AAV's Anatomy: Roadmap for Optimizing Vectors for Translational Success

Current Gene Therapy

Volumn 10, Issue 5, 2010, Pages 319-340

  Mitchell, Angela M ^a   Nicolson, Sarah C ^a   Warischalk, Jayme K ^a   Samulski, R Jude ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

Adeno associated virus; Capsid modification; Clinical trials; Directed evolution; Gene delivery; Immune response; Targeting

Indexed keywords

ALPHA SARCOGLYCAN; DEXAMETHASONE; GANCICLOVIR; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GLUCOSE TRANSPORTER 1; GLUTAMATE DECARBOXYLASE; GLYCOSIDASE; LIPOPROTEIN LIPASE; NEUROPEPTIDE Y; NEURTURIN; ONCOLYTIC VIRUS; PARVOVIRUS VECTOR; REOLYSIN; SARCOPLASMIC RETICULUM CALCIUM TRANSPORTING ADENOSINE TRIPHOSPHATASE; SPERMINE; THYMIDINE KINASE; TRANSMEMBRANE CONDUCTANCE REGULATOR; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; UNCLASSIFIED DRUG;

ABSENCE OF SIDE EFFECTS; ADENO ASSOCIATED VIRUS; ALZHEIMER DISEASE; ANTIBODY RESPONSE; ARTICLE; CANAVAN DISEASE; CLINICAL TRIAL (TOPIC); CYSTIC FIBROSIS; GENE EXPRESSION; GENE TARGETING; GENE THERAPY; GLYCOGEN STORAGE DISEASE TYPE 2; HEART FAILURE; HEMOPHILIA B; HUMAN; HYPERLIPOPROTEINEMIA TYPE 1; IMMUNE EVASION; LIMB GIRDLE MUSCULAR DYSTROPHY; LIVER CELL CARCINOMA; MELANOMA; MUTAGENESIS; NONHUMAN; PARKINSON DISEASE; PROSTATE CANCER; RHEUMATOID ARTHRITIS; RNA TRANSLATION; TEMPORAL LOBE EPILEPSY; VIRUS CAPSID;

ADENO-ASSOCIATED VIRUS; MIRIDAE;

EID: 78651336414     PISSN: 15665232     EISSN: None     Source Type: Journal    
DOI: 10.2174/156652310793180706     Document Type: Article

References (287)

1. Kawabata K, Takakura Y, Hashida M. The fate of plasmid DNAafter intravenous injection in mice: involvement of scavenger receptorsin its hepatic uptake. Pharm Res 1995; 12: 825-30.
2. Soutschek J, Akinc A, Bramlage B, et al. Therapeutic silencing ofan endogenous gene by systemic administration of modified siRNAs. Nature 2004; 432: 173-8.
3. Wooddell CI, Reppen T, Wolff JA, Herweijer H. Sustained liverspecifictransgene expression from the albumin promoter in micefollowing hydrodynamic plasmid DNA delivery. J Gene Med 2008; 10: 551-63.
4. Itaka K, Kataoka K. Recent development of nonviral gene deliverysystems with virus-like structures and mechanisms. Eur J Pharm Biopharm 2009; 71: 475-83.
5. Barteau B, Chevre R, Letrou-Bonneval E, Labas R, Lambert O, Pitard B. Physicochemical parameters of non-viral vectors thatgovern transfection efficiency. Curr Gene Ther 2008; 8: 313-23.
6. Montier T, Benvegnu T, Jaffres PA, Yaouanc JJ, Lehn P. Progressin cationic lipid-mediated gene transfection: a series of bio-inspiredlipids as an example. Curr Gene Ther 2008; 8: 296-312.
7. Itaka K, Harada A, Yamasaki Y, Nakamura K, Kawaguchi H, Kataoka K. In situ single cell observation by fluorescence resonanceenergy transfer reveals fast intra-cytoplasmic delivery andeasy release of plasmid DNA complexed with linear polyethylenimine. J Gene Med 2004; 6: 76-84.
8. Allen TM, Hansen C, Martin F, Redemann C, Yau-Young A. Liposomes containing synthetic lipid derivatives of poly(ethyleneglycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta 1991; 1066: 29-36.
