Emerging Issues in AAV-Mediated In Vivo Gene Therapy

Molecular Therapy Methods and Clinical Development

Volumn 8, Issue , 2018, Pages 87-104

  Colella, Pasqualina ^a   Ronzitti, Giuseppe ^a   Mingozzi, Federico ^a,b  

^a UNIVERSITÉ D EVRY VAL D ESSONNE   (France)

^b SORBONNE UNIVERSITÉ   (France)

Author keywords

AAV; AAV capsid; AAV genome; gene therapy; genotoxicity; inherited diseases; liver immunogenicity; persistence

Indexed keywords

ADENO ASSOCIATED VIRUS VECTOR; BORTEZOMIB; CORTICOSTEROID; DOUBLE STRANDED DNA; MONOCLONAL ANTIBODY; RAPAMYCIN; RECOMBINANT BLOOD CLOTTING FACTOR 8; RECOMBINANT BLOOD CLOTTING FACTOR 9; VIRUS ANTIBODY;

ADENO ASSOCIATED VIRUS; CELL MIGRATION; CELLULAR IMMUNITY; DRUG EFFICACY; DRUG MANUFACTURE; DRUG POTENCY; DRUG SAFETY; GENE CASSETTE; GENE EXPRESSION; GENETIC TRANSFECTION; GENOTOXICITY; HUMAN; HUMORAL IMMUNITY; IMMUNOGENICITY; IN VIVO GENE TRANSFER; IN VIVO STUDY; LIVER; LIVER CELL; MOLECULAR BIOLOGY; NONHUMAN; PRECLINICAL STUDY; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; TARGET TISSUE; TRANSGENE; VIRAL GENE DELIVERY SYSTEM; VIRUS CAPSID; VIRUS GENOME; VIRUS IMMUNITY;

EID: 85043533130     PISSN: None     EISSN: 23290501     Source Type: Journal    
DOI: 10.1016/j.omtm.2017.11.007     Document Type: Review

References (203)

1. Balakrishnan, B., Jayandharan, G.R., Basic biology of adeno-associated virus (AAV) vectors used in gene therapy. Curr. Gene Ther. 14 (2014), 86–100.
2. Sonntag, F., Schmidt, K., Kleinschmidt, J.A., A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc. Natl. Acad. Sci. USA 107 (2010), 10220–10225.
3. Calcedo, R., Morizono, H., Wang, L., McCarter, R., He, J., Jones, D., Batshaw, M.L., Wilson, J.M., Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin. Vaccine Immunol. 18 (2011), 1586–1588.
4. Erles, K., Sebökovà P., Schlehofer, J.R., Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J. Med. Virol. 59 (1999), 406–411.
5. Li, C., Narkbunnam, N., Samulski, R.J., Asokan, A., Hu, G., Jacobson, L.J., Manco-Johnson, M.J., Monahan, P.E., Joint Outcome Study Investigators. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 19 (2012), 288–294.
6. Smith, R.H., Adeno-associated virus integration: virus versus vector. Gene Ther. 15 (2008), 817–822.
7. Wright, J.F., Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 15 (2008), 840–848.
8. Grieger, J.C., Samulski, R.J., Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 507 (2012), 229–254.
9. Schultz, B.R., Chamberlain, J.S., Recombinant adeno-associated virus transduction and integration. Mol. Ther. 16 (2008), 1189–1199.
10. Valdmanis, P.N., Lisowski, L., Kay, M.A., rAAV-mediated tumorigenesis: still unresolved after an AAV assault. Mol. Ther. 20 (2012), 2014–2017.
11. Li, H., Malani, N., Hamilton, S.R., Schlachterman, A., Bussadori, G., Edmonson, S.E., Shah, R., Arruda, V.R., Mingozzi, F., Wright, J.F., et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood 117 (2011), 3311–3319.
12. Gao, G., Vandenberghe, L.H., Wilson, J.M., New recombinant serotypes of AAV vectors. Curr. Gene Ther. 5 (2005), 285–297.
13. Asokan, A., Schaffer, D.V., Samulski, R.J., The AAV vector toolkit: poised at the clinical crossroads. Mol. Ther. 20 (2012), 699–708.
14. Pillay, S., Meyer, N.L., Puschnik, A.S., Davulcu, O., Diep, J., Ishikawa, Y., Jae, L.T., Wosen, J.E., Nagamine, C.M., Chapman, M.S., Carette, J.E., An essential receptor for adeno-associated virus infection. Nature 530 (2016), 108–112.
15. Weinmann, J., Grimm, D., Next-generation AAV vectors for clinical use: an ever-accelerating race. Virus Genes 53 (2017), 707–713.
16. Robert, M.A., Chahal, P.S., Audy, A., Kamen, A., Gilbert, R., Gaillet, B., Manufacturing of recombinant adeno-associated viruses using mammalian expression platforms. Biotechnol. J., 12, 2017, 1600193.
17. Kotin, R.M., Large-scale recombinant adeno-associated virus production. Hum. Mol. Genet. 20:R1 (2011), R2–R6.
18. Ayuso, E., Mingozzi, F., Bosch, F., Production, purification and characterization of adeno-associated vectors. Curr. Gene Ther. 10 (2010), 423–436.
19. Ayuso, E., Mingozzi, F., Montane, J., Leon, X., Anguela, X.M., Haurigot, V., Edmonson, S.A., Africa, L., Zhou, S., High, K.A., et al. High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency. Gene Ther. 17 (2010), 503–510.
20. Wright, J.F., Wellman, J., High, K.A., Manufacturing and regulatory strategies for clinical AAV2-hRPE65. Curr. Gene Ther. 10 (2010), 341–349.
21. Deverman, B.E., Pravdo, P.L., Simpson, B.P., Kumar, S.R., Chan, K.Y., Banerjee, A., Wu, W.L., Yang, B., Huber, N., Pasca, S.P., Gradinaru, V., Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34 (2016), 204–209.
22. Tseng, Y.S., Agbandje-McKenna, M., Mapping the AAV capsid host antibody response toward the development of second generation gene delivery vectors. Front. Immunol., 5, 2014, 9.
23. Kotterman, M.A., Schaffer, D.V., Engineering adeno-associated viruses for clinical gene therapy. Nat. Rev. Genet. 15 (2014), 445–451.
24. Grimm, D., Büning, H., Small but increasingly mighty: latest advances in AAV vector research, design, and evolution. Hum. Gene Ther. 28 (2017), 1075–1086.
