In vivo genome editing restores haemostasis in a mouse model of haemophilia
Open accessAbstract
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The initial efficiency of repair using zinc finger nucleases was low and was substantially improved by subsequent work to correct hemophilia in mice.
“the initial efficiency of repair using zinc finger nucleases was also low and was substantially improved by subsequent work to correct hemophilia in mice12.”
From Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype (2014) · cites this paper as [12]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Metabolic and Molecular Bases of Inherited Disease
Scriver, R. C. (1995) · Medical Entomology and Zoology · Cited by 12,101 · see citing works
<i>LMO2</i> -Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M. P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C. S., Pawliuk, R., Morillon, E., et al. (2003) · Science · doi:10.1126/science.1088547 · Cited by 3,587 · see citing works
Genome editing with engineered zinc finger nucleases
Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S., & Gregory, P. D. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2842 · Cited by 2,285 · see citing works
Self-citationManno, C. S., Pierce, G. F., Arruda, V. R., Glader, B., Ragni, M., Rasko, J. J. E., Ozelo, M. C., Hoots, K., Blatt, P., Konkle, B., et al. (2006) · Nature Medicine · doi:10.1038/nm1358 · Cited by 2,163 · see citing works
Self-citationSafety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802315 · Cited by 2,145 · see citing works
Self-citationEffect of gene therapy on visual function in Leber’s congenital amaurosis
Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802268 · Cited by 1,924 · see citing works
Highly efficient endogenous human gene correction using designed zinc-finger nucleases
Urnov, F. D., Miller, J. C., Lee, Y.-L., Beausejour, C. M., Rock, J. M., Augustus, S., Jamieson, A. C., Porteus, M. H., Gregory, P. D., & Holmes, M. C. (2005) · Nature · doi:10.1038/nature03556 · Cited by 1,642 · see citing works
Self-citationHematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., et al. (2009) · Science · doi:10.1126/science.1171242 · Cited by 1,508 · see citing works
Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin
Hanna, J. H., Wernig, M., Markoulaki, S., Sun, C., Meissner, A., Cassady, J. P., Beard, C., Brambrink, T., Wu, L.-C., Townes, T. M., et al. (2007) · Science · doi:10.1126/science.1152092 · Cited by 1,493 · see citing works
Howe, S. J., Mansour, M. R., Schwarzwaelder, K., Bartholomae, C., Hubank, M., Kempski, H., Brugman, M. H., Pike-Overzet, K., Chatters, S. J., de Ridder, D., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35798 · Cited by 1,286 · see citing works
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Cavazzana-Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., et al. (2010) · Nature · doi:10.1038/nature09328 · Cited by 1,276 · see citing works
Self-citationGene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency
Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., Scaramuzza, S., Andolfi, G., Mirolo, M., Brigida, I., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805817 · Cited by 1,003 · see citing works
Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Perez, E. E., Wang, J., Miller, J. C., Jouvenot, Y., Kim, K. A., Liu, O., Wang, N., Lee, G., Bartsevich, V. V., Lee, Y.-L., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1410 · Cited by 999 · see citing works
Self-citationHeritable targeted gene disruption in zebrafish using designed zinc-finger nucleases
Doyon, Y., McCammon, J. M., Miller, J. C., Faraji, F., Ngo, C., Katibah, G. E., Amora, R., Hocking, T. D., Zhang, L., Rebar, E. J., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1409 · Cited by 896 · see citing works
