with “safe harbor” potential for targeted transgene insertion. Hum Gene Ther. https://doi.org/10.1089/hum.2018.169

    Article  PubMed  PubMed Central  Google Scholar 

  • Perabo L, Endell J, King S, Lux K, Goldnau D, Hallek M, Büning H (2006) Combinatorial engineering of a gene therapy vector: directed evolution of adeno-associated virus. J Gene Med 8(2):155–162

    CAS  PubMed  Google Scholar 

  • Periyasamy M, Singh AK, Gemma C, Kranjec C, Farzan R, Leach DA, Navaratnam N, Pálinkás HL, Vértessy BG, Fenton TR, Doorbar J, Fuller-Pace F, Meek DW, Coombes RC, Buluwela L, Ali S (2017) p53 controls expression of the DNA deaminase APOBEC3B to limit its potential mutagenic activity in cancer cells. Nucl Acids Res 45(19):11056–11069

    PubMed  PubMed Central  Google Scholar 

  • Pezzoli D, Chiesa R, De Nardo L et al (2012) We still have a long way to go to effectively deliver genes! J Appl Biomater Funct Mater 10(2):82–91

    CAS  PubMed  Google Scholar 

  • Pichon C, Guérin B, Réfrégiers M, Gonçalves C, Vigny P, Midoux P (2002) Zinc improves gene transfer mediated by DNA/cationic polymer complexes. J Gene Med 4(5):548–559

    CAS  PubMed  Google Scholar 

  • Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, Dahlman JE, Parnas O, Eisenhaure TM, Jovanovic M, Graham DB, Jhunjhunwala S, Heidenreich M, Xavier RJ, Langer R, Anderson DG, Hacohen N, Regev A, Feng G, Sharp PA, Zhang F (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159(2):440–455

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ponomarenko JV, Bourne PE (2007) Antibody-protein interactions: benchmark datasets and prediction tools evaluation. BMC Struct Biol 7:64

    PubMed  PubMed Central  Google Scholar 

  • Ponomarenko J, Bui HH, Li W, Fusseder N, Bourne PE, Sette A, Peters B (2008) ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinf 9:514

    Google Scholar 

  • Prades R, Oller-Salvia B, Schwarzmaier SM et al (2015) Applying the retro-enantio approach to obtain a peptide capable of overcoming the blood–brain barrier. Angew Chem Int Ed 54(13):3967–3972

    CAS  Google Scholar 

  • Ramakrishna S et al (2014a) Gene disruption by cell penetrating peptide-mediated delivery of Cas9 protein and guide RNA. Genome Res 24:1020–1027

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ramakrishna S, Cho SW, Kim S, Song M, Gopalappa R, Kim JS, Kim H (2014b) Surrogate reporter-based enrichment of cells containing RNA-guided Cas9 nuclease-induced mutations. Nat Commun 5:3378

    PubMed  Google Scholar 

  • Rampersad GC, Suck G, Sakac D, Fahim S, Foo A, Denomme GA, Langler RF, Branch DR (2005) Chemical compounds that target thiol-disulfide groups on mononuclear phagocytes inhibit immune mediated phagocytosis of red blood cells. Transfusion 45(3):384–393

    CAS  PubMed  Google Scholar 

  • Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, Zhang F (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154(6):1380–1389

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS, Koonin EV, Sharp PA, Zhang F (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520(7546):186–191

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reardon S (2016) First CRISPR clinical trial gets green light from US panel. Nat News. https://www.nature.com/news/first-crispr-clinical-trial-gets-green-light-from-us-panel-1.20137. Accessed 10 Jan 2019

  • Rees HA, Komor AC, Yeh WH, Caetano-Lopes J, Warman M, Edge ASB, Liu DR (2017) Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat Commun 8:15790

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ren C, Adams AN, Pyles B, Bailus BJ, O’Geen H, Segal DJ (2018) In vivo applications of cell-penetrating zinc-finger transcription factors. Methods Mol Biol 1867:239–251

    CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE (2016) Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol 34(3):339–344