25. Tse, L.V., Klinc, K.A., Madigan, V.J., Castellanos Rivera, R.M., Wells, L.F., Havlik, L.P., Smith, J.K., Agbandje-McKenna, M., Asokan, A., Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc. Natl. Acad. Sci. USA 114 (2017), E4812–E4821.
26. McCarty, D.M., Self-complementary AAV vectors; advances and applications. Mol. Ther. 16 (2008), 1648–1656.
27. Nathwani, A.C., Gray, J.T., Ng, C.Y., Zhou, J., Spence, Y., Waddington, S.N., Tuddenham, E.G., Kemball-Cook, G., McIntosh, J., Boon-Spijker, M., et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 107 (2006), 2653–2661.
28. Nathwani, A.C., Rosales, C., McIntosh, J., Rastegarlari, G., Nathwani, D., Raj, D., Nawathe, S., Waddington, S.N., Bronson, R., Jackson, S., et al. Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol. Ther. 19 (2011), 876–885.
29. Mendell, J.R., Al-Zaidy, S., Shell, R., Arnold, W.D., Rodino-Klapac, L.R., Prior, T.W., Lowes, L., Alfano, L., Berry, K., Church, K., et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377 (2017), 1713–1722.
30. Monahan, P.E., Lothrop, C.D., Sun, J., Hirsch, M.L., Kafri, T., Kantor, B., Sarkar, R., Tillson, D.M., Elia, J.R., Samulski, R.J., Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application. Mol. Ther. 18 (2010), 1907–1916.
31. Ghosh, A., Duan, D., Expanding adeno-associated viral vector capacity: a tale of two vectors. Biotechnol. Genet. Eng. Rev. 24 (2007), 165–177.
32. Grieger, J.C., Samulski, R.J., Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. J. Virol. 79 (2005), 9933–9944.
33. Dong, B., Nakai, H., Xiao, W., Characterization of genome integrity for oversized recombinant AAV vector. Mol. Ther. 18 (2010), 87–92.
34. Colella, P., Sommella, A., Marrocco, E., Di Vicino, U., Polishchuk, E., Garcia Garrido, M., Seeliger, M.W., Polishchuk, R., Auricchio, A., Myosin7a deficiency results in reduced retinal activity which is improved by gene therapy. PLoS ONE, 8, 2013, e72027.
35. Hirsch, M.L., Li, C., Bellon, I., Yin, C., Chavala, S., Pryadkina, M., Richard, I., Samulski, R.J., Oversized AAV transductifon is mediated via a DNA-PKcs-independent, Rad51C-dependent repair pathway. Mol. Ther. 21 (2013), 2205–2216.
36. Wu, Z., Yang, H., Colosi, P., Effect of genome size on AAV vector packaging. Mol. Ther. 18 (2010), 80–86.
37. Trapani, I., Colella, P., Sommella, A., Iodice, C., Cesi, G., de Simone, S., Marrocco, E., Rossi, S., Giunti, M., Palfi, A., et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol. Med. 6 (2014), 194–211.
38. Colella, P., Trapani, I., Cesi, G., Sommella, A., Manfredi, A., Puppo, A., Iodice, C., Rossi, S., Simonelli, F., Giunti, M., et al. Efficient gene delivery to the cone-enriched pig retina by dual AAV vectors. Gene Ther. 21 (2014), 450–456.
39. Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaïb, A., Miyake, K., Guerchet, N., Fougerousse, F., McNeil, P., Richard, I., Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum. Mol. Genet. 19 (2010), 1897–1907.
40. Sondergaard, P.C., Griffin, D.A., Pozsgai, E.R., Johnson, R.W., Grose, W.E., Heller, K.N., Shontz, K.M., Montgomery, C.L., Liu, J., Clark, K.R., et al. AAV.Dysferlin overlap vectors restore function in dysferlinopathy animal models. Ann. Clin. Transl. Neurol. 2 (2015), 256–270.
41. Kodippili, K., Hakim, C.H., Pan, X., Yang, H.T., Yue, Y., Zhang, Y., Shin, J.-H., Yang, N.N., Duan, D., Dual AAV gene therapy for Duchenne muscular dystrophy with a 7-kb mini-dystrophin gene in the canine model. Hum. Gene Ther., 2017, 10.1089/hum.2017.095 Published online August 4, 2017.
42. Potter, R.A., Griffin, D.A., Sondergaard, P.C., Johnson, R.W., Pozsgai, E.R., Heller, K.N., Peterson, E.L., Lehtimäki, K.K., Windish, H.P., Mittal, P.J., et al. Systemic delivery of dysferlin overlap vectors provides long-term gene expression and functional improvement for dysferlinopathy. Hum. Gene Ther., 2017, 10.1089/hum.2017.062 Published online July 13, 2017.
43. Trapani, I., Toriello, E., de Simone, S., Colella, P., Iodice, C., Polishchuk, E.V., Sommella, A., Colecchi, L., Rossi, S., Simonelli, F., et al. Improved dual AAV vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model of Stargardt disease. Hum. Mol. Genet. 24 (2015), 6811–6825.
44. Scallan, C.D., Liu, T., Parker, A.E., Patarroyo-White, S.L., Chen, H., Jiang, H., Vargas, J., Nagy, D., Powell, S.K., Wright, J.F., et al. Phenotypic correction of a mouse model of hemophilia A using AAV2 vectors encoding the heavy and light chains of FVIII. Blood 102 (2003), 3919–3926.
45. Li, J., Sun, W., Wang, B., Xiao, X., Liu, X.Q., Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. Hum. Gene Ther. 19 (2008), 958–964.
46. Sabatino, D.E., Lange, A.M., Altynova, E.S., Sarkar, R., Zhou, S., Merricks, E.P., Franck, H.G., Nichols, T.C., Arruda, V.R., Kazazian, H.H. Jr., Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol. Ther. 19 (2011), 442–449.
47. Jiang, H., Lillicrap, D., Patarroyo-White, S., Liu, T., Qian, X., Scallan, C.D., Powell, S., Keller, T., McMurray, M., Labelle, A., et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood 108 (2006), 107–115.
48. Nathwani, A.C., Tuddenham, E.G., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D.C., Chowdary, P., Riddell, A., Pie, A.J., Harrington, C., et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365 (2011), 2357–2365.
49. Nathwani, A.C., Reiss, U.M., Tuddenham, E.G., Rosales, C., Chowdary, P., McIntosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371 (2014), 1994–2004.