9. Fisher KD, Ulbrich K, Subr V, et al. A versatile system for receptor-mediated gene delivery permits increased entry of DNA intotarget cells, enhanced delivery to the nucleus and elevated rates oftransgene expression. Gene Ther 2000; 7: 1337-43.
10. Dow SW, Fradkin LG, Liggitt DH, Willson AP, Heath TD, Potter TA. Lipid-DNA complexes induce potent activation of innate immuneresponses and antitumor activity when administered intravenously. J Immunol 1999; 163: 1552-61.
11. Seow Y, Wood MJ. Biological Gene Delivery Vehicles: Beyond Viral Vectors. Mol Ther 2009; 17: 767-77.
12. Nemunaitis J, Cunningham C, Senzer N, et al. Pilot trial of geneticallymodified, attenuated Salmonella expressing the E. coli cytosinedeaminase gene in refractory cancer patients. Cancer Gene Ther 2003; 10: 737-44.
13. Schoen C, Kolb-Mäurer A, Geginat G, et al. Bacterial delivery offunctional messenger RNA to mammalian cells. Cell Microbiol 2005; 7: 709-24.
14. Moreno M, Kramer MG, Yim L, Chabalgoity JA. Salmonella aslive trojan horse for vaccine development and cancer gene therapy. Curr Gene Ther 2010; 10: 56-76.
15. Larsen MD, Griesenbach U, Goussard S, et al. Bactofection of lungepithelial cells in vitro and in vivo using a genetically modified Escherichiacoli. Gene Ther 2008; 15: 434-42.
16. Toso JF, Gill VJ, Hwu P, et al. Phase I study of the intravenousadministration of attenuated Salmonella typhimurium to patientswith metastatic melanoma. J Clin Oncol 2002; 20: 142-52.
17. Byun HM, Suh D, Yoon H, et al. Erythrocyte ghost-mediated genedelivery for prolonged and blood-targeted expression. Gene Ther 2004; 11: 492-6.
18. Doberstein SK, Wiegand G, Machesky LM, Pollard TD. Fluorescenterythrocyte ghosts as standards for quantitative flow cytometry. Cytometry 1995; 20: 14-8.
19. Wang M, Tsou TH, Chen LS, et al. Inhibition of simian virus 40large tumor antigen expression in human fetal glial cells by an antisenseoligodeoxynucleotide delivered by the JC virus-like particle. Hum Gene Ther 2004; 15: 1077-90.
20. Bundy BC, Franciszkowicz MJ, Swartz JR. Escherichia coli-basedcell-free synthesis of virus-like particles. Biotechnol Bioeng 2008; 100: 28-37.
21. Pattenden LK, Middelberg APJ, Niebert M, Lipin DI. Towards thepreparative and large-scale precision manufacture of virus-like particles. Trends Biotechnol 2005; 23: 523-9.
22. Shi W, Liu J, Huang Y, Qiao L. Papillomavirus pseudovirus: anovel vaccine to induce mucosal and systemic cytotoxic Tlymphocyteresponses. J Virol 2001; 75: 10139-48.
23. Hu Y-C. Baculoviral vectors for gene delivery: a review. Current Gene Therapy 2008; 8: 54-65.
24. Kost TA, Condreay JP, Jarvis DL. Baculovirus as versatile vectorsfor protein expression in insect and mammalian cells. Nat Biotech 2005; 23: 567-75.
25. Strauss R, Huser A, Ni S, Tuve S, Kiviat N, Sow PS, Hofmann C, Lieber A. Baculovirus-based vaccination vectors allow for efficientinduction of immune responses against Plasmodium falciparumcircumsporozoite protein. Mol Ther 2007; 15: 193-202.
26. Ho Y-C, Chung Y-C, Hwang S-M, Wang K-C, Hu Y-C. Transgeneexpression and differentiation of baculovirus-transduced humanmesenchymal stem cells. J Gene Med 2005; 7: 860-8.
27. Hervas-Stubbs S, Rueda P, Lopez L, Leclerc C. Insect baculovirusesstrongly potentiate adaptive immune responses by inducingtype I IFN. J Immunol 2007; 178: 2361-9.
28. Hoare J, Waddington S, Thomas HC, Coutelle C, McGarvey MJ. Complement inhibition rescued mice allowing observation oftransgene expression following intraportal delivery of baculovirusin mice. J Gene Med 2005; 7: 325-33.