    CAS  PubMed  Google Scholar 

  • Riechmann L, Clark M, Waldmann H, Winter G (1988) Reshaping human antibodies for therapy. Nature 332(6162):323–327

    CAS  PubMed  Google Scholar 

  • Rodrigues GA, Shalaev E, Karami TK, Cunningham J, Slater NKH, Rivers HM (2019) Pharmaceutical development of AAV-based gene therapy products for the eye. Pharm Res 36(2):29

    Google Scholar 

  • Rothenberg E, Grimme JM, Spies M, Ha T (2008) Human Rad52-mediated homology search and annealing occurs by continuous interactions between overlapping nucleoprotein complexes. Proc Natl Acad Sci USA 105(51):20274–20279

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rouet R, Thuma BA, Roy MD, Lintner NG, Rubitski DM, Finley JE, Wisniewska HM, Mendonsa R, Hirsh A, de Oñate L, Compte Barrón J, McLellan TJ, Bellenger J, Feng X, Varghese A, Chrunyk BA, Borzilleri K, Hesp KD, Zhou K, Ma N, Tu M, Dullea R, McClure KF, Wilson RC, Liras S, Mascitti V, Doudna JA (2018) Receptor-mediated delivery of CRISPR-Cas9 endonuclease for cell-type-specific gene editing. J Am Chem Soc 140(21):6596–6603

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ryu SM, Koo T, Kim K, Lim K, Baek G, Kim ST, Kim HS, Kim DE, Lee H, Chung E, Kim JS (2018) Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nat Biotechnol 36(6):536–539

    CAS  PubMed  Google Scholar 

  • Sakuma T, Nakade S, Sakane Y, Suzuki KT, Yamamoto T (2016) MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems. Nat Protoc 11(1):118–133

    CAS  PubMed  Google Scholar 

  • Sallach J, Di Pasquale G, Larcher F, Niehoff N, Rübsam M, Huber A, Chiorini J, Almarza D, Eming SA, Ulus H, Nishimura S, Hacker UT, Hallek M, Niessen CM, Büning H (2014) Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy. Mol Ther 22(5):929–939

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saunderson EA, Stepper P, Gomm JJ, Hoa L, Morgan A, Allen MD, Jones JL, Gribben JG, Jurkowski TP, Ficz G (2017) Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors. Nat Commun 8(1):1450

    PubMed  PubMed Central  Google Scholar 

  • Schwank G et al (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13:653–658

    CAS  PubMed  Google Scholar 

  • Segal DJ, Dreier B, Beerli RR, Barbas CF 3rd (1999) Toward controlling gene expression at will: selection and design of zinc finger domains recognizing each of the 5ʹ-GNN-3ʹ DNA target sequences. Proc Natl Acad Sci USA 96:2758–2763

    CAS  PubMed  PubMed Central  Google Scholar 

  • Senturk S, Shirole NH, Nowak DG, Corbo V, Pal D, Vaughan A, Tuveson DA, Trotman LC, Kinney JB, Sordella R (2017) Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization. Nat Commun 8:14370

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, Melief CJ, Oseroff C, Yuan L, Ruppert J et al (1994) The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 153:5586–5592

    CAS  PubMed  Google Scholar 

  • Shao S, Ren C, Liu Z, Bai Y, Chen Z, Wei Z, Wang X, Zhang Z, Xu K (2017) Enhancing CRISPR/Cas9-mediated homology-directed repair in mammalian cells by expressing Saccharomyces cerevisiae Rad 52. Int J Biochem Cell Biol 92:43–52

    CAS  PubMed  Google Scholar 

  • Shin J, Jiang F, Liu J-J, Bray NL, Rauch BJ, Baik SH, Nogales E, Bondy-Denomy J, Corn JE, Doudna JA (2017) Disabling Cas9 by an anti-CRISPR DNA mimic. Sci Adv 3(7):e1701620

    PubMed  PubMed Central  Google Scholar 

  • Simeonov DR, Brandt AJ, Chan AY, Cortez JT, Li Z, Woo JM, Lee Y, Carvalho CMB, Indart AC, Roth TL, Zou J, May AP, Lupski JR, Anderson MS, Buaas FW, Rokhsar DS, Marson A (2019) A large CRISPR-induced bystander mutation causes immune dysregulation. Commun Biol 2:70

