Large‐scale molecular characterization of adeno‐associated virus vector integration in mouse liver
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Recombinant adeno-associated virus (rAAV) vector holds promise for gene therapy. Despite a low frequency of chromosomal integration of vector genomes, recent studies have raised concerns about the risk of rAAV integration because integration occurs preferentially in genes and accompanies chromosomal deletions, which may lead to loss-of-function insertional mutagenesis. Here, by analyzing 347 rAAV integrations in mice, we elucidate novel features of rAAV integration: the presence of hot spots for integration and a strong preference for integrating near gene regulatory sequences. The most prominent hot spot was a harmless chromosomal niche in the rRNA gene repeats, whereas nearly half of the integrations landed near transcription start sites or CpG islands, suggesting the possibility of activating flanking cellular disease genes by vector integration, similar to retroviral gain-of-function insertional mutagenesis. Possible cancer-related genes were hit by rAAV integration at a frequency of 3.5%. In addition, the information about chromosomal changes at 218 integration sites and 602 breakpoints of vector genomes have provided a clue to how vector terminal repeats and host chromosomal DNA are joined in the integration process. Thus, the present study provides new insights into the risk of rAAV-mediated insertional mutagenesis and the mechanisms of rAAV integration.
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<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
A gene atlas of the mouse and human protein-encoding transcriptomes
Su, A. I., Wiltshire, T., Batalov, S., Lapp, H., Ching, K. A., Block, D., Zhang, J., Soden, R., Hayakawa, M., Kreiman, G., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400782101 · Cited by 3,475 · see citing works
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots
Schröder, A. R. W., Shinn, P., Chen, H., Berry, C., Ecker, J. R., & Bushman, F. (2002) · Cell · doi:10.1016/s0092-8674(02)00864-4 · Cited by 1,832 · see citing works
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
Gao, G.-P., Alvira, M. R., Wang, L., Calcedo, R., Johnston, J., & Wilson, J. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182412299 · Cited by 1,520 · see citing works
Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration
Wu, X., Li, Y., Crise, B., & Burgess, S. M. (2003) · Science · doi:10.1126/science.1083413 · Cited by 1,305 · see citing works
Self-citation(2007) · Wiley eBooks · doi:10.1128/9781555817954 · Cited by 1,296 · see citing works
Kay, M. A., Manno, C. S., Ragni, M. V., Larson, P. J., Couto, L. B., McClelland, A., Glader, B. E., Chew, A. K., Tai, S. J., Herzog, R. W., et al. (2000) · Nature Genetics · doi:10.1038/73464 · Cited by 1,019 · see citing works
Self-citationFerrari, F. K., Samulski, T., Shenk, T., & Samulski, R. J. (1996) · Journal of Virology · doi:10.1128/jvi.70.5.3227-3234.1996 · Cited by 761 · see citing works
McCarty, D., Monahan, P., & Samulski, R. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301514 · Cited by 735 · see citing works
Fisher, K. J., Gao, G. P., Weitzman, M. D., DeMatteo, R. P., Burda, J. F., & Wilson, J. M. (1996) · Journal of Virology · doi:10.1128/jvi.70.1.520-532.1996 · Cited by 546 · see citing works
Duan, D., Sharma, P., Yang, J., Yue, Y., Dudus, L., Zhang, Y., Fisher, K. J., & Engelhardt, J. F. (1998) · Journal of Virology · doi:10.1128/jvi.72.11.8568-8577.1998 · Cited by 522 · 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
Self-citationAAV 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
