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Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells

Gene Therapy volume 19, pages 375–384 (2012)Cite this article

Abstract

Our recent studies have revealed that among the 10 different commonly used adeno-associated virus (AAV) serotypes, AAV3 vectors transduce human liver cancer cells extremely efficiently because these cells express high levels of human hepatocyte growth factor receptor (hHGFR), and AAV3 utilizes hHGFR as a cellular co-receptor for viral entry. In this report, we provide further evidence that both extracellular as well as intracellular kinase domains of hHGFR are involved in AAV3 vector entry and AAV3-mediated transgene expression. We also document that AAV3 vectors are targeted for degradation by the host cell proteasome machinery, and that site-directed mutagenesis of surface-exposed tyrosine (Y) to phenylalanine (F) residues on AAV3 capsids significantly improves the transduction efficiency of Y701F, Y705F and Y731F mutant AAV3 vectors. The transduction efficiency of the Y705+731F double-mutant vector is significantly higher than each of the single mutants in liver cancer cells in vitro. In immunodeficient mouse xenograft models, direct intratumoral injection of AAV3 vectors also led to high-efficiency transduction of human liver tumor cells in vivo. We also document here that the optimized tyrosine-mutant AAV3 vectors lead to increased transduction efficiency following both intratumoral and tail-vein injections in vivo. The optimized tyrosine-mutant AAV3 serotype vectors containing proapoptotic genes should prove useful for the potential gene therapy of human liver cancers.

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References

  1. Muzyczka N . Use of adeno-associated virus as a general transduction vector for mammalian cells. Curr Top Microbiol Immunol 1992; 158: 97–129.

    CAS  PubMed  Google Scholar 

  2. Daya S, Berns KI . Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 2008; 21: 583–593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Muramatsu S, Mizukami H, Young NS, Brown KE . Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology 1996; 221: 208–217.

    Article  CAS  PubMed  Google Scholar 

  4. Chiorini JA, Yang L, Liu Y, Safer B, Kotin RM . Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol 1997; 71: 6823–6833.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Chiorini JA, Kim F, Yang L, Kotin RM . Cloning and characterization of adeno-associated virus type 5. J Virol 1999; 73: 1309–1319.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Rutledge EA, Halbert CL, Russell DW . Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 1998; 72: 309–319.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM . Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 11854–11859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol 2004; 78: 6381–6388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Summerford C, Samulski RJ . Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998; 72: 1438–1445.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Qing K, Mah C, Hansen J, Zhou S, Dwarki V, Srivastava A . Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 1999; 5: 71–77.

    Article  CAS  PubMed  Google Scholar 

  11. Summerford C, Bartlett JS, Samulski RJ . AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 1999; 5: 78–82.

    Article  CAS  PubMed  Google Scholar 

  12. Hansen J, Qing K, Kwon HJ, Mah C, Srivastava A . Impaired intracellular trafficking of adeno-associated virus type 2 vectors limits efficient transduction of murine fibroblasts. J Virol 2000; 74: 992–996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hansen J, Qing K, Srivastava A . Adeno-associated virus type 2-mediated gene transfer: altered endocytic processing enhances transduction efficiency in murine fibroblasts. J Virol 2001; 75: 4080–4090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sanlioglu S, Benson PK, Yang J, Atkinson EM, Reynolds T, Engelhardt JF . Endocytosis and nuclear trafficking of adeno-associated virus type 2 are controlled by rac1 and phosphatidylinositol-3 kinase activation. J Virol 2000; 74: 9184–9196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Douar AM, Poulard K, Stockholm D, Danos O . Intracellular trafficking of adeno-associated virus vectors: routing to the late endosomal compartment and proteasome degradation. J Virol 2001; 75: 1824–1833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao W, Zhong L, Wu J, Chen L, Qing K, Weigel-Kelley KA et al. Role of cellular FKBP52 protein in intracellular trafficking of recombinant adeno-associated virus 2 vectors. Virology 2006; 353: 283–293.

    Article  CAS  PubMed  Google Scholar 

  17. Thomas CE, Storm TA, Huang Z, Kay MA . Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors. J Virol 2004; 78: 3110–3122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhong L, Li W, Yang Z, Qing K, Tan M, Hansen J et al. Impaired nuclear transport and uncoating limit recombinant adeno-associated virus 2 vector-mediated transduction of primary murine hematopoietic cells. Hum Gene Ther 2004; 15: 1207–1218.