Self-citationZambrowicz, B., Imamoto, A., Fiering, S., Herzenberg, L. A., Kerr, W. G., & Soriano, P. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.8.3789 · Cited by 850 · see citing works
Chimeric nucleases stimulate gene targeting in human cells
Porteus, M. H., & Baltimore, D. (2003) · Science · doi:10.1126/science.1078395 · Cited by 741 · see citing works
Cideciyan, A. V., Alemán, T. S., Boye, S. L., Schwartz, S., Kaushal, S., Román, A. J., Pang, J., Sumaroka, A., Windsor, E. A. M., Wilson, J. M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807027105 · Cited by 674 · see citing works
Stimulation of Homologous Recombination through Targeted Cleavage by Chimeric Nucleases
Bibikova, M. V., Carroll, D., Segal, D. J., Trautman, J. K., Smith, J., Kim, Y., & Chandrasegaran, S. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.1.289-297.2001 · Cited by 614 · see citing works
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577 · see citing works
Nakai, H., Yant, S. R., Storm, T. A., Fuess, S., Meuse, L., & Kay, M. A. (2001) · Journal of Virology · doi:10.1128/jvi.75.15.6969-6976.2001 · Cited by 478 · see citing works
AAV serotype 2 vectors preferentially integrate into active genes in mice
Nakai, H., Montini, E., Fuess, S., Storm, T. A., Grompe, M., & Kay, M. A. (2003) · Nature Genetics · doi:10.1038/ng1179 · Cited by 392 · see citing works
Moehle, E. A., Rock, J. M., Lee, Y.-L., Jouvenot, Y., DeKelver, R. C., Gregory, P. D., Urnov, F. D., & Holmes, M. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611478104 · Cited by 371 · see citing works
Self-citationA Coagulation Factor IX-Deficient Mouse Model for Human Hemophilia B
Lin, H.-F., Maeda, N., Smithies, O., Straight, D. L., & Stafford, D. W. (1997) · Blood · doi:10.1182/blood.v90.10.3962 · Cited by 290 · see citing works
Ayuso, E., Mingozzi, F., Montané, J., León, X., Anguela, X. M., Haurigot, V., Edmonson, S. A., Africa, L. M., Zhou, S., High, K. A., et al. (2009) · Gene Therapy · doi:10.1038/gt.2009.157 · Cited by 279 · see citing works
Self-citationAdeno-associated virus vectors integrate at chromosome breakage sites
Miller, D. G., Petek, L. M., & Russell, D. W. (2004) · Nature Genetics · doi:10.1038/ng1380 · Cited by 266 · see citing works
Miao, C. H., Ohashi, K., Patijn, G. A., Meuse, L. A., Ye, X., Thompson, A. R., & Kay, M. A. (2000) · Molecular Therapy · doi:10.1006/mthe.2000.0075 · Cited by 246 · see citing works
Assessing the potential for AAV vector genotoxicity in a murine model
Li, H., Malani, N., Hamilton, S. R., Schlachterman, A., Bussadori, G., Edmonson, S. A., Shah, R., Arruda, V. R., Mingozzi, F., Wright, J. F., et al. (2010) · Blood · doi:10.1182/blood-2010-08-302729 · Cited by 234 · see citing works
Self-citationSelection of Target Sites for Mobile DNA Integration in the Human Genome
Berry, C., Hannenhalli, S., Leipzig, J., & Bushman, F. (2006) · PLoS Comput. Biol. · doi:10.1371/journal.pcbi.0020157 · Cited by 210 · see citing works
Self-citationGerm line origins of de novo mutations in hemophilia B families
Thompson, A., & Chen, S.-H. (1994) · Human Genetics · doi:10.1007/bf00208288 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
RNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210 · see citing works
ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering
Gaj, T., Gersbach, C. A., & Barbas, C. F. (2013) · Trends in Biotechnology · doi:10.1016/j.tibtech.2013.04.004 · Cited by 3,820 · see citing works
Non-viral vectors for gene-based therapy
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3763 · Cited by 3,123 · see citing works
Adeno-associated virus vector as a platform for gene therapy delivery
Wang, D., Tai, P. W. L., & Gao, G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0012-9 · Cited by 2,444 · see citing works
Therapeutic genome editing: prospects and challenges