29. Kenoutis C, Efrose RC, Swevers L, et al. Baculovirus-mediatedgene delivery into mammalian cells does not alter their transcriptionaland differentiating potential but is accompanied by early viralgene expression. J Virol 2006; 80: 4135-46.
30. Hu Y-c. Baculovirus as a highly efficient expression vector ininsect and mammalian cells. Acta Pharmacol Sin 2005; 26: 405-16.
31. Pieroni L, Maione D, La Monica N. In vivo gene transfer in mouseskeletal muscle mediated by baculovirus vectors. Hum Gene Ther 2001; 12: 871-81.
32. Jepson CD, March JB. Bacteriophage lambda is a highly stableDNA vaccine delivery vehicle. Vaccine 2004; 22: 2413-9.
33. Shearer WT, Lugg DJ, Rosenblatt HM, et al. Antibody responses tobacteriophage X-174 in human subjects exposed to the Antarcticwinter-over model of spaceflight. J Allergy Clin Immunol 2001; 107: 160-4.
34. Greenstein D, Brent R. Introduction to vectors derived from filamentousphages. Curr Protoc Mol Biol 2001; Chapter 1: Unit1 14.
35. Piersanti S, Cherubini G, Martina Y, et al. Mammalian cell transductionand internalization properties of? phages displaying thefull-length adenoviral penton base or its central domain. J Mol Med 2004; 82: 467-76.
36. Molenaar TJM, Michon I, de Haas SAM, van Berkel TJC, Kuiper J, Biessen EAL. Uptake and processing of modified bacteriophagem13 in mice: implications for phage display. Virology 2002; 293: 182-91.
37. Cripe TP, Wang P-Y, Marcato P, Mahller YY, Lee PWK. Targetingcancer-initiating cells with oncolytic viruses. Mol Ther 2009; 17: 1677-82.
38. Collins SA, Guinn BA, Harrison PT, Scallan MF, O'Sullivan GC, Tangney M. Viral vectors in cancer immunotherapy: which vectorfor which strategy? Curr Gene Ther 2008; 8: 66-78.
39. Fernandez M, Porosnicu M, Markovic D, Barber GN. Geneticallyengineered vesicular stomatitis virus in gene therapy: applicationfor treatment of malignant disease. J Virol 2002; 76: 895-904.
40. Otsuki A, Patel A, Kasai K, et al. Histone deacetylase inhibitorsaugment antitumor efficacy of herpes-based oncolytic Viruses. Mol Ther 2008; 16: 1546-55.
41. Eriksson M, Guse K, Bauerschmitz G, et al. Oncolytic adenoviruseskill breast cancer initiating CD44+CD24-/low cells. Mol Ther 2007; 15: 2088-93.
42. Jiang H, Gomez-Manzano C, Lang FF, Alemany R, Fueyo J. Oncolyticadenovirus: preclinical and clinical studies in patients withhuman malignant gliomas. Curr Gene Ther 2009; 9: 422-7.
43. Marcato P, Dean CA, Giacomantonio CA, Lee PWK. Oncolyticreovirus effectively targets breast cancer stem cells. Mol Ther 2009; 17: 972-9.
44. Galanis E, Hartmann LC, Cliby WA, et al. Phase I trial of intraperitonealadministration of an oncolytic measles virus strain engineeredto express carcinoembryonic antigen for recurrent ovariancancer. Cancer Res 70: 875-82.
45. Blechacz B, Russell SJ. Measles virus as an oncolytic vector platform. Curr Gene Ther 2008; 8: 162-75.
46. Garber K. China approves World's first oncolytic virus therapy forcancer treatment. J Natl Cancer Inst 2006; 98: 298-300.
47. Gollamudi R, Ghalib M, Desai K, et al. Intravenous administrationof Reolysin®, a live replication competent RNA virus is safe in patientswith advanced solid tumors. Investigat New Drugs 2010; 28(5): 641-9.
48. Douglas J. Adenoviral vectors for gene therapy. Mol Biotechnol 2007; 36: 71-80.
49. Schambach A, Baum C. Clinical application of lentiviral vectors--concepts and practice. Curr Gene Ther 2008; 8: 474-82.
50. Naldini L, Blomer U, Gallay P, et al. In Vivo Gene delivery andstable transduction of nondividing cells by a lentiviral vector. Science 1996; 272: 263-7.