Self-citationChao, H., Liu, Y., Rabinowitz, J., Li, C., Samulski, R. J., & Walsh, C. E. (2000) · Molecular Therapy · doi:10.1006/mthe.2000.0219 · Cited by 366 · see citing works
RTCGD: retroviral tagged cancer gene database
Akagi, K. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh013 · Cited by 320 · see citing works
Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors
Donsante, A., Vogler, C. A., Muzyczka, N., Crawford, J., Barker, J. E., Flotte, T. R., Campbell‐Thompson, M., Daly, T., & Sands, M. S. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301541 · Cited by 320 · see citing works
Adeno-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
Genetic Fate of Recombinant Adeno-Associated Virus Vector Genomes in Muscle
Schnepp, B. C., Clark, K. R., Klemanski, D. L., Pacak, C. A., & Johnson, P. R. (2003) · Journal of Virology · doi:10.1128/jvi.77.6.3495-3504.2003 · Cited by 262 · see citing works
Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy
Grimm, D., Zhou, S., Nakai, H., Thomas, C. E., Storm, T. A., Fuess, S., Matsushita, T., Allen, J. M., Surosky, R. T., Lochrie, M. A., et al. (2003) · Blood · doi:10.1182/blood-2003-02-0495 · Cited by 208 · see citing works
Self-citationThe kinetics of rAAV integration in the liver
Miao, C. H., Snyder, R., Schowalter, D., Patijn, G., Donahue, B., Winther, B. L., & Kay, M. (1998) · Nature Genetics · doi:10.1038/ng0598-13 · Cited by 198 · see citing works
Self-citationNakai, H., Storm, T. A., & Kay, M. A. (2000) · Journal of Virology · doi:10.1128/jvi.74.20.9451-9463.2000 · Cited by 194 · see citing works
Self-citationIsolation of Recombinant Adeno-Associated Virus Vector-Cellular DNA Junctions from Mouse Liver
Nakai, H., Iwaki, Y., Kay, M. A., & Couto, L. B. (1999) · Journal of Virology · doi:10.1128/jvi.73.7.5438-5447.1999 · Cited by 186 · see citing works
Self-citationChromosomal effects of adeno-associated virus vector integration
Miller, D. G., Rutledge, E. A., & Russell, D. W. (2002) · Nature Genetics · doi:10.1038/ng824 · Cited by 155 · see citing works
Adeno-associated virus vector integration junctions
Rutledge, E. A., & Russell, D. W. (1997) · Journal of Virology · doi:10.1128/jvi.71.11.8429-8436.1997 · Cited by 135 · see citing works
Complete sequence of the 45-kb mouse ribosomal DNA repeat: analysis of the intergenic spacer☆
Grozdanov, P., Georgiev, O., & Karagyozov, L. K. (2003) · Genomics · doi:10.1016/s0888-7543(03)00199-x · Cited by 97 · see citing works
Enhancers for RNA Polymerase I in Mouse Ribosomal DNA
Pikaard, C. S., Pape, L. K., Henderson, S. L., Ryan, K., Paalman, M. H., Lopata, M. A., Reeder, R. H., & Sollner-Webb, B. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.9.4816 · Cited by 92 · see citing works
R2 and Related Site‐Specific Non‐Long Terminal Repeat Retrotransposons
Eickbush, T. H. (2007) · doi:10.1128/9781555817954.ch34 · Cited by 78 · see citing works
Looking into the safety of AAV vectors
Kay, M. A., & Nakai, H. (2003) · Nature · doi:10.1038/424251b · Cited by 62 · see citing works
Self-citationNakai, H., Montini, E., Fuess, S., Storm, T. A., Meuse, L., Finegold, M., Grompe, M., & Kay, M. A. (2003) · Molecular Therapy · doi:10.1016/s1525-0016(02)00023-0 · Cited by 52 · see citing works
Self-citationEnhancers for RNA Polymerase I in Mouse Ribosomal DNA
Pikaard, C. S., Ραρε, L. Κ., Henderson, S. L., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.9.4816-4825.1990 · Cited by 40 · see citing works
Mapping of replication initiation sites in the mouse ribosomal gene cluster
G�gel, E., L�ngst, G., Grummt, I., Kunkel, E., & Grummt, F. (1996) · Chromosoma · doi:10.1007/s004120050143 · Cited by 36 · see citing works