Cox, D. B. T., Platt, R. J., & Zhang, F. (2015) · Nature Medicine · doi:10.1038/nm.3793 · Cited by 1,336 · see citing works
Cas9 as a versatile tool for engineering biology
Mali, P., Esvelt, K. M., & Church, G. M. (2013) · Nature Methods · doi:10.1038/nmeth.2649 · Cited by 1,197 · see citing works
Gene therapy returns to centre stage
Naldini, L. (2015) · Nature · doi:10.1038/nature15818 · Cited by 1,184 · see citing works
A guide to genome engineering with programmable nucleases
Kim, S., & Kim, J. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3686 · Cited by 1,162 · see citing works
Chehelgerdi, M., Chehelgerdi, M., Allela, O. Q. B., Pecho, R. D. C., Narayanan, J., Rao, D. P., Thamaraikani, T., Vasanthan, M., Viktor, P., Lakshmaiya, N., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01865-0 · Cited by 1,116 · see citing works
Pleiotropy in complex traits: challenges and strategies
Solovieff, N., Cotsapas, C., Lee, P. H., Purcell, S. M., & Smoller, J. W. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3461 · Cited by 1,085 · see citing works
Immune responses to AAV vectors: overcoming barriers to successful gene therapy
Mingozzi, F., & High, K. A. (2013) · Blood · doi:10.1182/blood-2013-01-306647 · Cited by 955 · see citing works
Self-citationGenome editing with Cas9 in adult mice corrects a disease mutation and phenotype
Yin, H., Xue, W., Chen, S., Bogorad, R. L., Benedetti, E., Grompe, M., Koteliansky, V., Sharp, P. A., Jacks, T., & Anderson, D. G. (2014) · Nature Biotechnology · doi:10.1038/nbt.2884 · Cited by 951 · see citing works
Emerging issues in AAV-mediated in vivo gene therapy
Colella, P., Ronzitti, G., & Mingozzi, F. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2017.11.007 · Cited by 881 · see citing works
Yin, H., Song, C.-Q., Dorkin, J. R., Zhu, L. J., Li, Y., Wu, Q., Park, A., Yang, J., Suresh, S., Bizhanova, A., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3471 · Cited by 876 · see citing works
Engineering adeno-associated viruses for clinical gene therapy
Kotterman, M. A., & Schaffer, D. V. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3742 · Cited by 761 · see citing works
Genome-editing Technologies for Gene and Cell Therapy
Maeder, M. L., & Gersbach, C. A. (2016) · Molecular Therapy · doi:10.1038/mt.2016.10 · Cited by 722 · see citing works
CRISPR/Cas9 for genome editing: progress, implications and challenges
Zhang, F., Wen, Y., & Guo, X. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu125 · Cited by 694 · see citing works
CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy
Rosenblum, D., Gutkin, A., Kedmi, R., Ramishetti, S., Veiga, N., Jacobi, A. M., Schubert, M. S., Friedmann-Morvinski, D., Cohen, Z. R., Behlke, M. A., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc9450 · Cited by 614 · see citing works
Delivery technologies for genome editing
Yin, H., Kauffman, K. J., & Anderson, D. G. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.280 · Cited by 597 · see citing works
Targeted genome editing in human repopulating haematopoietic stem cells
Genovese, P., Schiroli, G., Escobar, G., Di Tomaso, T., Firrito, C., Calabria, A., Moi, D., Mazzieri, R., Bonini, C., Holmes, M. C., et al. (2014) · Nature · doi:10.1038/nature13420 · Cited by 555 · see citing works
Self-citationGenome Engineering with Targetable Nucleases
Carroll, D. (2014) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060713-035418 · Cited by 541 · see citing works
Cholangiocarcinomas can originate from hepatocytes in mice
Fan, B., Malato, Y., Calvisi, D. F., Naqvi, S., Razumilava, N., Ribback, S., Gores, G. J., Dombrowski, F., Evert, M., Chen, X., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63212 · Cited by 529 · see citing works
Genetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