    PubMed  PubMed Central  Google Scholar 

  • Singla S, Harjai K, Katare OP, Chhibber S (2016) Encapsulation of bacteriophage in liposome accentuates its entry into macrophage and shields it from neutralizing antibodies. PLoS One 11(4):e0153777

    PubMed  PubMed Central  Google Scholar 

  • Sinha S, Li F, Villarreal D, Shim JH, Yoon S, Myung K, Shim EY, Lee SE (2017) Microhomology-mediated end joining induces hypermutagenesis at breakpoint junctions. PLoS Genet 13(4):e1006714

    PubMed  PubMed Central  Google Scholar 

  • Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351(6268):84–88

    CAS  PubMed  Google Scholar 

  • Spraggon L, Martelotto LG, Hmeljak J, Hitchman TD, Jiang Wang L, Wang EK, Slotkin P-DF, Reis-Filho JS, Ladanyi M (2017) Generation of conditional oncogenic chromosomal translocations using CRISPR-Cas9 genomic editing and homology-directed repair. J Pathol 242(1):102–112

    CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava A (2016) In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol 21:75–80

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sternberg SH, Redding S, Jinek M, Greene EC, Doudna JA (2014) DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. Nature 507(7490):62–67

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stoller F, Schlegel A, Viecelli HM, Rüfenacht V, Cesarovic N, Viecelli C, Deplazes S, Bettschart R, Hurter K, Schmierer P, Sidler X, Kron P, Dutkowski P, Graf R, Thöny B, Häberle J (2015) Hepatocyte transfection in small pigs after weaning by hydrodynamic intraportal injection of naked DNA/minicircle vectors. Hum Gene Ther Methods 26(5):181–192

    CAS  PubMed  Google Scholar 

  • Sun W et al (2015) Self-assembled DNA nanoclews for the efficient delivery of CRISPR-Cas9 for genome editing. Angew Chem Int Ed 54:12029–12033

    CAS  Google Scholar 

  • Swiech L, Heidenreich M, Banerjee A, Habib N, Li Y, Trombetta J, Sur M, Zhang F (2015) In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat Biotechnol 33(1):102–106

    CAS  PubMed  Google Scholar 

  • Szebeni J, Moghimi SM (2009) Liposome triggering of innate immune responses: a perspective on benefits and adverse reactions. J Liposome Res 19(2):85–90

    CAS  PubMed  Google Scholar 

  • Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J et al (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 101:3516–3521

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tabuchi Y, Ando H, Takasaki I, Feril LB Jr, Zhao QL, Ogawa R, Kudo N, Tachibana K, Kondo T (2007) Identification of genes responsive to low intensity pulsed ultrasound in a human leukemia cell line Molt-4. Cancer Lett 246(1–2):149–156

    CAS  PubMed  Google Scholar 

  • Taketani Y, Kitamoto K, Sakisaka T, Kimakura M, Toyono T, Yamagami S, Amano S, Kuroda M, Moore T, Usui T, Ouchi Y (2017) Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair. Sci Rep 7:16713

    PubMed  PubMed Central  Google Scholar 

  • Tang W, Hu JH, Liu DR (2017) Aptazyme-embedded guide rnas enable ligand-responsive genome editing and transcriptional activation. Nat Commun 8:15939

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thakore PI, D’Ippolito AM, Song L, Safi A, Shivakumar NK, Kabadi AM, Reddy TE, Crawford GE, Gersbach CA (2015) Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods 12:1143–1149

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tröder SE, Ebert LK, Butt L, Assenmacher S, Schermer B, Zevnik B (2018) An optimized electroporation approach for efficient CRISPR/Cas9 genome editing in murine zygotes. PLoS One 13(5):e0196891

    PubMed  PubMed Central  Google Scholar 

  • Truong LN, Li Y, Shi LZ, Hwang PY, He J, Wang H, Razavian N, Berns MW, Wu X (2013) Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc Natl Acad Sci USA 110(19):7720–7725