Längst, G. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.3.511 · Cited by 30 · see citing works
Hüser, D., Weger, S., & Heilbronn, R. (2003) · Journal of Virology · doi:10.1128/jvi.77.8.4881-4887.2003 · Cited by 29 · see citing works
Adeno-associated virus vectors under scrutiny
Senior, K. (2002) · The Lancet · doi:10.1016/s0140-6736(02)08258-2 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Analysis of AAV Serotypes 1–9 Mediated Gene Expression and Tropism in Mice After Systemic Injection
Zincarelli, C., Soltys, S., Rengo, G., & Rabinowitz, J. E. (2008) · Molecular Therapy · doi:10.1038/mt.2008.76 · Cited by 1,490 · see citing works
State-of-the-art gene-based therapies: the road ahead
Kay, M. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2971 · Cited by 672 · see citing works
Self-citationAAV vector integration sites in mouse hepatocellular carcinoma
Donsante, A., Miller, D. G., Li, Y., Vogler, C., Brunt, E. M., Russell, D. W., & Sands, M. S. (2007) · Science · doi:10.1126/science.1142658 · Cited by 662 · see citing works
[19] Gene Expression Omnibus: Microarray Data Storage, Submission, Retrieval, and Analysis
Barrett, T., & Edgar, R. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(06)11019-8 · Cited by 511 · see citing works
Nguyen, G. N., Everett, J. K., Kafle, S., Roche, A. M., Raymond, H. E., Leiby, J. S., Wood, C. M., Assenmacher, C., Merricks, E. P., Long, C. T., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0741-7 · Cited by 429 · see citing works
Mutagenesis and Oncogenesis by Chromosomal Insertion of Gene Transfer Vectors
Baum, C., Kustikova, O. S., Modlich, U., Li, Z., & Fehse, B. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.253 · Cited by 360 · see citing works
Nathwani, A. C., Rosales, C., McIntosh, J., Rastegarlari, G., Nathwani, D., Raj, D., Nawathe, S., Waddington, S. N., Bronson, R., Jackson, S., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2010.274 · Cited by 345 · see citing works
Adeno-Associated Virus Vector Genomes Persist as Episomal Chromatin in Primate Muscle
Penaud‐Budloo, M., Guiner, C. L., Nowrouzi, A., Toromanoff, A., Chérel, Y., Chenuaud, P., Schmidt, M., Kalle, C. V., Rolling, F., Moullier, P., et al. (2008) · Journal of Virology · doi:10.1128/jvi.00649-08 · Cited by 319 · see citing works
High-Resolution Genome-Wide Mapping of Transposon Integration in Mammals
Yant, S. R., Wu, X., Huang, Y., Garrison, B. S., Burgess, S. M., & Kay, M. A. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.6.2085-2094.2005 · Cited by 318 · see citing works
Self-citationNiemeyer, G. P., Herzog, R. W., Mount, J., Arruda, V. R., Tillson, D. M., Hathcock, J., van Ginkel, F. W., High, K. A., & Lothrop, C. D. (2009) · Blood · doi:10.1182/blood-2008-10-181479 · Cited by 276 · 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
Characterization of Genome Integrity for Oversized Recombinant AAV Vector
Dong, B., Nakai, H., & Xiao, W. (2010) · Molecular Therapy · doi:10.1038/mt.2009.258 · Cited by 230 · see citing works
Self-citationRecombinant Adeno-associated Virus Transduction and Integration
Schultz, B. R., & Chamberlain, J. S. (2008) · Molecular Therapy · doi:10.1038/mt.2008.103 · Cited by 216 · see citing works
Sabatino, D. E., Bushman, F. D., Chandler, R. J., Crystal, R. G., Davidson, B. L., Dolmetsch, R. E., Eggan, K. C., Gao, G., Gil-Fariña, I., Kay, M. A., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.06.004 · Cited by 213 · see citing works
Self-citationA Transposon and Transposase System for Human Application
Hackett, P. B., Largaespada, D. A., & Cooper, L. J. N. (2010) · Molecular Therapy · doi:10.1038/mt.2010.2 · Cited by 205 · see citing works
Adeno-associated virus vector integration.