50. Niemeyer, 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. Jr., Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 113 (2009), 797–806.
51. Mingozzi, F., Liu, Y.L., Dobrzynski, E., Kaufhold, A., Liu, J.H., Wang, Y., Arruda, V.R., High, K.A., Herzog, R.W., Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J. Clin. Invest. 111 (2003), 1347–1356.
52. Mingozzi, F., Hasbrouck, N.C., Basner-Tschakarjan, E., Edmonson, S.A., Hui, D.J., Sabatino, D.E., Zhou, S., Wright, J.F., Jiang, H., Pierce, G.F., et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110 (2007), 2334–2341.
53. Dobrzynski, E., Mingozzi, F., Liu, Y.L., Bendo, E., Cao, O., Wang, L., Herzog, R.W., Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer. Blood 104 (2004), 969–977.
54. Cao, O., Dobrzynski, E., Wang, L., Nayak, S., Mingle, B., Terhorst, C., Herzog, R.W., Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110 (2007), 1132–1140.
55. Kattenhorn, L.M., Tipper, C.H., Stoica, L., Geraghty, D.S., Wright, T.L., Clark, K.R., Wadsworth, S.C., Adeno-associated virus gene therapy for liver disease. Hum. Gene Ther. 27 (2016), 947–961.
56. Mount, J.D., Herzog, R.W., Tillson, D.M., Goodman, S.A., Robinson, N., McCleland, M.L., Bellinger, D., Nichols, T.C., Arruda, V.R., Lothrop, C.D. Jr., High, K.A., Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 99 (2002), 2670–2676.
57. Manno, C.S., Pierce, G.F., Arruda, V.R., Glader, B., Ragni, M., Rasko, J.J., Ozelo, M.C., Hoots, K., Blatt, P., Konkle, B., et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat. Med. 12 (2006), 342–347.
58. Mingozzi, F., Maus, M.V., Hui, D.J., Sabatino, D.E., Murphy, S.L., Rasko, J.E., Ragni, M.V., Manno, C.S., Sommer, J., Jiang, H., et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13 (2007), 419–422.
59. Vandamme, C., Adjali, O., Mingozzi, F., Unraveling the complex story of immune responses to AAV vectors trial after trial. Hum. Gene Ther. 28 (2017), 1061–1074.
60. Mingozzi, F., Büning, H., Adeno-associated viral vectors at the frontier between tolerance and immunity. Front. Immunol., 6, 2015, 120.
61. Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M.F., Masurier, C., 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. 21 (2010), 704–712.
62. Veron, P., Leborgne, C., Monteilhet, V., Boutin, S., Martin, S., Moullier, P., Masurier, C., Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J. Immunol. 188 (2012), 6418–6424.
63. Mingozzi, F., High, K.A., Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu. Rev. Virol. 4 (2017), 511–534.
64. Finn, J.D., Hui, D., Downey, H.D., Dunn, D., Pien, G.C., Mingozzi, F., Zhou, S., High, K.A., Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol. Ther. 18 (2010), 135–142.
65. Pien, G.C., Basner-Tschakarjan, E., Hui, D.J., Mentlik, A.N., Finn, J.D., Hasbrouck, N.C., Zhou, S., Murphy, S.L., Maus, M.V., Mingozzi, F., et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J. Clin. Invest. 119 (2009), 1688–1695.
66. Monahan, P., Powell, W.C., Konkle, J.S., Josephson, B.A., Escobar, N.C., McPhee, M., Litchev, S.J., et al. Update on a phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for hemophilia B: LB010. J. Thromb. Haemost., 13, 2015, 87.
67. 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. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl. Med., 5, 2013, 194ra92.
68. Tardieu, M., Zérah, M., Gougeon, M.L., Ausseil, J., de Bournonville, S., Husson, B., Zafeiriou, D., Parenti, G., Bourget, P., Poirier, B., et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 16 (2017), 712–720.
69. Mingozzi, F., Meulenberg, J.J., Hui, D.J., Basner-Tschakarjan, E., Hasbrouck, N.C., Edmonson, S.A., Hutnick, N.A., Betts, M.R., Kastelein, J.J., Stroes, E.S., High, K.A., AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood 114 (2009), 2077–2086.
70. Montenegro-Miranda, P.S., ten Bloemendaal, L., Kunne, C., de Waart, D.R., Bosma, P.J., Mycophenolate mofetil impairs transduction of single-stranded adeno-associated viral vectors. Hum. Gene Ther. 22 (2011), 605–612.
71. Li, C., Hirsch, M., Asokan, A., Zeithaml, B., Ma, H., Kafri, T., Samulski, R.J., Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J. Virol. 81 (2007), 7540–7547.
72. Li, H., Murphy, S.L., Giles-Davis, W., Edmonson, S., Xiang, Z., Li, Y., Lasaro, M.O., High, K.A., Ertl, H.C., Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol. Ther. 15 (2007), 792–800.
73. Wang, L., Figueredo, J., Calcedo, R., Lin, J., Wilson, J.M., Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum. Gene Ther. 18 (2007), 185–194.
74. Martino, A.T., Basner-Tschakarjan, E., Markusic, D.M., Finn, J.D., Hinderer, C., Zhou, S., Ostrov, D.A., Srivastava, A., Ertl, H.C., Terhorst, C., et al. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 121 (2013), 2224–2233.
75. Li, H., Tuyishime, S., Wu, T.L., Giles-Davis, W., Zhou, D., Xiao, W., High, K.A., Ertl, H.C., Adeno-associated virus vectors serotype 2 induce prolonged proliferation of capsid-specific CD8+ T cells in mice. Mol. Ther. 19 (2011), 536–546.
76. Calcedo, R., Vandenberghe, L.H., Gao, G., Lin, J., Wilson, J.M., Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199 (2009), 381–390.
77. Mingozzi, F., Chen, Y., Edmonson, S.C., Zhou, S., Thurlings, R.M., Tak, P.P., High, K.A., Vervoordeldonk, M.J., Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther. 20 (2013), 417–424.
78. Gao, G.P., Alvira, M.R., Wang, L., Calcedo, R., Johnston, J., Wilson, J.M., Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl. Acad. Sci. USA 99 (2002), 11854–11859.
79. Jiang, H., Couto, L.B., Patarroyo-White, S., Liu, T., Nagy, D., Vargas, J.A., Zhou, S., Scallan, C.D., Sommer, J., Vijay, S., et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 108 (2006), 3321–3328.