51. Funke S, Maisner A, Muhlebach MD, et al. Targeted cell entry oflentiviral vectors. Mol Ther 2008; 16: 1427-36.
52. Mitchell RS, Beitzel BF, Schroder ARW, et al. Retroviral DNAintegration: ASLV, HIV, and MLV show distinct target site preferences. PLo S Biol 2004; 2: e234.
53. Lewinski MK, Yamashita M, Emerman M, et al. Retroviral DNAintegration: viral and cellular determinants of target-site selection. PLo S Pathog 2006; 2: e60.
54. Ellis J. Silencing and variegation of gammaretrovirus and lentivirusvectors. Hum Gene Ther 2005; 16: 1241-6.
55. Towers G. The control of viral infection by tripartite motif proteinsand cyclophilin A. Retrovirology 2007; 4: 40.
56. Engelman A, Cherepanov P. The lentiviral integrase binding proteinLEDGF/p75 and HIV-1 replication. PLo S Pathog 2008; 4:e1000046.
57. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Hematopoieticstem cell gene therapy with a lentiviral vector in x-linkedadrenoleukodystrophy. Science 2009; 326: 818-23.
58. Bayer M, Kantor B, Cockrell A, et al. A large U3 deletion causesincreased in vivo expression from a nonintegrating lentiviral vector. Mol Ther 2008; 16: 1968-76.
59. Sarkis C, Philippe S, Mallet J, Serguera C. Non-integrating lentiviralvectors. Curr Gene Ther 2008; 8: 430-7.
60. Mueller C, Flotte TR. Clinical gene therapy using recombinantadeno-associated virus vectors. Gene Ther 2008; 15: 858-63.
61. Berns KI, Pinkerton TC, Thomas GF, Hoggan MD. Detection ofadeno-associated virus (AAV)-specific nucleotide sequences inDNA isolated from latently infected Detroit 6 cells. Virology 1975; 68: 556-60.
62. Rabinowitz JE, Rolling F, Li C, et al. Cross-packaging of a singleadeno-associated virus (AAV) type 2 vector genome into multipleAAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791-801.
63. Atchison RW, Casto BC, Hammon WM. Adenovirus-Associateddefective virus particles. Science 1965; 149: 754-6.
64. Gao G, Vandenberghe LH, Alvira MR, et al. Clades of adenoassociatedviruses are widely disseminated in human tissues. J Virol 2004; 78: 6381-8.
65. McCarty DM, Ryan JH, Zolotukhin S, Zhou X, Muzyczka N. Interactionof the adeno-associated virus Rep protein with a sequencewithin the A palindrome of the viral terminal repeat. J Virol 1994; 68: 4998-5006.
66. Kyostio SR, Owens RA, Weitzman MD, Antoni BA, Chejanovsky N, Carter BJ. Analysis of adeno-associated virus (AAV) wild-typeand mutant Rep proteins for their abilities to negatively regulateAAV p5 and p19 mRNA levels. J Virol 1994; 68: 2947-57.
67. King JA, Dubielzig R, Grimm D, Kleinschmidt JA. DNA helicasemediatedpackaging of adeno-associated virus type 2 genomes intopreformed capsids. EMBO J 2001; 20: 3282-91.
68. Miller EB, Gurda-Whitaker B, Govindasamy L, et al. Production, purification and preliminary X-ray crystallographic studies ofadeno-associated virus serotype 1. Acta Crystallogr Sect F Struc Biol Cryst Commun 2006; 62: 1271-4.
69. Kronenberg S, Kleinschmidt JA, Bottcher B. Electron cryomicroscopyand image reconstruction of adeno-associated virustype 2 empty capsids. EMBO Rep 2001; 2: 997-1002.
70. Kaludov N, Padron E, Govindasamy L, McKenna R, Chiorini JA, Agbandje-McKenna M. Production, purification and preliminaryX-ray crystallographic studies of adeno-associated virus serotype 4. Virology 2003; 306: 1-6.
71. Walters RW, Agbandje-McKenna M, Bowman VD, et al. Structureof adeno-associated virus serotype 5. J Virol 2004; 78: 3361-71.
72. Xie Q, Ongley HM, Hare J, Chapman MS. Crystallization andpreliminary X-ray structural studies of adeno-associated virus serotype6. Acta Crystallogr Sect F Struct Biol Cryst Commun 2008; 64: 1074-8.