DeWitt, M. A., Magis, W., Bray, N. L., Wang, T., Berman, J. R., Urbinati, F., Heo, S.-J., Mitros, T., Muñoz, D. P., Boffelli, D., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf9336 · Cited by 477 · see citing works
Ousterout, D. G., Kabadi, A. M., Thakore, P. I., Majoros, W. H., Reddy, T. E., & Gersbach, C. A. (2015) · Nature Communications · doi:10.1038/ncomms7244 · Cited by 470 · see citing works
Engineering the next generation of cell-based therapeutics
Bashor, C. J., Hilton, I. B., Bandukwala, H. S., Smith, D. M., & Omid Veiseh, A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00476-6 · Cited by 448 · see citing works
Viral Vectors for Gene Therapy: Translational and Clinical Outlook
Kotterman, M. A., Chalberg, T. W., & Schaffer, D. V. (2015) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071813-104938 · Cited by 444 · see citing works
Genome-Editing Technologies: Principles and ApplicationsPreprint
Gaj, T., Sirk, S. J., Shui, S., & Liu, J. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a023754 · Cited by 425 · see citing works
Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities
Li, L., Hu, S., & Chen, X. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.031 · Cited by 415 · see citing works
Multiplex CRISPR/Cas9-based genome engineering from a single lentiviral vector
Kabadi, A. M., Ousterout, D. G., Hilton, I. B., & Gersbach, C. A. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku749 · Cited by 371 · see citing works
Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys
Mingozzi, F., Anguela, X. M., Pavani, G., Chen, Y., Davidson, R. J., Hui, D. J., Yazicioglu, M., Elkouby, L., Hinderer, C. J., Faella, A., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005795 · Cited by 355 · see citing works
Self-citationUsher syndrome: Hearing loss, retinal degeneration and associated abnormalities
Mathur, P. D., & Yang, J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.11.020 · Cited by 334 · see citing works
Maresca, M., Lin, V. G., Guo, N., & Yang, Y. (2012) · Genome Research · doi:10.1101/gr.145441.112 · Cited by 310 · see citing works
In vivo genome editing of the albumin locus as a platform for protein replacement therapy
Sharma, R., Anguela, X. M., Doyon, Y., Wechsler, T., DeKelver, R. C., Sproul, S., Paschon, D. E., Miller, J. C., Davidson, R. J., Shivak, D., et al. (2015) · Blood · doi:10.1182/blood-2014-12-615492 · Cited by 297 · see citing works
Self-citationPromoterless gene targeting without nucleases ameliorates haemophilia B in mice
Barzel, A., Paulk, N. K., Shi, Y., Huang, Y., Chu, K. C., Zhang, F., Valdmanis, P. N., Spector, L. P., Porteus, M. H., Gaensler, K. M. L., et al. (2014) · Nature · doi:10.1038/nature13864 · Cited by 257 · see citing works
Refining strategies to translate genome editing to the clinic
Cornu, T. I., Mussolino, C., & Cathomen, T. (2017) · Nature Medicine · doi:10.1038/nm.4313 · Cited by 247 · see citing works
Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication
Dong, C., Qu, L., Wang, H., Wei, L., Dong, Y., & Xiong, S. (2015) · Antiviral Research · doi:10.1016/j.antiviral.2015.03.015 · Cited by 245 · see citing works
Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned
Morgan, R. A., Gray, D., Lomova, A., & Kohn, D. B. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.10.010 · Cited by 243 · see citing works
Clinical development of gene therapy: results and lessons from recent successes
Kumar, S. R. P., Markusic, D. M., Biswas, M., High, K. A., & Herzog, R. W. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2016.34 · Cited by 235 · see citing works
Self-citationA New Class of Medicines through DNA Editing
Porteus, M. H. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1800729 · Cited by 229 · see citing works
Sather, B. D., Romano Ibarra, G. S., Sommer, K., Curinga, G., Hale, M., Khan, I. F., Singh, S., Song, Y., Gwiazda, K., Sahni, J., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac5530 · Cited by 223 · see citing works