80. Masat, E., Pavani, G., Mingozzi, F., Humoral immunity to AAV vectors in gene therapy: challenges and potential solutions. Discov. Med. 15 (2013), 379–389.
81. Meliani, A., Leborgne, C., Triffault, S., Jeanson-Leh, L., Veron, P., Mingozzi, F., Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. Hum. Gene Ther. Methods 26 (2015), 45–53.
82. Scallan, C.D., Jiang, H., Liu, T., Patarroyo-White, S., Sommer, J.M., Zhou, S., Couto, L.B., Pierce, G.F., Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 107 (2006), 1810–1817.
83. Shin, J.H., Yue, Y., Smith, B., Duan, D., Humoral immunity to AAV-6, 8, and 9 in normal and dystrophic dogs. Hum. Gene Ther. 23 (2012), 287–294.
84. Arnett, A.L., Garikipati, D., Wang, Z., Tapscott, S., Chamberlain, J.S., Immune responses to rAAV6: the influence of canine parvovirus vaccination and neonatal administration of viral vector. Front. Microbiol., 2, 2011, 220.
85. Rapti, K., Louis-Jeune, V., Kohlbrenner, E., Ishikawa, K., Ladage, D., Zolotukhin, S., Hajjar, R.J., Weber, T., Neutralizing antibodies against AAV serotypes 1, 2, 6, and 9 in sera of commonly used animal models. Mol. Ther. 20 (2012), 73–83.
86. Thomson, A.W., Knolle, P.A., Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10 (2010), 753–766.
87. Franco, L.M., Sun, B., Yang, X., Bird, A., Zhang, H., Schneider, A., Brown, T., Young, S.P., Clay, T.M., Amalfitano, A., et al. Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II. Mol. Ther. 12 (2005), 876–884.
88. Martino, A.T., Nayak, S., Hoffman, B.E., Cooper, M., Liao, G., Markusic, D.M., Byrne, B.J., Terhorst, C., Herzog, R.W., Tolerance induction to cytoplasmic beta-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity. PLoS ONE, 4, 2009, e6376.
89. Zhang, P., Sun, B., Osada, T., Rodriguiz, R., Yang, X.Y., Luo, X., Kemper, A.R., Clay, T.M., Koeberl, D.D., Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease. Hum. Gene Ther. 23 (2012), 460–472.
90. Han, S.O., Ronzitti, G., Arnson, B., Leborgne, C., Li, S., Mingozzi, F., Koeberl, D., Low-dose liver-targeted gene therapy for Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol. Ther. Methods Clin. Dev. 4 (2017), 126–136.
91. Markusic, D.M., Hoffman, B.E., Perrin, G.Q., Nayak, S., Wang, X., LoDuca, P.A., High, K.A., Herzog, R.W., Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies. EMBO Mol. Med. 5 (2013), 1698–1709.
92. Finn, J.D., Ozelo, M.C., Sabatino, D.E., Franck, H.W., Merricks, E.P., Crudele, J.M., Zhou, S., Kazazian, H.H., Lillicrap, D., Nichols, T.C., Arruda, V.R., Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116 (2010), 5842–5848.
93. Crudele, J.M., Finn, J.D., Siner, J.I., Martin, N.B., Niemeyer, G.P., Zhou, S., Mingozzi, F., Lothrop, C.D. Jr., Arruda, V.R., AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood 125 (2015), 1553–1561.
94. van der Ploeg, A.T., Reuser, A.J., Pompe's disease. Lancet 372 (2008), 1342–1353.
95. Pratt, K.P., Inhibitory antibodies in hemophilia A. Curr. Opin. Hematol. 19 (2012), 399–405.
96. Hösel, M., Broxtermann, M., Janicki, H., Esser, K., Arzberger, S., Hartmann, P., Gillen, S., Kleeff, J., Stabenow, D., Odenthal, M., et al. Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology 55 (2012), 287–297.
97. Martino, A.T., Suzuki, M., Markusic, D.M., Zolotukhin, I., Ryals, R.C., Moghimi, B., Ertl, H.C., Muruve, D.A., Lee, B., Herzog, R.W., The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 117 (2011), 6459–6468.
98. Zhu, J., Huang, X., Yang, Y., The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J. Clin. Invest. 119 (2009), 2388–2398.
99. Sudres, M., Ciré S., Vasseur, V., Brault, L., Da Rocha, S., Boisgérault, F., Le Bec, C., Gross, D.A., Blouin, V., Ryffel, B., Galy, A., MyD88 signaling in B cells regulates the production of Th1-dependent antibodies to AAV. Mol. Ther. 20 (2012), 1571–1581.
100. Rogers, G.L., Suzuki, M., Zolotukhin, I., Markusic, D.M., Morel, L.M., Lee, B., Ertl, H.C., Herzog, R.W., Unique roles of TLR9- and MyD88-dependent and -independent pathways in adaptive immune responses to AAV-mediated gene transfer. J. Innate Immun. 7 (2015), 302–314.
101. Faust, S.M., Bell, P., Cutler, B.J., Ashley, S.N., Zhu, Y., Rabinowitz, J.E., Wilson, J.M., CpG-depleted adeno-associated virus vectors evade immune detection. J. Clin. Invest. 123 (2013), 2994–3001.
102. Haurigot, V., Marcó S., Ribera, A., Garcia, M., Ruzo, A., Villacampa, P., Ayuso, E., Añor, S., Andaluz, A., Pineda, M., et al. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J. Clin. Invest. 123 (2013), 3254–3271.
103. Tessitore, A., Faella, A., O'Malley, T., Cotugno, G., Doria, M., Kunieda, T., Matarese, G., Haskins, M., Auricchio, A., Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol. Ther. 16 (2008), 30–37.
104. Ross, C.J., Twisk, J., Bakker, A.C., Miao, F., Verbart, D., Rip, J., Godbey, T., Dijkhuizen, P., Hermens, W.T., Kastelein, J.J., et al. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum. Gene Ther. 17 (2006), 487–499.
105. Fields, P.A., Arruda, V.R., Armstrong, E., Chu, K., Mingozzi, F., Hagstrom, J.N., Herzog, R.W., High, K.A., Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9. Mol. Ther. 4 (2001), 201–210.
106. McIntosh, J., Lenting, P.J., Rosales, C., Lee, D., Rabbanian, S., Raj, D., Patel, N., Tuddenham, E.G., Christophe, O.D., McVey, J.H., et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 121 (2013), 3335–3344.