Deyle, D. R., & Russell, D. W. (2009) · PubMed · Cited by 206 · see citing works
Selection 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
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
Gil-Farina, I., Fronza, R., Kaeppel, C., Lopez-Franco, E., Ferreira, V., D'Avola, D., Benito, A., Prieto, J., Petry, H., Gonzalez-Aseguinolaza, G., et al. (2016) · Molecular Therapy · doi:10.1038/mt.2016.52 · Cited by 179 · see citing works
Adeno-Associated Virus Integration: Virus versus Vector
Smith, R. H. (2008) · Gene Therapy · doi:10.1038/gt.2008.55 · Cited by 178 · see citing works
Large-Scale Analysis of Adeno-Associated Virus Vector Integration Sites in Normal Human Cells
Miller, D. G., Trobridge, G. D., Petek, L. M., Jacobs, M. A., Kaul, R., & Russell, D. W. (2005) · Journal of Virology · doi:10.1128/jvi.79.17.11434-11442.2005 · Cited by 171 · see citing works
Kwon, I., & Schaffer, D. V. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9431-0 · Cited by 164 · see citing works
Treatment of human disease by adeno-associated viral gene transfer
Warrington, K. H., & Herzog, R. W. (2006) · Human Genetics · doi:10.1007/s00439-006-0165-6 · Cited by 155 · see citing works
Adeno‐associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo†‡
Paulk, N. K., Wursthorn, K., Wang, Z., Finegold, M. J., Kay, M. A., & Grompe, M. (2010) · Hepatology · doi:10.1002/hep.23481 · Cited by 135 · see citing works
Self-citationAAV-Mediated Liver-Directed Gene Therapy
Sands, M. S. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-370-7_6 · Cited by 134 · see citing works
Ferrari, S., Jacob, A., Cesana, D., Laugel, M., Beretta, S., Varesi, A., Unali, G., Conti, A., Canarutto, D., Albano, L., et al. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.09.001 · Cited by 133 · see citing works
Self-citationGuan, S., Munder, A., Hedtfeld, S., Braubach, P., Glage, S., Zhang, L., Lienenklaus, S., Schultze, A., Hasenpusch, G., Garrels, W., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-018-0358-x · Cited by 130 · see citing works
Adeno-associated virus in the liver: natural history and consequences in tumour development
Bella, T. L., Imbeaud, S., Péneau, C., Mami, I., Datta, S., Bayard, Q., Caruso, S., Hirsch, T. Z., Caldéraro, J., Morcrette, G., et al. (2019) · Gut · doi:10.1136/gutjnl-2019-318281 · Cited by 129 · see citing works
Precise hit: adeno-associated virus in gene targeting
Vasileva, A., & Jessberger, R. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1266 · Cited by 148 · see citing works
AAV integration in human hepatocytes
Dalwadi, D. A., Calabria, A., Tiyaboonchai, A., Posey, J., Naugler, W. E., Montini, E., & Grompe, M. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.08.031 · Cited by 126 · see citing works
Self-citationGenome 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
Grimm, D., Pandey, K., Nakai, H., Storm, T. A., & Kay, M. A. (2006) · Journal of Virology · doi:10.1128/jvi.80.1.426-439.2006 · Cited by 118 · see citing works
Self-citationMeasles and rubella elimination in the WHO Region for Europe: progress and challenges
O’Connor, P. M., Jankovic, D., Muscat, M., Mamou, M. C. B., Reef, S. E., Papania, M. J., Singh, S., Kaloumenos, T., Butler, R., & Datta, S. S. (2017) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2017.01.003 · Cited by 123 · see citing works
Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice
Dalwadi, D. A., Torrens, L., Abril‐Fornaguera, J., Pinyol, R., Willoughby, C. E., Posey, J., Llovet, J. M., Lanciault, C., Russell, D. W., Grompe, M., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.10.018 · Cited by 104 · see citing works
Self-citationmiRNA cassettes in viral vectors: Problems and solutions