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vakulskas CA, Dever DP, Rettig GR, Turk R, Jacobi AM, Collingwood MA, Bode NM, McNeill MS, Yan S, Camarena J, Lee CM, Park SH, Wiebking V, Bak RO, Gomez-Ospina N, Pavel-Dinu M, Sun W, Bao G, Porteus MH, Behlke MA (2018) A high-fidelity Cas9 mutant delivered as a ribonucleoprotein complex enables efficient gene editing in human haematopoietic stem and progenitor cells. Nat Med 24(8):1216–1224

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vanoli F, Tomishima M, Feng W, Lamribet K, Babin L, Brunet E, Jasin M (2017) CRISPR-Cas9–guided oncogenic chromosomal translocations with conditional fusion protein expression in human mesenchymal cells. Proc Natl Acad Sci USA 114(14):3696–3701

    CAS  PubMed  PubMed Central  Google Scholar 

  • Villiger L, Grisch-Chan HM, Lindsay H, Ringnalda F, Pogliano CB, Allegri G, Fingerhut R, Häberle J, Matos J, Robinson MD, Thöny B, Schwank G (2018) Treatment of a metabolic liver disease by in vivo genome base editing in adult mice. Nat Med 24(10):1519–1525

    CAS  PubMed  Google Scholar 

  • Waehler R, Russell SJ, Curiel DT (2007) Engineering targeted viral vectors for gene therapy. Nat Rev Genet 8:573–587

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner DL, Amini L, Wendering DJ, Burkhardt LM, Akyüz L, Reinke P, Volk HD, Schmueck-Henneresse M (2019) High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population. Nat Med 25(2):242–248

    CAS  PubMed  Google Scholar 

  • Wang Q, Ui-Tei K (2017) Computational prediction of CRISPR/Cas9 target sites reveals potential off-target risks in human and mouse. Methods Mol Biol 1630:43–53

    CAS  PubMed  Google Scholar 

  • Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004) Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10:1366–1373

    CAS  PubMed  Google Scholar 

  • Wang H et al (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153:910–918

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J et al (2016a) Highly efficient homology-driven genome editing in human T cells by combining zincfinger nuclease mRNA and AAV6 donor delivery. Nucl Acid Res 44:e30

    Google Scholar 

  • Wang X, Huang X, Fang X, Zhang Y, Wang W (2016b) CRISPR-Cas9 system as a versatile tool for genome engineering in human cells. Mol Ther Nucl Acids 5(11):e388

    CAS  Google Scholar 

  • Wang M, Sun Z, Zou Z, Ding F, Li L, Wang H, Zhao C, Li N, Dai Y (2018) Efficient targeted integration into the bovine Rosa26 locus using TALENs. Sci Rep 8:10385

    PubMed  PubMed Central  Google Scholar 

  • Wienert B, Wyman SK, Richardson CD, Yeh CD, Akcakaya P, Porritt MJ, Morlock M, Vu JT, Kazane KR, Watry HL, Judge LM, Conklin LM, Maresca M, Corn JE (2018) Unbiased detection of CRISPR off-targets in vivo using DISCOVER-seq. Science. https://doi.org/10.1101/469635

    Article  Google Scholar 

  • Wiley LA, Burnight ER, Kaalberg EE, Jiao C, Riker MJ, Halder JA, Luse MA, Han IC, Russell SR, Sohn EH, Stone EM, Tucker BA, Mullins RF (2018) Assessment of adeno-associated virus serotype tropism in human retinal explantsm. Hum Gene Ther 29(4):424–436

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wojtal D, Kemaladewi DU, Malam Z, Abdullah S, Wong TW, Hyatt E, Baghestani Z, Pereira S, Stavropoulos J, Mouly V, Mamchaoui K, Muntoni F, Voit T, Gonorazky HD, Dowling JJ, Wilson MD, Mendoza-Londono R, Ivakine EA, Cohn RD (2016) Spell Checking Nature: versatility of CRISPR/Cas9 for developing treatments for inherited disorders. Am J Hum Genet 98(1):90–101