Schiroli, G., Ferrari, S., Conway, A., Jacob, A., Capo, V., Albano, L., Plati, T., Castiello, M. C., Sanvito, F., Gennery, A. R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aan0820 · Cited by 214 · see citing works
Self-citationGene editing and CRISPR in the clinic: current and future perspectives
Hirakawa, M. P., Krishnakumar, R., Timlin, J. A., Carney, J. P., & Butler, K. S. (2020) · Bioscience Reports · doi:10.1042/bsr20200127 · Cited by 197 · see citing works
Viral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190 · see citing works
In vivo genome editing improves motor function and extends survival in a mouse model of ALS
Gaj, T., Ojala, D. S., Ekman, F. K., Byrne, L. C., Limsirichai, P., & Schaffer, D. V. (2017) · Science Advances · doi:10.1126/sciadv.aar3952 · Cited by 185 · see citing works
Ousterout, D. G., Pérez‐Piñera, P., Thakore, P. I., Kabadi, A. M., Brown, M. T., Qin, X., Fedrigo, O. D., Mouly, V., Tremblay, J. P., & Gersbach, C. A. (2013) · Molecular Therapy · doi:10.1038/mt.2013.111 · Cited by 181 · see citing works
Robust ZFN-mediated genome editing in adult hemophilic mice
Anguela, X. M., Sharma, R., Doyon, Y., Miller, J. C., Li, H., Haurigot, V., Rohde, M., Wong, S., Davidson, R. J., Zhou, S., et al. (2013) · Blood · doi:10.1182/blood-2013-04-497354 · Cited by 178 · see citing works
Self-citationGuan, Y., Ma, Y., Li, Q., Sun, Z., Ma, L., Wu, L., Wang, L., Zeng, L., Shao, Y., Chen, Y., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506039 · Cited by 178 · see citing works
Bak, R. O., Gomez‐Ospina, N., & Porteus, M. H. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.05.004 · Cited by 176 · see citing works
Carlson-Stevermer, J., Abdeen, A. A., Kohlenberg, L., Goedland, M., Molugu, K., Lou, M., & Saha, K. (2017) · Nature Communications · doi:10.1038/s41467-017-01875-9 · Cited by 170 · see citing works
Advances in targeted genome editing
Pérez‐Piñera, P., Ousterout, D. G., & Gersbach, C. A. (2012) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2012.06.007 · Cited by 158 · see citing works
Qu, X., Wang, P., Ding, D., Li, L., Wang, H., Ma, L., Zhou, X., Liu, S., Lin, S., Wang, X., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt571 · Cited by 155 · see citing works
Engineered Viruses as Genome Editing Devices
Chen, X., & Gonçalves, M. A. F. V. (2015) · Molecular Therapy · doi:10.1038/mt.2015.164 · Cited by 151 · see citing works
Araki, M., & Ishii, T. (2014) · Reproductive Biology and Endocrinology · doi:10.1186/1477-7827-12-108 · Cited by 150 · see citing works
Rezvani, M., Español-Suñer, R., Malato, Y., Dumont, L., Grimm, A. A., Kienle, E., Bindman, J. G., Wiedtke, E., Hsu, B. Y., Naqvi, S. J., et al. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2016.05.005 · Cited by 150 · see citing works
Durability of transgene expression after rAAV gene therapy
Muhuri, M., Lévy, D., Schulz, M., McCarty, D. M., & Gao, G. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.03.004 · Cited by 148 · see citing works
CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo—Brief Report
Wang, X., Raghavan, A., Chen, T., Qiao, L., Zhang, Y., Ding, Q., & Musunuru, K. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.307227 · Cited by 146 · see citing works
Mitigating off-target effects in CRISPR/Cas9-mediated in vivo gene editing
Han, H. A., Pang, J. K. S., & Soh, B.-S. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01893-z · Cited by 143 · see citing works
Ohmori, T., Nagao, Y., Mizukami, H., Sakata, A., Muramatsu, S., Ozawa, K., Tominaga, S., Hanazono, Y., Nishimura, S., Nureki, O., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-04625-5 · Cited by 142 · see citing works
Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System