Liu, Y. P., & Berkhout, B. (2011) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.05.014 · Cited by 101 · see citing works
Wang, J., Xie, J., Lu, H., Chen, L., Hauck, B., Samulski, R., & Xiao, W. (2007) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0702778104 · Cited by 98 · see citing works
Richter, M., Saydaminova, K., Yumul, R., Krishnan, R., Liu, J., Nagy, E.-E., Singh, M., Izsvák, Z., Cattaneo, R., Uckert, W., et al. (2016) · Blood · doi:10.1182/blood-2016-04-711580 · Cited by 99 · see citing works
Rosas, L. E., Grieves, J. L., Zaraspe, K., Perle, K. M. D. L., Fu, H., & McCarty, D. M. (2012) · Molecular Therapy · doi:10.1038/mt.2012.197 · Cited by 95 · see citing works
Stephen, S. L., Freestone, K., Dunn, S., Twigg, M., Homer-Vanniasinkam, S., Walker, J. H., Wheatcroft, S., & Ponnambalam, S. (2010) · International Journal of Hypertension · doi:10.4061/2010/646929 · Cited by 120 · see citing works
Salmon, F., Grosios, K., & Petry, H. (2013) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2014.852065 · Cited by 93 · see citing works
Chromosomal Integration of Adenoviral Vector DNA In Vivo
Stephen, S. L., Montini, E., Sivanandam, V., Al-Dhalimy, M., Kestler, H., Finegold, M., Grompe, M., & Kochanek, S. (2010) · Journal of Virology · doi:10.1128/jvi.00751-10 · Cited by 92 · see citing works
Self-citationAdeno-associated Virus as a Mammalian DNA Vector
Salganik, M., Hirsch, M. L., & Samulski, R. J. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0052-2014 · Cited by 88 · see citing works
Molecular Analysis of Chromosomal Rearrangements in Mammalian Cells After ø C31-Mediated Integration
Ehrhardt, A., Engler, J. A., Xu, H., Cherry, A. M., & Kay, M. A. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.1077 · Cited by 86 · see citing works
Self-citationGene therapy for haemophilia: a long and winding road
High, K. A. (2011) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04369.x · Cited by 84 · see citing works
Improving miRNA Delivery by Optimizing miRNA Expression Cassettes in Diverse Virus Vectors
Herrera-Carrillo, E., Liu, Y. P., & Berkhout, B. (2017) · Human Gene Therapy Methods · doi:10.1089/hgtb.2017.036 · Cited by 83 · see citing works
Transfection of cells using flow-through electroporation based on constant voltage
Geng, T., Zhan, Y., Wang, J., & Lu, C. (2011) · Nature Protocols · doi:10.1038/nprot.2011.360 · Cited by 80 · see citing works
Gene therapy for liver diseases — progress and challenges
Zabaleta, N., Unzu, C., Weber, N. D., & González‐Aseguinolaza, G. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00729-0 · Cited by 76 · see citing works
Valdmanis, P. N., Kim, H. K., Chu, K. C., Zhang, F., Xu, J., Munding, E. M., Shen, J. Y., & Kay, M. A. (2018) · Nature Communications · doi:10.1038/s41467-018-07786-7 · Cited by 72 · see citing works
Self-citationAdeno-associated Vector Toxicity—To Be or Not to Be?
Büning, H., & Schmidt, M. (2015) · Molecular Therapy · doi:10.1038/mt.2015.182 · Cited by 71 · see citing works
McIntosh, J. H., Cochrane, M., Cobbold, S., Waldmann, H., Nathwani, S. A., Davidoff, A. M., & Nathwani, A. C. (2012) · Gene Therapy · doi:10.1038/gt.2011.64 · Cited by 70 · see citing works
The Role of DNA-PKcs and Artemis in Opening Viral DNA Hairpin Termini in Various Tissues in Mice
Inagaki, K., Ma, C.-R., Storm, T. A., Kay, M., & Nakai, H. (2007) · Journal of Virology · doi:10.1128/jvi.01225-07 · Cited by 76 · see citing works
Self-citationRaupp, C., Naumer, M., Müller, O. J., Gurda, B. L., Agbandje‐McKenna, M., & Kleinschmidt, J. A. (2012) · Journal of Virology · doi:10.1128/jvi.00209-12 · Cited by 63 · see citing works