73. Quesada O, Gurda B, Govindasamy L, et al. Agbandje-McKenna M. Production, purification and preliminary X-ray crystallographicstudies of adeno-associated virus serotype 7. Acta Crystallogr Sect F Struct Biol Cryst Commun 2007; 63: 1073-6.
74. Nam H-J, Lane MD, Padron E, et al. Structure of adeno-associatedvirus serotype 8, a gene therapy vector. J Virol 2007; 81: 12260-71.
75. Mitchell M, Nam HJ, Carter A, et al. Production, purification andpreliminary X-ray crystallographic studies of adeno-associated virusserotype 9. Acta Crystallogr Sect F Struct Biol Cryst Commun 2009; 65: 715-8.
76. Wistuba A, Kern A, Weger S, Grimm D, Kleinschmidt JA. Subcellularcompartmentalization of adeno-associated virus type 2 assembly. J Virol 1997; 71: 1341-52.
77. Bartlett JS, Wilcher R, Samulski RJ. Infectious entry pathway ofadeno-associated virus and adeno-associated virus vectors. J Virol 2000; 74: 2777-85.
78. Johnson JS, Samulski RJ. Enhancement of adeno-associated virusinfection by mobilizing capsids into and out of the nucleolus. J Virol 2009; 83: 2632-44.
79. Grieger JC, Johnson JS, Gurda-Whitaker B, Agbandje-McKenna M, Samulski RJ. Surface-Exposed adeno-associated virus Vp1-NLS capsid fusion protein rescues infectivity of noninfectiouswild-type Vp2/Vp3 and Vp3-only capsids but not that of fivefoldpore mutant virions. J Virol 2007; 81: 7833-43.
80. Rabinowitz JE, Samulski RJ. Building a better vector: the manipulationof AAV virions. Virology 2000; 278: 301-8.
81. Ferrari FK, Samulski T, Shenk T, Samulski RJ. Second-strandsynthesis is a rate-limiting step for efficient transduction by recombinantadeno-associated virus vectors. J Virol 1996; 70: 3227-34.
82. Cheung AK, Hoggan MD, Hauswirth WW, Berns KI. Integrationof the adeno-associated virus genome into cellular DNA in latentlyinfected human Detroit 6 cells. J Virol 1980; 33: 739-48.
83. Kotin RM, Siniscalco M, Samulski RJ, et al. Site-specific integrationby adeno-associated virus. Proc Nat Acad Sci USA 1990; 87: 2211-5.
84. Samulski RJ, Zhu X, Xiao X, et al. Targeted integration of adenoassociatedvirus (AAV) into human chromosome 19. EMBO J 1991; 10: 3941-50.
85. Georg-Fries B, Biederlack S, Wolf J, Zur Hausen H. Analysis ofproteins, helper dependence, and seroepidemiology of a new humanparvovirus. Virology 1984; 134: 64-71.
86. Schlehofer JR, Ehrbar M, Hausen HZ. Vaccinia virus, herpes simplexvirus, and carcinogens induce DNA amplification in a humancell line and support replication of a helpervirus dependent parvovirus. Virology 1986; 152: 110-7.
87. Walz C, Deprez A, Dupressoir T, Durst M, Rabreau M, Schlehofer JR. Interaction of human papillomavirus type 16 and adenoassociatedvirus type 2 co-infecting human cervical epithelium. JGen Virol 1997; 78: 1441-52.
88. Ogston P, Raj K, Beard P. Productive replication of adenoassociatedvirus can occur in human papillomavirus type 16 (HPV-16) episome-containing keratinocytes and is augmented by theHPV-16 E2 Protein. J Virol 2000; 74: 3494-504.
89. Yakobson B, Koch T, Winocour E. Replication of adeno-associatedvirus in synchronized cells without the addition of a helper virus. JVirol 1987; 61: 972-81.
90. Yakobson B, Hrynko TA, Peak MJ, Winocour E. Replication ofadeno-associated virus in cells irradiated with UV light at 254 nm. J Virol 1989; 63: 1023-30.
91. Xiao W, Warrington KH, Jr., Hearing P, Hughes J, Muzyczka N. Adenovirus-Facilitated nuclear translocation of adeno-associatedvirus type 2. J Virol 2002; 76: 11505-17.