Zacchigna, S., Zentilin, L., & Giacca, M. (2014) · Circulation Research · doi:10.1161/circresaha.114.302331 · Cited by 140 · see citing works
Adenoviral vector DNA for accurate genome editing with engineered nucleases
Holkers, M., Maggio, I., Henriques, S. F. D., Janssen, J. M., Cathomen, T., & Gonçalves, M. A. F. V. (2014) · Nature Methods · doi:10.1038/nmeth.3075 · Cited by 138 · see citing works
Delivery and therapeutic applications of gene editing technologies ZFNs, TALENs, and CRISPR/Cas9
LaFountaine, J. S., Fathe, K., & Smyth, H. D. C. (2015) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2015.08.029 · Cited by 137 · see citing works
Current Progress in Therapeutic Gene Editing for Monogenic Diseases
Prakash, V., Moore, M., & Yáñez‐Muñoz, R. J. (2016) · Molecular Therapy · doi:10.1038/mt.2016.5 · Cited by 135 · see citing works
Genome editing at the crossroads of delivery, specificity, and fidelity
Maggio, I., & Gonçalves, M. A. F. V. (2015) · Trends in biotechnology · doi:10.1016/j.tibtech.2015.02.011 · Cited by 132 · see citing works
Chen, L., Hong, M., Luan, C., Gao, H., Ru, G., Guo, X., Zhang, D., Zhang, S., Li, C., Wu, J., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-023-01821-9 · Cited by 131 · see citing works
Current and future delivery systems for engineered nucleases: ZFN, TALEN and RGEN
Ain, Q. U., Chung, J. Y., & Kim, Y.-H. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.12.036 · Cited by 130 · see citing works
Targets for future clinical trials in Huntington's disease: What's in the pipeline?
Wild, E. J., & Tabrizi, S. J. (2014) · Movement Disorders · doi:10.1002/mds.26007 · Cited by 130 · see citing works
Diversifying the structure of zinc finger nucleases for high-precision genome editing
Paschon, D. E., Lussier, S. J., Wangzor, T., Xia, D. F., Li, P. W., Hinkley, S. J., Scarlott, N. A., Lam, S. C., Waite, A. J., Truong, L. N., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08867-x · Cited by 128 · see citing works
Self-citationEfficient delivery of nuclease proteins for genome editing in human stem cells and primary cells
Liu, J., Gaj, T., Yang, Y., Wang, N., Shui, S., Kim, S., Kanchiswamy, C. N., Kim, J., & Barbas, C. F. (2015) · Nature Protocols · doi:10.1038/nprot.2015.117 · Cited by 127 · see citing works
Laoharawee, K., DeKelver, R. C., Podetz-Pedersen, K. M., Rohde, M., Sproul, S., Nguyen, H.-O., Nguyen, T., St. Martin, S. J., Ou, L., Tom, S., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.03.002 · Cited by 125 · see citing works
Self-citationMatsa, E., Dixon, J. E., Medway, C., Georgiou, O., Patel, M. J., Morgan, K., Kemp, P. J., Staniforth, A., Mellor, I. R., & Denning, C. N. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht067 · Cited by 125 · see citing works
Genome Engineering at the Dawn of the Golden Age
Segal, D. J., & Meckler, J. F. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153435 · Cited by 125 · see citing works
Wienert, B., Funnell, A. P. W., Norton, L. J., Pearson, R. C. M., Wilkinson‐White, L. E., Lester, K. L., Vadolas, J., Porteus, M. H., Matthews, J. M., Quinlan, K. G. R., et al. (2015) · Nature Communications · doi:10.1038/ncomms8085 · Cited by 125 · see citing works
The NIH Somatic Cell Genome Editing program
Saha, K., Sontheimer, E. J., Brooks, P. J., Dwinell, M. R., Gersbach, C. A., Liu, D. R., Murray, S. A., Tsai, S. Q., Wilson, R. C., Anderson, D. G., et al. (2021) · Nature · doi:10.1038/s41586-021-03191-1 · Cited by 125 · see citing works
Adeno-associated Virus Vectors in Gene Therapy
Mary, B., Khan, N., Arumugam, S., Saxena, H., Kumar, M., Manimaran, P., Chattopadhyay, S., & Jayandharan, G. R. (2018) · Springer eBooks · doi:10.1007/978-981-13-0481-1_2 · Cited by 124 · see citing works
From Genomics to Gene Therapy: Induced Pluripotent Stem Cells Meet Genome Editing