Kuck, D., Lau, T., Leuchs, B., Kern, A., Müller, M., Gissmann, L., & Kleinschmidt, J. A. (2006) · Journal of Virology · doi:10.1128/jvi.80.6.2621-2630.2006 · Cited by 64 · see citing works
Hackett, C. S., Geurts, A., & Hackett, P. (2007) · Genome Biology · doi:10.1186/gb-2007-8-s1-s12 · Cited by 61 · see citing works
Homologous recombination is required for AAV-mediated gene targeting
Vasileva, A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl455 · Cited by 61 · see citing works
Designing Heart Performance by Gene Transfer
Davis, J., Westfall, M. V., Townsend, D., Blankinship, M. J., Herron, T. J., Guerrero‐Serna, G., Wang, W., Devaney, E. J., & Metzger, J. M. (2008) · Physiological Reviews · doi:10.1152/physrev.00039.2007 · Cited by 58 · see citing works
Ohbayashi, F., Balamotis, M. A., Kishimoto, A., Aizawa, E., Diaz, A., Hasty, P., Graham, F. L., Caskey, C. T., & Mitani, K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506598102 · Cited by 60 · see citing works
Oh, S., Harvey, A., Zimbric, J., Wang, Y., Nguyen, T., Jackson, P. J., & Hendrickson, E. A. (2014) · DNA Repair · doi:10.1016/j.dnarep.2014.04.015 · Cited by 58 · see citing works
The Role of Recombinant AAV in Precise Genome Editing
Bijlani, S., Pang, K. M., Sivanandam, V., Singh, A., & Chatterjee, S. (2022) · Frontiers in Genome Editing · doi:10.3389/fgeed.2021.799722 · Cited by 58 · see citing works
Breton, C. A., Clark, P., Wang, L., Greig, J. A., & Wilson, J. M. (2020) · BMC Genomics · doi:10.1186/s12864-020-6655-4 · Cited by 57 · see citing works
Inagaki, K., Piao, C., Kotchey, N. M., Wu, X., & Nakai, H. (2008) · Journal of Virology · doi:10.1128/jvi.01001-08 · Cited by 57 · see citing works
Self-citationInagaki, K., Lewis, S. M., Wu, X., Ma, C., Munroe, D. J., Fuess, S., Storm, T. A., Kay, M. A., & Nakai, H. (2007) · Journal of Virology · doi:10.1128/jvi.00963-07 · Cited by 54 · see citing works
Self-citationFrequent Endonuclease Cleavage at Off-target Locations In Vivo
Petek, L. M., Russell, D. W., & Miller, D. G. (2010) · Molecular Therapy · doi:10.1038/mt.2010.35 · Cited by 53 · see citing works
AAV Vectors, Insertional Mutagenesis, and Cancer
Russell, D. W. (2007) · Molecular Therapy · doi:10.1038/sj.mt.6300299 · Cited by 53 · see citing works
The Mechanism of Gene Targeting in Human Somatic Cells
Kan, Y., Ruis, B. L., Lin, S. G., & Hendrickson, E. A. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004251 · Cited by 50 · see citing works
Cunningham, S., Siew, S. M., Hallwirth, C., Bolitho, C., Sasaki, N., Garg, G., Michael, I. P., Hetherington, N. A., Carpenter, K., de Alencastro, G., et al. (2015) · Hepatology · doi:10.1002/hep.27842 · Cited by 47 · see citing works
Bec, C. L., & Douar, A. M. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302724 · Cited by 48 · see citing works
Wang, Z., Lisowski, L., Finegold, M. J., Nakai, H., Kay, M. A., & Grompe, M. (2012) · Molecular Therapy · doi:10.1038/mt.2012.157 · Cited by 44 · see citing works
Self-citationDeciphering conundrums of adeno-associated virus liver-directed gene therapy: focus on hemophilia
Pierce, G. F., Fong, S., Long, B. R., & Kaczmarek, R. (2023) · Journal of Thrombosis and Haemostasis · doi:10.1016/j.jtha.2023.12.005 · Cited by 45 · see citing works
AAV vectors and tumorigenicity
Kay, M. A. (2007) · Nature Biotechnology · doi:10.1038/nbt1007-1111 · Cited by 43 · see citing works
Self-citationSite-directed genome modification: derivatives of DNA-modifying enzymes as targeting tools
Coates, C. J., Kaminski, J., Summers, J. B., Segal, D. J., Miller, A. D., & Kolb, A. F. (2005) · Trends in biotechnology · doi:10.1016/j.tibtech.2005.06.009 · Cited by 43 · see citing works
Barriers for retinal gene therapy: separating fact from fiction.