    CAS  PubMed  Google Scholar 

  • Wolfe D, Mata M, Fink DJ (2009) A human trial of HSV-mediated gene transfer for the treatment of chronic pain. Gene Ther 16(4):455–460

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wortmann A, Vöhringer S, Engler T, Corjon S, Schirmbeck R, Reimann J, Kochanek S, Kreppel F (2008) Fully detargeted polyethylene glycol-coated adenovirus vectors are potent genetic vaccines and escape from pre-existing anti-adenovirus antibodies. Mol Ther 16(1):154–162

    CAS  PubMed  Google Scholar 

  • Wu Y et al (2013) Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell Stem Cell 13:659–662

    CAS  PubMed  Google Scholar 

  • Wu H, Wang J, Lu J, Wang Y, Niu Z (2016) Treatment of renal stones ≥ 20 mm with extracorporeal shock wave lithotripsy. Urol Int 96(1):99–105

    CAS  PubMed  Google Scholar 

  • Xia E, Duan R, Shi F, Seigel KE, Grasemann H, Hu J (2018) Overcoming the undesirable CRISPR-Cas9 expression in gene correction. Mol Therap Nucl Acids. https://doi.org/10.1016/j.omtn.2018.10.015

    Article  Google Scholar 

  • Xiao Y, Ng S, Nam KH, Ke A (2017) How type II CRISPR-Cas establish immunity through Cas1–Cas2-mediated spacer integration. Nature 550(7674):137–141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L, Yang H, Gao Y, Chen Z, Xie L, Liu Y, Liu Y, Wang X, Li H, Lai W, He Y, Yao A, Ma L, Shao Y, Zhang B, Wang C, Chen H, Deng H (2017a) CRISPR/Cas9-mediated CCR183 ablation in human hematopoietic stem/progenitor cells confers HIV-1 resistance in vivo. Mol Ther 25(8):1782–1789

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xu X, Li J, Zhu Y, Xie B, Wang X, Wang S, Xie H, Yan H, Ying Y, Lin Y, Liu B, Wang W, Zheng X (2017b) CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancer in vitro and in vivo. Oncotarget 8(60):102078–102087

    PubMed  PubMed Central  Google Scholar 

  • Yang H, Patel DJ (2017) Inhibition mechanism of an Anti-CRISPR suppressor AcrIIA4 targeting SpyCas9. Mol Cell 67(1):117–127

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Wang L, Bell P et al (2016) A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol 34(3):334–338

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang S, Chang R, Yang H, Zhao T, Hong Y, Kong HE, Sun X, Qin Z, Jin P, Li S, Li XJ (2017a) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J Clin Invest 127(7):2719–2724

    PubMed  PubMed Central  Google Scholar 

  • Yang X, Gao L, Zhang S (2017b) Comparative pan-cancer DNA methylation analysis reveals cancer common and specific patterns. Brief Bioinform 18(5):761–773

    CAS  PubMed  Google Scholar 

  • Yeh WH, Chiang H, Rees HA, Edge ASB, Liu DR (2018) In vivo base editing of post-mitotic sensory cells. Nat Commun 9(1):2184

    PubMed  PubMed Central  Google Scholar 

  • Yen J, Fiorino M, Liu Y, Paula S, Clarkson S, Quinn L, Tschantz WR, Klock H, Guo N, Russ C, Yu Vionnie W C, Mickanin C, Stevenson SC, Lee C, Yang Y (2018) TRIAMF: a new method for delivery of Cas9 ribonucleoprotein complex to human hematopoietic stem cells. Sci Rep 8:16304

    PubMed  PubMed Central  Google Scholar 

  • Yeung VP, Chang J, Miller J, Barnett C, Stickler M, Harding FA (2004) Elimination of an immunodominant CD4 + T cell epitope in human IFN-beta does not result in an in vivo response directed at the subdominant epitope. J Immunol 172:6658–6665

    CAS  PubMed  Google Scholar 

  • Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M, Koteliansky V, Sharp PA, Jacks T, Anderson DG (2014) Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol 32(6):551–553

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yin H et al (2016) Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol 34:328–333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yokoda R, Nagalo BM, Vernon B, Oklu R, Albadawi H, DeLeon TT, Zhou Y, Egan JB, Duda DG, Borad MJ (2017) Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect. Oncolytic Virother 6:39–49