    Article  CAS  PubMed  Google Scholar 

  19. Ferrari FK, Samulski T, Shenk T, Samulski RJ . Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 1996; 70: 3227–3234.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Fisher KJ, Gao GP, Weitzman MD, DeMatteo R, Burda JF, Wilson JM . Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J Virol 1996; 70: 520–532.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Qing K, Hansen J, Weigel-Kelley KA, Tan M, Zhou S, Srivastava A . Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression. J Virol 2001; 75: 8968–8976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhong L, Qing K, Si Y, Chen L, Tan M, Srivastava A . Heat-shock treatment-mediated increase in transduction by recombinant adeno-associated virus 2 vectors is independent of the cellular heat-shock protein 90. J Biol Chem 2004; 279: 12714–12723.

    Article  CAS  PubMed  Google Scholar 

  23. Zhong L, Li W, Yang Z, Chen L, Li Y, Qing K et al. Improved transduction of primary murine hepatocytes by recombinant adeno-associated virus 2 vectors in vivo. Gene Therapy 2004; 11: 1165–1169.

    Article  CAS  PubMed  Google Scholar 

  24. Zhong L, Zhou X, Li Y, Qing K, Xiao X, Samulski RJ et al. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. Mol Ther 2008; 16: 290–295.

    Article  CAS  PubMed  Google Scholar 

  25. McCarty DM, Young Jr SM, Samulski RJ . Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu Rev Genet 2004; 38: 819–845.

    Article  CAS  PubMed  Google Scholar 

  26. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med 2008; 358: 2231–2239.

    Article  CAS  PubMed  Google Scholar 

  27. Zincarelli C, Soltys S, Rengo G, Koch WJ, Rabinowitz JE . Comparative cardiac gene delivery of adeno-associated virus serotypes 1–9 reveals that AAV6 mediates the most efficient transduction in mouse heart. Clin Transl Sci 2010; 3: 81–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE . Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 2008; 16: 1073–1080.

    Article  CAS  PubMed  Google Scholar 

  29. Glushakova LG, Lisankie MJ, Eruslanov EB, Ojano-Dirain C, Zolotukhin I, Liu C et al. AAV3-mediated transfer and expression of the pyruvate dehydrogenase E1 alpha subunit gene causes metabolic remodeling and apoptosis of human liver cancer cells. Mol Genet Metab 2009; 98: 289–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ling C, Lu Y, Kelsi JK, Jayandharan GR, Li B, Ma W et al. Human hepatocyte growth factor receptor is a cellular co-receptor for AAV3. Hum Gene Ther 2010; 21: 1741–1747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhong L, Zhao W, Wu J, Li B, Zolotukhin S, Govindasamy L et al. A dual role of EGFR protein tyrosine kinase signaling in ubiquitination of AAV2 capsids and viral second-strand DNA synthesis. Mol Ther 2007; 15: 1323–1330.

    Article  CAS  PubMed  Google Scholar 

  32. Duan D, Yue Y, Yan Z, Yang J, Engelhardt JF . Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest 2000; 105: 1573–1587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhong L, Li B, Jayandharan G, Mah CS, Govindasamy L, Agbandje-McKenna M et al. Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression. Virology 2008; 381: 194–202.

    Article  CAS  PubMed  Google Scholar 

  34. Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M et al. 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 2008; 105: 7827–7832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Markusic DM, Herzog RW, Aslanidi GV, Hoffman BE, Li B, Li M et al. High-efficiency transduction and correction of murine hemophilia b using aav2 vectors devoid of multiple surface-exposed tyrosines. Mol Ther 2010; 18: 2048–2056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Petrs-Silva H, Dinculescu A, Li Q, Min SH, Chiodo V, Pang JJ et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 2009; 17: 463–471.

    Article  CAS  PubMed  Google Scholar 

  37. Qiao C, Zhang W, Yuan Z, Shin JH, Li J, Jayandharan GR et al. AAV6 capsid tyrosine to phenylalanine mutations improve gene transfer to skeletal muscle. Hum Gene Ther 2010; 21: 1343–1348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Taylor J, Ussher JE . Optimized transduction of human monocyte-derived dendritic cells by recombinant adeno-associated virus serotype 6 (rAAV6). Hum Gene Ther 2010; 21: 1675–1686.

    Article  PubMed  Google Scholar 

  39. Abella JV, Peschard P, Naujokas MA, Lin T, Saucier C, Urbe S et al. Met/hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. Mol Cell Biol 2005; 25: 9632–9645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nguyen L, Holgado-Madruga M, Maroun C, Fixman ED, Kamikura D, Fournier T et al. Association of the multisubstrate docking protein Gab1 with the hepatocyte growth factor receptor requires a functional Grb2 binding site involving tyrosine 1356. J Biol Chem 1997; 272: 20811–20819.