Hotta, A., & Yamanaka, S. (2015) · Annual Review of Genetics · doi:10.1146/annurev-genet-112414-054926 · Cited by 121 · see citing works
Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol
Wang, L., Smith, J., Breton, C. A., Clark, P., Zhang, J., Lei, Y., Che, Y., Lape, J., Bell, P. L., Calcedo, R., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4182 · Cited by 119 · see citing works
Weber, N. D., Stone, D., Sedlak, R. H., Feelixge, H. S. D. S., Roychoudhury, P., Schiffer, J. T., Aubert, M., & Jerome, K. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097579 · Cited by 118 · see citing works
Engineering Delivery Vehicles for Genome Editing
Nelson, C. E., & Gersbach, C. A. (2016) · Annual Review of Chemical and Biomolecular Engineering · doi:10.1146/annurev-chembioeng-080615-034711 · Cited by 118 · see citing works
Wan, T. Y., Niu, D., Wu, C., Xu, F., Church, G. M., & Yuan, P. (2019) · Materials Today · doi:10.1016/j.mattod.2018.12.003 · Cited by 118 · see citing works
Genome Engineering Using Adeno-associated Virus: Basic and Clinical Research Applications
Gaj, T., Epstein, B. E., & Schaffer, D. V. (2015) · Molecular Therapy · doi:10.1038/mt.2015.151 · Cited by 117 · see citing works
Ousterout, D. G., Kabadi, A. M., Thakore, P. I., Pérez‐Piñera, P., Brown, M. T., Majoros, W. H., Reddy, T. E., & Gersbach, C. A. (2014) · Molecular Therapy · doi:10.1038/mt.2014.234 · Cited by 117 · see citing works
Genome Editing: A New Approach to Human Therapeutics
Porteus, M. H. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124454 · Cited by 116 · see citing works
Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells
Vassena, R., Heindryckx, B., Peco, R., Pennings, G., Raya, Á., Sermon, K., & Veiga, A. (2016) · Human Reproduction Update · doi:10.1093/humupd/dmw005 · Cited by 115 · see citing works
In vivo genome editing via the HITI method as a tool for gene therapy
Suzuki, K., & Belmonte, J. C. I. (2017) · Journal of Human Genetics · doi:10.1038/s10038-017-0352-4 · Cited by 115 · see citing works
Tools for efficient genome editing; ZFN, TALEN, and CRISPR
Shamshirgaran, Y., Liu, J., Sumer, H., Verma, P. J., & Taheri-Ghahfarokhi, A. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2301-5_2 · Cited by 114 · see citing works
Technological Overview of iPS Induction from Human Adult Somatic Cells
Bayart, É., & Cohen‐Haguenauer, O. (2013) · Current Gene Therapy · doi:10.2174/1566523211313020002 · Cited by 112 · see citing works
Lessard, S., Francioli, L. C., Alföldi, J., Tardif, J., Ellinor, P. T., MacArthur, D. G., Lettre, G., Orkin, S. H., & Canver, M. C. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714640114 · Cited by 112 · see citing works
Non-viral delivery of genome-editing nucleases for gene therapy
Wang, M., Glass, Z., & Xu, Q. (2016) · Gene Therapy · doi:10.1038/gt.2016.72 · Cited by 110 · see citing works
Genome editing: the road of CRISPR/Cas9 from bench to clinic
Eid, A., & Mahfouz, M. M. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.111 · Cited by 109 · see citing works
TAL effectors: tools for DNA Targeting
Jankele, R., & Svoboda, P. (2014) · Briefings in Functional Genomics · doi:10.1093/bfgp/elu013 · Cited by 108 · see citing works
Modeling human neurodegenerative diseases in transgenic systems
Sosa, M. A. G., Gasperi, R. D., & Elder, G. A. (2011) · Human Genetics · doi:10.1007/s00439-011-1119-1 · Cited by 107 · see citing works
Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases
Cai, Y., Bak, R. O., & Mikkelsen, J. G. (2014) · eLife · doi:10.7554/elife.01911 · Cited by 105 · see citing works
Programmable Genome Editing Tools and their Regulation for Efficient Genome Engineering
Guha, T. K., Wai, A., & Hausner, G. (2017) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2016.12.006 · Cited by 105 · see citing works
Genome editing in livestock: Are we ready for a revolution in animal breeding industry?