107. Siner, J.I., Iacobelli, N.P., Sabatino, D.E., Ivanciu, L., Zhou, S., Poncz, M., Camire, R.M., Arruda, V.R., Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype. Blood 121 (2013), 4396–4403.
108. Finn, J.D., Nichols, T.C., Svoronos, N., Merricks, E.P., Bellenger, D.A., Zhou, S., Simioni, P., High, K.A., Arruda, V.R., The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy. Blood 120 (2012), 4521–4523.
109. Davidoff, A.M., Gray, J.T., Ng, C.Y., Zhang, Y., Zhou, J., Spence, Y., Bakar, Y., Nathwani, A.C., Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol. Ther. 11 (2005), 875–888.
110. Zhong, L., Li, B., Mah, C.S., Govindasamy, L., Agbandje-McKenna, M., Cooper, M., Herzog, R.W., Zolotukhin, I., Warrington, K.H. Jr., Weigel-Van Aken, K.A., 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 105 (2008), 7827–7832.
111. Gabriel, N., Hareendran, S., Sen, D., Gadkari, R.A., Sudha, G., Selot, R., Hussain, M., Dhaksnamoorthy, R., Samuel, R., Srinivasan, N., et al. Bioengineering of AAV2 capsid at specific serine, threonine, or lysine residues improves its transduction efficiency in vitro and in vivo. Hum. Gene Ther. Methods 24 (2013), 80–93.
112. Shen, S., Horowitz, E.D., Troupes, A.N., Brown, S.M., Pulicherla, N., Samulski, R.J., Agbandje-McKenna, M., Asokan, A., Engraftment of a galactose receptor footprint onto adeno-associated viral capsids improves transduction efficiency. J. Biol. Chem. 288 (2013), 28814–28823.
113. Zinn, E., Pacouret, S., Khaychuk, V., Turunen, H.T., Carvalho, L.S., Andres-Mateos, E., Shah, S., Shelke, R., Maurer, A.C., Plovie, E., et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep. 12 (2015), 1056–1068.
114. Markusic, D.M., Nichols, T.C., Merricks, E.P., Palaschak, B., Zolotukhin, I., Marsic, D., Zolotukhin, S., Srivastava, A., Herzog, R.W., Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models. J. Transl. Med., 15, 2017, 94.
115. Lisowski, L., Dane, A.P., Chu, K., Zhang, Y., Cunningham, S.C., Wilson, E.M., Nygaard, S., Grompe, M., Alexander, I.E., Kay, M.A., Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506 (2014), 382–386.
116. Vercauteren, K., Hoffman, B.E., Zolotukhin, I., Keeler, G.D., Xiao, J.W., Basner-Tschakarjan, E., High, K.A., Ertl, H.C., Rice, C.M., Srivastava, A., et al. Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol. Ther. 24 (2016), 1042–1049.
117. Duan, D., Yue, Y., Yan, Z., Yang, J., Engelhardt, J.F., Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J. Clin. Invest. 105 (2000), 1573–1587.
118. Nathwani, A.C., Cochrane, M., McIntosh, J., Ng, C.Y., Zhou, J., Gray, J.T., Davidoff, A.M., Enhancing transduction of the liver by adeno-associated viral vectors. Gene Ther. 16 (2009), 60–69.
119. Mitchell, A.M., Li, C., Samulski, R.J., Arsenic trioxide stabilizes accumulations of adeno-associated virus virions at the perinuclear region, increasing transduction in vitro and in vivo. J. Virol. 87 (2013), 4571–4583.
120. Wang, L.N., Wang, Y., Lu, Y., Yin, Z.F., Zhang, Y.H., Aslanidi, G.V., Srivastava, A., Ling, C.Q., Ling, C., Pristimerin enhances recombinant adeno-associated virus vector-mediated transgene expression in human cell lines in vitro and murine hepatocytes in vivo. J. Integr. Med. 12 (2014), 20–34.
121. Alé A., Bruna, J., Herrando, M., Navarro, X., Udina, E., Toxic effects of bortezomib on primary sensory neurons and Schwann cells of adult mice. Neurotox. Res. 27 (2015), 430–440.
122. Sen, D., Gadkari, R.A., Sudha, G., Gabriel, N., Kumar, Y.S., Selot, R., Samuel, R., Rajalingam, S., Ramya, V., Nair, S.C., et al. Targeted modifications in adeno-associated virus serotype 8 capsid improves its hepatic gene transfer efficiency in vivo. Hum. Gene Ther. Methods 24 (2013), 104–116.
123. Hösel, M., Huber, A., Bohlen, S., Lucifora, J., Ronzitti, G., Puzzo, F., Boisgerault, F., Hacker, U.T., Kwanten, W.J., Klöting, N., et al. Autophagy determines efficiency of liver-directed gene therapy with adeno-associated viral vectors. Hepatology 66 (2017), 252–265.
124. Hösel, M., Lucifora, J., Michler, T., Holz, G., Gruffaz, M., Stahnke, S., Zoulim, F., Durantel, D., Heikenwalder, M., Nierhoff, D., et al. Hepatitis B virus infection enhances susceptibility toward adeno-associated viral vector transduction in vitro and in vivo. Hepatology 59 (2014), 2110–2120.
125. Mimuro, J., Mizukami, H., Hishikawa, S., Ikemoto, T., Ishiwata, A., Sakata, A., Ohmori, T., Madoiwa, S., Ono, F., Ozawa, K., Sakata, Y., Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. Mol. Ther. 21 (2013), 318–323.
126. Zabaleta, N., Salas, D., Paramo, M., Hommel, M., Sier-Ferreira, V., Hernandez-Alcoceba, R., Prieto, J., Bilbao, J.I., Gonzalez-Aseguinolaza, G., Improvement of adeno-associated virus-mediated liver transduction efficacy by regional administration in Macaca fascicularis. Hum. Gene Ther. Clin. Dev. 28 (2017), 68–73.
127. Arruda, V.R., Stedman, H.H., Haurigot, V., Buchlis, G., Baila, S., Favaro, P., Chen, Y., Franck, H.G., Zhou, S., Wright, J.F., et al. Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood 115 (2010), 4678–4688.
128. György, B., Maguire, C.A., Extracellular vesicles: nature's nanoparticles for improving gene transfer with adeno-associated virus vectors. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2017, 10.1002/wnan.1488 Published August 11, 2017.
129. Meliani, A., Boisgerault, F., Fitzpatrick, Z., Marmier, S., Leborgne, C., Collaud, F., Sola, M.S., Charles, S., Ronzitti, G., Vignaud, A., et al. Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors. Blood Adv. 1 (2017), 2019–2031.