    Article  CAS  PubMed  Google Scholar 

  41. Schroeder GM, An Y, Cai ZW, Chen XT, Clark C, Cornelius LA et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluor ophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem 2009; 52: 1251–1254.

    Article  CAS  PubMed  Google Scholar 

  42. Dai Y, Siemann DW . BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther 2010; 9: 1554–1561.

    Article  CAS  PubMed  Google Scholar 

  43. Kashiwakura Y, Tamayose K, Iwabuchi K, Hirai Y, Shimada T, Matsumoto K et al. Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection. J Virol 2005; 79: 609–614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yan Z, Zak R, Luxton GW, Ritchie TC, Bantel-Schaal U, Engelhardt JF . Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J Virol 2002; 76: 2043–2053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J . Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res 1982; 42: 3858–3863.

    CAS  PubMed  Google Scholar 

  46. Chen TT, Rakheja D, Hung JY, Hornsby PJ, Tabaczewski P, Malogolowkin M et al. Establishment and characterization of a cancer cell line derived from an aggressive childhood liver tumor. Pediatr Blood Cancer 2009; 53: 1040–1047.

    Article  PubMed  Google Scholar 

  47. Mah C, Qing K, Khuntirat B, Ponnazhagan S, Wang XS, Kube DM et al. Adeno-associated virus type 2-mediated gene transfer: role of epidermal growth factor receptor protein tyrosine kinase in transgene expression. J Virol 1998; 72: 9835–9843.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA 2008; 105: 15112–15117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maguire AM, Simonelli F, Pierce EA, Pugh Jr EN, Mingozzi F, Bennicelli J et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 2008; 358: 2240–2248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010; 21: 704–712.

    Article  CAS  PubMed  Google Scholar 

  51. Mendell JR, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S et al. Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med 2010; 363: 1429–1437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347.

    Article  CAS  PubMed  Google Scholar 

  53. Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009; 137: 1005–1017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Su H, Chang JC, Xu SM, Kan YW . Selective killing of AFP-positive hepatocellular carcinoma cells by adeno-associated virus transfer of the herpes simplex virus thymidine kinase gene. Hum Gene Ther 1996; 7: 463–470.

    Article  CAS  PubMed  Google Scholar 

  55. Peng D, Qian C, Sun Y, Barajas MA, Prieto J . Transduction of hepatocellular carcinoma (HCC) using recombinant adeno-associated virus (rAAV): in vitro and in vivo effects of genotoxic agents. J Hepatol 2000; 32: 975–985.

    Article  CAS  PubMed  Google Scholar 

  56. Su H, Lu R, Ding R, Kan YW . Adeno-associated viral-mediated gene transfer to hepatoma: thymidine kinase/interleukin 2 is more effective in tumor killing in non-ganciclovir (GCV)-treated than in GCV-treated animals. Mol Ther 2000; 1: 509–515.

    Article  CAS  PubMed  Google Scholar 

  57. Ma H, Liu Y, Liu S, Xu R, Zheng D . Oral adeno-associated virus-sTRAIL gene therapy suppresses human hepatocellular carcinoma growth in mice. Hepatology 2005; 42: 1355–1363.

    Article  CAS  PubMed  Google Scholar 

  58. Wang Y, Huang F, Cai H, Zhong S, Liu X, Tan WS . Potent antitumor effect of TRAIL mediated by a novel adeno-associated viral vector targeting to telomerase activity for human hepatocellular carcinoma. J Gene Med 2008; 10: 518–526.

    Article  PubMed  Google Scholar 

  59. Tse LY, Sun X, Jiang H, Dong X, Fung PW, Farzaneh F et al. Adeno-associated virus-mediated expression of kallistatin suppresses local and remote hepatocellular carcinomas. J Gene Med 2008; 10: 508–517.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang Y, Ma H, Zhang J, Liu S, Liu Y, Zheng D . AAV-mediated TRAIL gene expression driven by hTERT promoter suppressed human hepatocellular carcinoma growth in mice. Life Sci 2008; 82: 1154–1161.

    Article  CAS  PubMed  Google Scholar 

  61. Malecki M, Swoboda P, Pachecka J . Recombinant adeno-associated virus derived vectors (rAAV2) efficiently transduce ovarian and hepatocellular carcinoma cells--implications for cancer gene therapy. Acta Pol Pharma 2009; 66: 93–99.