92. Fisher KJ, Gao GP, Weitzman MD, De Matteo R, Burda JF, Wilson JM. Transduction with recombinant adeno-associated virus forgene therapy is limited by leading-strand synthesis. J Virol 1996; 70: 520-32.
93. Duan D, Sharma P, Dudus L, et al. Formation of adeno-associatedvirus circular genomes is differentially regulated by adenovirus E4ORF6 and E2a gene expression. J Virol 1999; 73: 161-9.
94. Duan D, Sharma P, Yang J, et al. Circular Intermediates of recombinantadeno-associated virus have defined structural characteristicsresponsible for long-term episomal persistence in muscle tissue. J Virol 1998; 72: 8568-77.
95. Chang LS, Shenk T. The adenovirus DNA-binding protein stimulatesthe rate of transcription directed by adenovirus and adenoassociatedvirus promoters. J Virol 1990; 64: 2103-9.
96. Chang LS, Shi Y, Shenk T. Adeno-associated virus P5 promotercontains an adenovirus E1A-inducible element and a binding sitefor the major late transcription factor. J Virol 1989; 63: 3479-88.
97. Shi Y, Seto E, Chang LS, Shenk T. Transcriptional repression byYY1, a human GLI-Kruppel-related protein, and relief of repressionby adenovirus E1A protein. Cell 1991; 67: 377-88.
98. Mouw MB, Pintel DJ. Adeno-Associated virus RNAs appear in atemporal order and their splicing is stimulated during coinfectionwith adenovirus. J Virol 2000; 74: 9878-88.
99. Samulski RJ, Shenk T. Adenovirus E1B 55-Mr polypeptide facilitatestimely cytoplasmic accumulation of adeno-associated virusmRNAs. J Virol 1988; 62: 206-10.
100. Janik JE, Huston MM, Cho K, Rose JA. Efficient synthesis ofadeno-associated virus structural proteins requires both adenovirusDNA binding protein and VA I RNA. Virology 1989; 168: 320-9.
101. Carter BJ, Marcus-Sekura CJ, Laughlin CA, Ketner G. Propertiesof an adenovirus type 2 mutant, Ad2d/807, having a deletion nearthe right-hand genome terminus: Failure to help AAV replication. Virology 1983; 126: 505-16.
102. Huang MM, Hearing P. Adenovirus early region 4 encodes twogene products with redundant effects in lytic infection. J Virol 1989; 63: 2605-15.
103. Ward P, Dean FB, O'Donnell ME, Berns KI. Role of the Adenovirus DNA-binding protein in in vitro adeno-associated virus DNAreplication. J Virol 1998; 72: 420-7.
104. Geoffroy M-C, Salvetti A. Helper functions required for wild typeand recombinant adeno-associated virus growth. Curr Gene Ther 2005; 5: 265-71.
105. Xiao X, Xiao W, Li J, Samulski RJ. A novel 165-base-pair terminalrepeat sequence is the sole cis requirement for the adeno-associatedvirus life cycle. J Virol 1997; 71: 941-8.
106. Grieger JC, Choi VW, Samulski RJ. Production and characterizationof adeno-associated viral vectors. Nat Protoc 2006; 1: 1412-28.
107. McCarty DM, Monahan PE, Samulski RJ. Self-complementaryrecombinant adeno-associated virus (scAAV) vectors promote efficienttransduction independently of DNA synthesis. Gene Ther 2001; 8: 1248-54.
108. McCarty DM, Fu H, Monahan PE, Toulson CE, Naik P, Samulski RJ. Adeno-associated virus terminal repeat (TR) mutant generatesself-complementary vectors to overcome the rate-limiting step totransduction in vivo. Gene Ther 2003; 10: 2112-8.
109. Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. Extrachromosomalrecombinant adeno-associated virus vector genomesare primarily responsible for stable liver transduction invivo. J Virol 2001; 75: 6969-76.
110. Miao CH, Snyder RO, Schowalter DB, et al. The kinetics of rAAVintegration in the liver. Nat Genet 1998; 19: 13-5.
111. Miller DG, Trobridge GD, Petek LM, Jacobs MA, Kaul R, Russell DW. Large-Scale analysis of adeno-associated virus vector integrationsites in normal human cells. J Virol 2005; 79: 11434-42.