130. Nathwani, A.C., Gray, J.T., McIntosh, J., Ng, C.Y., Zhou, J., Spence, Y., Cochrane, M., Gray, E., Tuddenham, E.G., Davidoff, A.M., Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 109 (2007), 1414–1421.
131. Wu, Z., Sun, J., Zhang, T., Yin, C., Yin, F., Van Dyke, T., Samulski, R.J., Monahan, P.E., Optimization of self-complementary AAV vectors for liver-directed expression results in sustained correction of hemophilia B at low vector dose. Mol. Ther. 16 (2008), 280–289.
132. Gao, G.P., Lu, Y., Sun, X., Johnston, J., Calcedo, R., Grant, R., Wilson, J.M., High-level transgene expression in nonhuman primate liver with novel adeno-associated virus serotypes containing self-complementary genomes. J. Virol. 80 (2006), 6192–6194.
133. Jayandharan, G.R., Zhong, L., Sack, B.K., Rivers, A.E., Li, M., Li, B., Herzog, R.W., Srivastava, A., Optimized adeno-associated virus (AAV)-protein phosphatase-5 helper viruses for efficient liver transduction by single-stranded AAV vectors: therapeutic expression of factor IX at reduced vector doses. Hum. Gene Ther. 21 (2010), 271–283.
134. Nakai, H., Storm, T.A., Kay, M.A., Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors. Nat. Biotechnol. 18 (2000), 527–532.
135. Sarkar, R., Tetreault, R., Gao, G., Wang, L., Bell, P., Chandler, R., Wilson, J.M., Kazazian, H.H. Jr., Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. Blood 103 (2004), 1253–1260.
136. Xie, J., Mao, Q., Tai, P.W.L., He, R., Ai, J., Su, Q., Zhu, Y., Ma, H., Li, J., Gong, S., et al. Short DNA hairpins compromise recombinant adeno-associated virus genome homogeneity. Mol. Ther. 25 (2017), 1363–1374.
137. Papadakis, E.D., Nicklin, S.A., Baker, A.H., White, S.J., Promoters and control elements: designing expression cassettes for gene therapy. Curr. Gene Ther. 4 (2004), 89–113.
138. Choi, J.H., Yu, N.K., Baek, G.C., Bakes, J., Seo, D., Nam, H.J., Baek, S.H., Lim, C.S., Lee, Y.S., Kaang, B.K., Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons. Mol. Brain, 7, 2014, 17.
139. Ronzitti, G., Bortolussi, G., van Dijk, R., Collaud, F., Charles, S., Leborgne, C., Vidal, P., Martin, S., Gjata, B., Sola, M.S., et al. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Mol. Ther. Methods Clin. Dev., 3, 2016, 16049.
140. Miao, C.H., Ohashi, K., Patijn, G.A., Meuse, L., Ye, X., Thompson, A.R., Kay, M.A., Inclusion of the hepatic locus control region, an intron, and untranslated region increases and stabilizes hepatic factor IX gene expression in vivo but not in vitro. Mol. Ther. 1 (2000), 522–532.
141. Nair, N., Rincon, M.Y., Evens, H., Sarcar, S., Dastidar, S., Samara-Kuko, E., Ghandeharian, O., Man Viecelli, H., Thöny, B., De Bleser, P., et al. Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy. Blood 123 (2014), 3195–3199.
142. Presnyak, V., Alhusaini, N., Chen, Y.H., Martin, S., Morris, N., Kline, N., Olson, S., Weinberg, D., Baker, K.E., Graveley, B.R., Coller, J., Codon optimality is a major determinant of mRNA stability. Cell 160 (2015), 1111–1124.
143. Sack, B.K., Merchant, S., Markusic, D.M., Nathwani, A.C., Davidoff, A.M., Byrne, B.J., Herzog, R.W., Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy. PLoS ONE, 7, 2012, e37671.
144. Ward, N.J., Buckley, S.M., Waddington, S.N., Vandendriessche, T., Chuah, M.K., Nathwani, A.C., McIntosh, J., Tuddenham, E.G., Kinnon, C., Thrasher, A.J., McVey, J.H., Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 117 (2011), 798–807.
145. Bell, P., Wang, L., Chen, S.J., Yu, H., Zhu, Y., Nayal, M., He, Z., White, J., Lebel-Hagan, D., Wilson, J.M., Effects of self-complementarity, codon optimization, transgene, and dose on liver transduction with AAV8. Hum. Gene Ther. Methods 27 (2016), 228–237.
146. Simioni, P., Tormene, D., Tognin, G., Gavasso, S., Bulato, C., Iacobelli, N.P., Finn, J.D., Spiezia, L., Radu, C., Arruda, V.R., X-linked thrombophilia with a mutant factor IX (factor IX Padua). N. Engl. J. Med. 361 (2009), 1671–1675.
147. Zhang, R., Wang, Q., Zhang, L., Chen, S., Optimized human factor IX expression cassettes for hepatic-directed gene therapy of hemophilia B. Front. Med. 9 (2015), 90–99.
148. Colella, P., Puzzo, F., Biferi, M., Bali, D., Paulk, N., Vidal, P., Collaud, F., Simon-Sola, M., Charles, S., Hardet, R., et al. Whole-body rescue of Pompe disease with AAV liver delivery of engineered secretable GAA transgenes. Neuromuscul. Disord., 27, 2017, S246.
149. George, L., Sullivan, S., Giermasz, A., Ducore, J., Teitel, J., Cuker, A., Sullivan, L., Majumdar, S., McGuinn, C.E., Galvao, A.M., et al. SPK-9001: adeno-associated virus mediated gene transfer for hemophilia B achieves sustained mean factor IX activity levels of > 30% without immunosuppression. Blood, 128, 2016, 3.
150. Pasi, J., Wong, W., Rangarajan, S., Walsh, S., Lester, W., Perry, D., et al. Interim results of an open-label, phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A. Res. Pract. Thromb. Haemost. 1 (2017), 1–15.
151. Hurlbut, G.D., Ziegler, R.J., Nietupski, J.B., Foley, J.W., Woodworth, L.A., Meyers, E., Bercury, S.D., Pande, N.N., Souza, D.W., Bree, M.P., et al. Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy. Mol. Ther. 18 (2010), 1983–1994.
152. Nakai, H., Iwaki, Y., Kay, M.A., Couto, L.B., Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J. Virol. 73 (1999), 5438–5447.