    PubMed  PubMed Central  Google Scholar 

  • Yu X, Gabriel A (2003) Ku-dependent and Ku-independent end-joining pathways lead to chromosomal rearrangements during double-strand break repair in Saccharomyces cerevisiae. Genetics 163(3):843–856

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu W, Mookherjee S, Chaitankar V et al (2017) Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun 8:14716

    PubMed  PubMed Central  Google Scholar 

  • Zetsche B, Volz SE, Zhang F (2015) A split-Cas9 architecture for inducible genome editing and transcription modulation. Nat Biotechnol 33(2):139–142

    CAS  PubMed  Google Scholar 

  • Zhang Y, Ge X, Yang F, Zhang L, Zheng J, Tan X, Jin ZB, Qu J, Gu F (2014) Comparison of non-canonical PAMs for CRISPR/Cas9-mediated DNA cleavage in human cells. Sci Rep 4:5405

    PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Qin W, Lu X, Xu J, Huang H, Bai H, Li S, Lin S (2017) Programmable base editing of zebrafish genome using a modified CRISPR-Cas9 system. Nat Commun 8(1):118

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XG, Liu JW, Tang P, Liu ZY, Guo GJ, Sun QY, Yin JJ (2018a) Identification of a new uncompetitive inhibitor of adenosine deaminase from endophyte Aspergillus niger sp. Curr Microbiol 75(5):565–573

    CAS  PubMed  Google Scholar 

  • Zhang S, Li X, Lin Q, Wong KC (2018b) Synergizing CRISPR/Cas9 off-target predictions for ensemble insights and practical applications. Bioinformatics. https://doi.org/10.1093/bioinformatics/bty748

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M, Herzog RW, Zolotukhin I, Warrington KH Jr, Weigel-Van Aken KA, Hobbs JA, Zolotukhin S, Muzyczka N, Srivastava A (2008) Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci USA 105(22):7827–7832

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Liu J, Zhou C, Gao N, Rao Z, Li H, Hu X, Li C, Yao X, Shen X, Sun Y, Wei Y, Liu F, Ying W, Zhang J, Tang C, Zhang X, Xu H, Shi L, Cheng L, Huang P, Yang H (2018) In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice. Nat Neurosci 21(3):440–446

    CAS  PubMed  Google Scholar 

  • Zhu X, Guo J, He C, Geng H, Gengsheng Yu, Li J, Zheng H, Ji X, Yan F (2016) Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles. Sci Rep 6:21683

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu H, Zhang L, Tong S, Lee CM, Deshmukh H, Bao G (2019) Spatial control of in vivo CRISPR–Cas9 genome editing via nanomagnets. Nature Biomed Eng 3:126–136

    CAS  Google Scholar 

  • Zuo E, Huo X, Yao X, Xinde H, Sun Y, Yin J, He B, Wang X, Shi L, Jie Ping Yu, Wei WY, Wei W, Liu W, Tang C, Li Y, Jiazhi H, Yang H (2017) CRISPR/Cas9-mediated targeted chromosome elimination. Genome Biol 18:224

    PubMed  PubMed Central  Google Scholar 

  • Zuo E et al (2019) Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science. https://doi.org/10.1126/science.aav9973

    Article  PubMed  PubMed Central  Google Scholar 

  • Zuris JA et al (2014) Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol 33:73–80

    PubMed  PubMed Central  Google Scholar 

  • Zuris JA, Thompson DB, Shu Y, Guilinger JP, Bessen JL, Hu JH, Maeder ML, Joung JK, Chen ZY, Liu DR (2015) Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol 33(1):73–80

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Minyoung Lee

  2. Department of Pharmacology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Hyongbum Kim

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  1. Minyoung Lee
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  2. Hyongbum Kim
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Correspondence to Minyoung Lee.

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Lee, M., Kim, H. Therapeutic application of the CRISPR system: current issues and new prospects. Hum Genet 138, 563–590 (2019). https://doi.org/10.1007/s00439-019-02028-2

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