    CAS  Google Scholar 

  62. Wang Y, Huang F, Cai H, Wu Y, He G, Tan WS . The efficacy of combination therapy using adeno-associated virus-TRAIL targeting to telomerase activity and cisplatin in a mice model of hepatocellular carcinoma. J Cancer Res Clin Oncol 2010; 136: 1827–1837.

    Article  CAS  PubMed  Google Scholar 

  63. Liu X, Yao W, Newton RC, Scherle PA . Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs 2008; 17: 997–1011.

    Article  CAS  PubMed  Google Scholar 

  64. Tang ZY . Hepatocellular carcinoma surgery--review of the past and prospects for the 21st century. J Surg Oncol 2005; 91: 95–96.

    Article  PubMed  Google Scholar 

  65. Liu S, Yu M, He Y, Xiao L, Wang F, Song C et al. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology 2008; 47: 1964–1973.

    Article  CAS  PubMed  Google Scholar 

  66. Zhang C, Li B, Lu SQ, Li Y, Su YH, Ling CQ . Effects of melittin on expressions of mitochondria membrane protein 7A6, cell apoptosis-related gene products Fas and Fas ligand in hepatocarcinoma cells. Zhong Xi Yi Jie He Xue Bao 2007; 5: 559–563.

    Article  PubMed  Google Scholar 

  67. Wang C, Chen T, Zhang N, Yang M, Li B, Lu X et al. Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J Biol Chem 2009; 284: 3804–3813.

    Article  CAS  PubMed  Google Scholar 

  68. Ling CQ, Li B, Zhang C, Zhu DZ, Huang XQ, Gu W et al. Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Ann Oncol 2005; 16: 109–115.

    Article  PubMed  Google Scholar 

  69. Wu J, Zhao W, Zhong L, Han Z, Li B, Ma W et al. Self-complementary recombinant adeno-associated viral vectors: packaging capacity and the role of rep proteins in vector purity. Hum Gene Ther 2007; 18: 171–182.

    Article  CAS  PubMed  Google Scholar 

  70. Kube DM, Srivastava A . Quantitative DNA slot blot analysis: inhibition of DNA binding to membranes by magnesium ions. Nucleic Acids Res 1997; 25: 3375–3376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Drs R Jude Samulski and Xiao Xiao for their kind gifts of recombinant AAV3 and AAV2–CBAp–EGFP plasmids, respectively, and Dr Gail E Tomlinson for generously providing the Hep293TT cell line. We also thank Drs Regino Gonzalez-Peralta and Satish K Walia for a critical review of the manuscript as well as for their general counsel. The expert technical assistance of Mr Baozheng Li and Ms Wenqin Ma is gratefully acknowledged. This research was supported, in part, by a Junior Investigator Award from the University of Florida Shands Cancer Center, American Cancer Society Chris DiMarco Institutional Research Grant (to GVA), and Public Health Service Grants R01 HL-076901, R01 HL-097088 and P01 DK-058327 (Project 1) from the National Institutes of Health (to AS). BC was supported by a state-sponsored program for Graduate Students from China Scholarship Council, Government of China.

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  1. B Cheng and C Ling: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cellular and Molecular Therapy, Departments of Pediatics and Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA

    B Cheng, C Ling, Y Lu, S W Y Gee, K E McGoogan, G V Aslanidi & A Srivastava

  2. Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA

    B Cheng, C Ling, Y Lu, S W Y Gee, K E McGoogan, G V Aslanidi & A Srivastava

  3. Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China

    B Cheng & C Ling

  4. Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA

    C Ling, Y Lu & A Srivastava

  5. Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, USA

    Y Dai & D Siemann

  6. Division of Endocrinology and Metabolism, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    L G Glushakova & P W Stacpoole

  7. Division of Critical Care Medicine, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA

    S W Y Gee

  8. Division of Gastroenterology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA

    K E McGoogan

  9. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    M Park

  10. Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA

    P W Stacpoole

  11. Shands Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA

    D Siemann & A Srivastava

  12. Department of Pathology and Laboratory Medicine,

    C Liu

  13. University of Florida College of Medicine, Gainesville, FL, USA

    C Liu

  14. Genetics Institute, University of Florida College of Medicine, Gainesville, FL, USA

    A Srivastava

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  1. B Cheng
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Cheng, B., Ling, C., Dai, Y. et al. Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells. Gene Ther 19, 375–384 (2012). https://doi.org/10.1038/gt.2011.105

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