153. Nakai, H., Montini, E., Fuess, S., Storm, T.A., Grompe, M., Kay, M.A., AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat. Genet. 34 (2003), 297–302.
154. Inagaki, K., Piao, C., Kotchey, N.M., Wu, X., Nakai, H., Frequency and spectrum of genomic integration of recombinant adeno-associated virus serotype 8 vector in neonatal mouse liver. J. Virol. 82 (2008), 9513–9524.
155. Chandler, R.J., LaFave, M.C., Varshney, G.K., Trivedi, N.S., Carrillo-Carrasco, N., Senac, J.S., Wu, W., Hoffmann, V., Elkahloun, A.G., Burgess, S.M., Venditti, C.P., Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J. Clin. Invest. 125 (2015), 870–880.
156. Russell, D.W., AAV loves an active genome. Nat. Genet. 34 (2003), 241–242.
157. Donsante, A., Miller, D.G., Li, Y., Vogler, C., Brunt, E.M., Russell, D.W., Sands, M.S., AAV vector integration sites in mouse hepatocellular carcinoma. Science, 317, 2007, 477.
158. Rosas, L.E., Grieves, J.L., Zaraspe, K., La Perle, K.M., Fu, H., McCarty, D.M., Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol. Ther. 20 (2012), 2098–2110.
159. Gauttier, V., Pichard, V., Aubert, D., Kaeppel, C., Schmidt, M., Ferry, N., Conchon, S., No tumour-initiating risk associated with scAAV transduction in newborn rat liver. Gene Ther. 20 (2013), 779–784.
160. Bell, P., Wang, L., Lebherz, C., Flieder, D.B., Bove, M.S., Wu, D., Gao, G.P., Wilson, J.M., Wivel, N.A., No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol. Ther. 12 (2005), 299–306.
161. Gao, G., Lu, Y., Calcedo, R., Grant, R.L., Bell, P., Wang, L., Figueredo, J., Lock, M., Wilson, J.M., Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates. Mol. Ther. 13 (2006), 77–87.
162. Wang, L., Calcedo, R., Nichols, T.C., Bellinger, D.A., Dillow, A., Verma, I.M., Wilson, J.M., Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood 105 (2005), 3079–3086.
163. Bell, P., Moscioni, A.D., McCarter, R.J., Wu, D., Gao, G., Hoang, A., Sanmiguel, J.C., Sun, X., Wivel, N.A., Raper, S.E., et al. Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. Mol. Ther. 14 (2006), 34–44.
164. Zhong, L., Malani, N., Li, M., Brady, T., Xie, J., Bell, P., Li, S., Jones, H., Wilson, J.M., Flotte, T.R., et al. Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum. Gene Ther. 24 (2013), 520–525.
165. Nault, J.C., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., Letouzé E., Pilati, C., Verret, B., Blanc, J.F., et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat. Genet. 47 (2015), 1187–1193.
166. Nault, J.C., Mami, I., La Bella, T., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., Letouzé E., Pilati, C., et al. Wild-type AAV insertions in hepatocellular carcinoma do not inform debate over genotoxicity risk of vectorized AAV. Mol. Ther. 24 (2016), 660–661.
167. Logan, G.J., Dane, A.P., Hallwirth, C.V., Smyth, C.M., Wilkie, E.E., Amaya, A.K., Zhu, E., Khandekar, N., Ginn, S.L., Liao, S.H.Y., et al. Identification of liver-specific enhancer-promoter activity in the 3′ untranslated region of the wild-type AAV2 genome. Nat. Genet. 49 (2017), 1267–1273.
168. Gil-Farina, I., Fronza, R., Kaeppel, C., Lopez-Franco, E., Ferreira, V., D'Avola, D., Benito, A., Prieto, J., Petry, H., Gonzalez-Aseguinolaza, G., Schmidt, M., Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol. Ther. 24 (2016), 1100–1105.
169. Ehrhardt, A., Xu, H., Kay, M.A., Episomal persistence of recombinant adenoviral vector genomes during the cell cycle in vivo. J. Virol. 77 (2003), 7689–7695.
170. Nakai, H., Yant, S.R., Storm, T.A., Fuess, S., Meuse, L., Kay, M.A., Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J. Virol. 75 (2001), 6969–6976.
171. Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A.F., Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. FASEB J. 26 (2012), 1052–1063.
172. Bortolussi, G., Zentillin, L., Vaníkova, J., Bockor, L., Bellarosa, C., Mancarella, A., Vianello, E., Tiribelli, C., Giacca, M., Vitek, L., Muro, A.F., Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler-Najjar syndrome. Hum. Gene Ther. 25 (2014), 844–855.
173. Fox, I.J., Chowdhury, J.R., Kaufman, S.S., Goertzen, T.C., Chowdhury, N.R., Warkentin, P.I., Dorko, K., Sauter, B.V., Strom, S.C., Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 338 (1998), 1422–1426.
174. High, K.A., Theodore E. Woodward Award. AAV-mediated gene transfer for hemophilia. Trans. Am. Clin. Climatol. Assoc. 114 (2003), 337–351 discussion 351–352.
175. Junge, N., Mingozzi, F., Ott, M., Baumann, U., Adeno-associated virus vector-based gene therapy for monogenetic metabolic diseases of the liver. J. Pediatr. Gastroenterol. Nutr. 60 (2015), 433–440.
176. Cunningham, S.C., Kok, C.Y., Spinoulas, A., Carpenter, K.H., Alexander, I.E., AAV-encoded OTC activity persisting to adulthood following delivery to newborn spf(ash) mice is insufficient to prevent shRNA-induced hyperammonaemia. Gene Ther. 20 (2013), 1184–1187.
177. Magami, Y., Azuma, T., Inokuchi, H., Kokuno, S., Moriyasu, F., Kawai, K., Hattori, T., Cell proliferation and renewal of normal hepatocytes and bile duct cells in adult mouse liver. Liver 22 (2002), 419–425.
178. Malato, Y., Naqvi, S., Schürmann, N., Ng, R., Wang, B., Zape, J., Kay, M.A., Grimm, D., Willenbring, H., Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest. 121 (2011), 4850–4860.
179. Coppoletta, J.M., Wolbach, S.B., Body length and organ weights of infants and children: a study of the body length and normal weights of the more important vital organs of the body between birth and twelve years of age. Am. J. Pathol. 9 (1933), 55–70.