Kumar-Singh, R. (2008) · Vision Research · doi:10.1016/j.visres.2008.05.005 · Cited by 43 · see citing works
Zhang, W., Mück-Häusl, M., Wang, J., Sun, C., Gebbing, M., Miskey, C., Ivics, Z., Izsvák, Z., & Ehrhardt, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075344 · Cited by 42 · see citing works
Integrating HDAd5/35++ Vectors as a New Platform for HSC Gene Therapy of Hemoglobinopathies
Li, C., Psatha, N., Wang, H., Singh, M., Samal, H. B., Zhang, W., Ehrhardt, A., Izsvák, Z., Papayannopoulou, T., & Lieber, A. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.02.004 · Cited by 42 · see citing works
Adeno-Associated Virus-Based Gene Therapy for Lifelong Correction of Genetic Disease
Brommel, C. M., Cooney, A. L., & Sinn, P. L. (2020) · Human Gene Therapy · doi:10.1089/hum.2020.138 · Cited by 42 · see citing works
Fah Knockout Animals as Models for Therapeutic Liver Repopulation
Grompe, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55780-9_20 · Cited by 42 · see citing works
Self-citationEmerging Strategies for the Treatment of Hereditary Metabolic Storage Disorders
Brady, R. O. (2006) · Rejuvenation Research · doi:10.1089/rej.2006.9.237 · Cited by 40 · see citing works
Guenzel, A. J., Collard, R., Kraus, J. P., Matern, D., & Barry, M. A. (2015) · Human Gene Therapy · doi:10.1089/hum.2014.126 · Cited by 40 · see citing works
Gellhaus, K., Cornu, T. I., Heilbronn, R., & Cathomen, T. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.167 · Cited by 39 · see citing works
Wong, G. K. Y., & Chiu, A. T. (2010) · Biotechnology Advances · doi:10.1016/j.biotechadv.2010.07.005 · Cited by 37 · see citing works
Valdmanis, P. N., Gu, S., Chu, K. C., Jin, L., Zhang, F., Munding, E. M., Zhang, Y., Huang, Y., Kutay, H., Ghoshal, K., et al. (2016) · Nature Medicine · doi:10.1038/nm.4079 · Cited by 37 · see citing works
Self-citationRibosomal DNA integrating rAAV-rDNA vectors allow for stable transgene expression.
Lisowski, L., Lau, A., Wang, Z., Zhang, Y., Zhang, F.-J., Grompe, M., & Kay, M. A. (2012) · Molecular Therapy · doi:10.1038/mt.2012.164 · Cited by 36 · see citing works
Self-citationrAAV-Mediated Tumorigenesis: Still Unresolved After an AAV Assault
Valdmanis, P. N., Lisowski, L., & Kay, M. A. (2012) · Molecular Therapy · doi:10.1038/mt.2012.220 · Cited by 36 · see citing works
Self-citationZhang, W., Solanki, M., Müther, N., Ebel, M., Wang, J., Sun, C., Izsvák, Z., & Ehrhardt, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076771 · Cited by 34 · see citing works
Peruta, M. D., Badar, A., Rosales, C., Chokshi, S., Kia, A., Nathwani, D., Galante, E., Yan, R., Årstad, E., Davidoff, A. M., et al. (2015) · Human Gene Therapy · doi:10.1089/hum.2014.052 · Cited by 35 · see citing works
Paulk, N. K., Loza, L. I. M., Finegold, M. J., & Grompe, M. (2012) · Human Gene Therapy · doi:10.1089/hum.2012.038 · Cited by 35 · see citing works
Self-citationHan, Z., Li, Z., Maina, N., Hu, Z., Li, X., Chouthai, N. S., Bischof, D., Weigel-Kelley, K. A., Slayton, W. B., Yöder, M. C., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2007.161 · Cited by 35 · see citing works
Martins, K. M., Breton, C. A., Zheng, Q., Zhang, Z., Latshaw, C., Greig, J. A., & Wilson, J. M. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.134 · Cited by 34 · see citing works
Anguela, X. M., Tafuro, S., Roca, C., Callejas, D., Agudo, J., Obach, M., Ribera, A., Ruzo, A., Mann, C. J., Casellas, A., et al. (2012) · Diabetes · doi:10.2337/db11-1776 · Cited by 31 · see citing works
Recombinant adeno-associated Virus: Clinical Application and Development As a gene-therapy Vector