Ruan, J., Xu, J., Chen-Tsai, R. Y., & Li, K. (2017) · Transgenic Research · doi:10.1007/s11248-017-0049-7 · Cited by 104 · see citing works
Enabling functional genomics with genome engineeringPreprint
Hilton, I. B., & Gersbach, C. A. (2015) · Genome Research · doi:10.1101/gr.190124.115 · Cited by 104 · see citing works
Advances and challenges for hemophilia gene therapy
Batty, P. A., & Lillicrap, D. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz157 · Cited by 103 · see citing works
Genome Editing Technologies: Defining a Path to Clinic
Corrigan‐Curay, J., O’Reilly, M., Kohn, D. B., Cannon, P. M., Bao, G., Bushman, F. D., Carroll, D., Cathomen, T., Joung, J. K., Roth, D. B., et al. (2015) · Molecular Therapy · doi:10.1038/mt.2015.54 · Cited by 101 · see citing works
Self-citationZandarashvili, L., Esadze, A., Vuzman, D., Kemme, C. A., Levy, Y., & Iwahara, J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1507726112 · Cited by 100 · see citing works
Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery
Lundin, A., Porritt, M. J., Jaiswal, H., Seeliger, F., Johansson, C., Bidar, A. W., Badertscher, L., Wimberger, S., Davies, E. J., Hardaker, E. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18548-9 · Cited by 100 · see citing works
- Authors
- Li, H., Haurigot, V., Doyon, Y., Li, T., Wong, S. Y., Bhagwat, A. S., Malani, N., Anguela, X. M., Sharma, R., Ivanciu, L., Murphy, S. L., Finn, J. D., Khazi, F. R., Zhou, S., Paschon, D. E., Rebar, E. J., Bushman, F. D., Gregory, P. D., Holmes, M. C., & High, K. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Sangamo BioSciences (United States) (US)
- University of Pennsylvania (US)
- Corresponding author
- Holmes, Michael C.
- High, Katherine A.
- ORCID
- Venue
- Nature
- Published
- 2011-06-26
- Volume
- 475
- Issue
- 7355
- Pages
- 217-221
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3152293
- OpenAlex
- W2038866304
- Cited by
- 548
- References
- 29
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 13 · 2022: 22 · 2021: 19 · 2020: 34 · 2019: 33 · 2018: 48 · 2017: 54 · 2016: 66 · 2015: 62 · 2014: 66 · 2013: 44 · 2012: 40
- FWCI
- 35.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (P01HL064190, T32HL007150)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- zinc finger nucleases, genome editing, hemophilia B, in vivo gene targeting, DNA double-strand breaks, homology-directed repair, gene replacement, liver regeneration, genetic disease treatment
- MeSH terms
- Animals, Base Sequence, Hemophilia B, Disease Models, Animal, DNA Repair, Endonucleases, Exons, Factor IX, Genetic Vectors, Hemostasis, Humans, Introns, Liver, Liver Regeneration, Mice, Inbred C57BL, Mutation, Phenotype, Genetic Therapy, Zinc Fingers, Genome, Sequence Homology, Gene Targeting, Cell Line, Tumor, Mice, DNA Breaks, Double-Stranded, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