180. Merle, U., Stremmel, W., Encke, J., Perspectives for gene therapy of Wilson disease. Curr. Gene Ther. 7 (2007), 217–220.
181. Wang, Z., Lisowski, L., Finegold, M.J., Nakai, H., Kay, M.A., Grompe, M., AAV vectors containing rDNA homology display increased chromosomal integration and transgene persistence. Mol. Ther. 20 (2012), 1902–1911.
182. Barzel, A., Paulk, N.K., Shi, Y., Huang, Y., Chu, K., Zhang, F., Valdmanis, P.N., Spector, L.P., Porteus, M.H., Gaensler, K.M., Kay, M.A., Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature 517 (2015), 360–364.
183. Porro, F., Bortolussi, G., Barzel, A., De Caneva, A., Iaconcig, A., Vodret, S., Zentilin, L., Kay, M.A., Muro, A.F., Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model. EMBO Mol. Med. 9 (2017), 1346–1355.
184. Anguela, X.M., Sharma, R., Doyon, Y., Miller, J.C., Li, H., Haurigot, V., Rohde, M.E., Wong, S.Y., Davidson, R.J., Zhou, S., et al. Robust ZFN-mediated genome editing in adult hemophilic mice. Blood 122 (2013), 3283–3287.
185. Li, H., Haurigot, V., Doyon, Y., Li, T., Wong, S.Y., Bhagwat, A.S., Malani, N., Anguela, X.M., Sharma, R., Ivanciu, L., et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475 (2011), 217–221.
186. Yang, Y., Wang, L., Bell, P., McMenamin, D., He, Z., White, J., Yu, H., Xu, C., Morizono, H., Musunuru, K., et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat. Biotechnol. 34 (2016), 334–338.
187. 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. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34 (2016), 328–333.
188. Jarrett, K.E., Lee, C.M., Yeh, Y.H., Hsu, R.H., Gupta, R., Zhang, M., Rodriguez, P.J., Lee, C.S., Gillard, B.K., Bissig, K.D., et al. Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci. Rep., 7, 2017, 44624.
189. Ran, F.A., Cong, L., Yan, W.X., Scott, D.A., Gootenberg, J.S., Kriz, A.J., Zetsche, B., Shalem, O., Wu, X., Makarova, K.S., et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520 (2015), 186–191.
190. Chadwick, A.C., Wang, X., Musunuru, K., In vivo base editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a therapeutic alternative to genome editing. Arterioscler. Thromb. Vasc. Biol. 37 (2017), 1741–1747.
191. Majowicz, A., Salas, D., Zabaleta, N., Rodríguez-Garcia, E., González-Aseguinolaza, G., Petry, H., Ferreira, V., Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5ch and AAV1. Mol. Ther. 25 (2017), 1831–1842.
192. Bočkor, L., Bortolussi, G., Iaconcig, A., Chiaruttini, G., Tiribelli, C., Giacca, M., Benvenuti, F., Zentilin, L., Muro, A.F., Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type I. Gene Ther. 24 (2017), 649–660.
193. Demaster, A., Luo, X., Curtis, S., Williams, K.D., Landau, D.J., Drake, E.J., Kozink, D.M., Bird, A., Crane, B., Sun, F., et al. Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia. Hum. Gene Ther. 23 (2012), 407–418.
194. Corti, M., Cleaver, B., Clément, N., Conlon, T.J., Faris, K.J., Wang, G., Benson, J., Tarantal, A.F., Fuller, D., Herzog, R.W., Byrne, B.J., Evaluation of readministration of a recombinant adeno-associated virus vector expressing acid alpha-glucosidase in Pompe disease: preclinical to clinical planning. Hum. Gene Ther. Clin. Dev. 26 (2015), 185–193.
195. Meliani, A., Boisgerault, F., Ronzitti, G., Collaud, F., Leborgne, C., Kishimoto, T.K., Mingozzi, F., Antigen-specific modulation of capsid immunogenicity with tolerogenic nanoparticles results in successful AAV vector readministration. Mol. Ther., 24(Suppl 1), 2016, S34.
196. Monteilhet, V., Saheb, S., Boutin, S., Leborgne, C., Veron, P., Montus, M.F., Moullier, P., Benveniste, O., Masurier, C., A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol. Ther. 19 (2011), 2084–2091.
197. Chicoine, L.G., Montgomery, C.L., Bremer, W.G., Shontz, K.M., Griffin, D.A., Heller, K.N., Lewis, S., Malik, V., Grose, W.E., Shilling, C.J., et al. Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol. Ther. 22 (2014), 338–347.
198. Mingozzi, F., Chen, Y., Murphy, S.L., Edmonson, S.C., Tai, A., Price, S.D., Metzger, M.E., Zhou, S., Wright, J.F., Donahue, R.E., et al. Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B. Mol. Ther. 20 (2012), 1410–1416.
199. Sarkar, D., Biswas, M., Liao, G., Seay, H.R., Perrin, G.Q., Markusic, D.M., Hoffman, B.E., Brusko, T.M., Terhorst, C., Herzog, R.W., Ex vivo expanded autologous polyclonal regulatory T cells suppress inhibitor formation in hemophilia. Mol. Ther. Methods Clin. Dev., 1, 2014, 14030.
200. Mendell, J.R., Campbell, K., Rodino-Klapac, L., Sahenk, Z., Shilling, C., Lewis, S., Bowles, D., Gray, S., Li, C., Galloway, G., et al. Dystrophin immunity in Duchenne's muscular dystrophy. N. Engl. J. Med. 363 (2010), 1429–1437.
201. Calcedo, R., Somanathan, S., Qin, Q., Betts, M.R., Rech, A.J., Vonderheide, R.H., Mueller, C., Flotte, T.R., Wilson, J.M., Class I-restricted T-cell responses to a polymorphic peptide in a gene therapy clinical trial for α-1-antitrypsin deficiency. Proc. Natl. Acad. Sci. USA 114 (2017), 1655–1659.
202. Dobrzynski, E., Fitzgerald, J.C., Cao, O., Mingozzi, F., Wang, L., Herzog, R.W., Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells. Proc. Natl. Acad. Sci. USA 103 (2006), 4592–4597.
203. Boisgerault, F., Gross, D.A., Ferrand, M., Poupiot, J., Darocha, S., Richard, I., Galy, A., Prolonged gene expression in muscle is achieved without active immune tolerance using microrRNA 142.3p-regulated rAAV gene transfer. Hum. Gene Ther. 24 (2013), 393–405.