Xiao, P.-J., Lentz, T. B., & Samulski, R. J. (2012) · Therapeutic Delivery · doi:10.4155/tde.12.63 · Cited by 30 · see citing works
Emerging therapeutic approaches in the management of retinal angiogenesis and edema
Truong, A., Wong, T. Y., & Khachigian, L. M. (2010) · Journal of Molecular Medicine · doi:10.1007/s00109-010-0709-z · Cited by 27 · see citing works
Advances in understanding disease mechanisms and potential treatments for Crigler–Najjar syndrome
Bortolussi, G., & Muro, A. F. (2018) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2018.1495558 · Cited by 26 · see citing works
Gene therapy for lysosomal storage disorders
Gritti, A. (2011) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.582036 · Cited by 28 · see citing works
Combining CRISPR/Cas9 and rAAV Templates for Efficient Gene Editing
Kaulich, M., & Dowdy, S. F. (2015) · Nucleic Acid Therapeutics · doi:10.1089/nat.2015.0545 · Cited by 25 · see citing works
Intégration des vecteurs AAV et mutagenèse insertionnelle
Rossi, A., & Salvetti, A. (2016) · médecine/sciences · doi:10.1051/medsci/20163202010 · Cited by 26 · see citing works
Naumer, M., Ying, Y., Michelfelder, S., Reuter, A., Trepel, M., Müller, O. J., & Kleinschmidt, J. A. (2011) · Human Gene Therapy · doi:10.1089/hum.2011.139 · Cited by 24 · see citing works
Gene Therapy for Coagulation Disorders
Swystun, L. L., & Lillicrap, D. (2016) · Circulation Research · doi:10.1161/circresaha.115.307015 · Cited by 24 · see citing works
Gernoux, G., Guilbaud, M., Dubreil, L., Larcher, T., Babarit, C., Ledevin, M., Jaulin, N., Planel, P., Moullier, P., & Adjali, O. (2014) · Human Gene Therapy · doi:10.1089/hum.2014.070 · Cited by 21 · see citing works
Exploiting Natural Diversity of AAV for the Design of Vectors with Novel Properties
Gao, G., Li, Z., & Danos, O. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-370-7_4 · Cited by 22 · see citing works
Perinatal systemic gene delivery using adeno-associated viral vectors
Karda, R., Buckley, S. M. K., Mattar, C. N. Z., Ng, J., Massaro, G., Hughes, M. P., Kurian, M. A., Baruteau, J., Gissen, P., Chan, J. K. Y., et al. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00089 · Cited by 22 · see citing works
- Authors
- Nakai, H., Wu, X., Fuess, S., Storm, T. A., Munroe, D., Montini, E., Burgess, S. M., Grompe, M., & Kay, M. A.
- Affiliations
- Stanford Medicine (US)
- National Institutes of Health (US)
- Oregon Health & Science University (US)
- Corresponding author
- Nakai, Hiroyuki
- ORCID
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2005-03-15
- Volume
- 79
- Issue
- 6
- Pages
- 3606-3614
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC1075691
- OpenAlex
- W2151713466
- Cited by
- 190
- References
- 33
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 1 · 2020: 11 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 10 · 2015: 13 · 2014: 8 · 2013: 6 · 2012: 13
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health (n01co12400-79-0-22, N01-CO-12400)
- National Heart, Lung, and Blood Institute (HL66948, U01HL066948)
- National Cancer Institute (N01CO12400, N01-CO-012400)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK18252, DK068636, R21DK068636)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- adeno-associated virus, insertional mutagenesis, liver, CpG islands, transcription start sites, cancer genes, chromosomal breakpoints, terminal repeats, gene therapy safety, mice
- MeSH terms
- Dependovirus, Animals, Genetic Vectors, Oncogenes, Regulatory Sequences, Nucleic Acid, Genetic Therapy, Mutagenesis, Insertional, Virus Integration, CpG Islands, Genes, rRNA, Hepatocytes, Transcription Initiation Site, Mice
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