112. Wagner JA, Messner AH, Moran ML, et al. Safety and biologicalefficacy of an adeno-associated virus vector-cystic fibrosis transmembraneregulator (AAV-CFTR) in the cystic fibrosis maxillarysinus. Laryngoscope 1999; 109: 266-74.
113. Wagner JA, Nepomuceno IB, Messner AH, et al. A phase II, double-blind, randomized, placebo-controlled clinical trial oftgAAVCF using maxillary sinus delivery in patients with cystic fibrosiswith antrostomies. Hum Gene Ther 2002; 13: 1349-59.
114. Flotte TR, Zeitlin PL, Reynolds TC, et al. Phase I trial of intranasaland endobronchial administration of a recombinant adenoassociatedvirus serotype 2 (rAAV2)-CFTR vector in adult cysticfibrosis patients: a two-part clinical study. Hum Gene Ther 2003; 14: 1079-88.
115. Aitken ML, Moss RB, Waltz DA, et al. A phase I study of aerosolizedadministration of tgAAVCF to cystic fibrosis subjects withmild lung disease. Hum Gene Ther 2001; 12: 1907-16.
116. Moss RB, Rodman D, Spencer LT, et al. Repeated adenoassociatedvirus serotype 2 aerosol-mediated cystic fibrosis transmembraneregulator gene transfer to the lungs of patients with cysticfibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 2004; 125: 509-21.
117. Moss RB, Milla C, Colombo J, et al. Repeated aerosolized AAVCFTRfor treatment of cystic fibrosis: a randomized placebocontrolledphase 2B trial. Hum Gene Ther 2007; 18: 726-32.
118. Fabb SA, Dickson JG. Technology evaluation: AAV factor IX genetherapy, Avigen Inc. Curr Opin Mol Ther 2000; 2: 601-6.
119. Schuettrumpf J, Liu JH, Couto LB, et al. Inadvertent germlinetransmission of AAV2 vector: findings in a rabbit model correlatewith those in a human clinical trial. Mol Ther 2006; 13: 1064-73.
120. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction ofliver in hemophilia by AAV-Factor IX and limitations imposed bythe host immune response. Nat Med 2006; 12: 342-7.
121. Snyder RO, Miao CH, Patijn GA, et al. Persistent and therapeuticconcentrations of human factor IX in mice after hepatic gene transferof recombinant AAV vectors. Nat Genet 1997; 16: 270-6.
122. Kay MA, Manno CS, Ragni MV, et al. Evidence for gene transferand expression of factor IX in haemophilia B patients treated withan AAV vector. Nat Genet 2000; 24: 257-61.
123. Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IXgene transfer to skeletal muscle in patients with severe hemophiliaB. Blood 2003; 101: 2963-72.
124. Jiang H, Pierce GF, Ozelo MC, et al. Evidence of multiyear factorIX expression by AAV-mediated gene transfer to skeletal muscle inan individual with severe hemophilia B. Mol Ther 2006; 14: 452-5.
125. McPhee SW, Janson CG, Li C, et al. Immune responses to AAV ina phase I study for Canavan disease. J Gene Med 2006; 8: 577-88.
126. Carlsson T, Bjorklund T, Kirik D. Restoration of the striatal dopaminesynthesis for Parkinson's disease: viral vector-mediated enzymereplacement strategy. Curr Gene Ther 2007; 7: 109-20.
127. Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of genetherapy with an adeno-associated virus (AAV) borne GAD gene forParkinson's disease: an open label, phase I trial. Lancet 2007; 369: 2097-105.
128. Marks WJ, Jr., Ostrem JL, Verhagen L, et al. Safety and tolerabilityof intraputaminal delivery of CERE-120 (adeno-associated virusserotype 2-neurturin) to patients with idiopathic Parkinson's disease:an open-label, phase I trial. Lancet Neurol 2008; 7: 400-8.
129. Brantly ML, Spencer LT, Humphries M, et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 2006; 17: 1177-86.
130. Mease PJ, Hobbs K, Chalmers A, et al. Local delivery of a recombinantadenoassociated vector containing a tumour necrosis factoralpha antagonist gene in inflammatory arthritis: a phase 1 doseescalationsafety and tolerability study. Ann Rheum Dis 2009; 68: 1247-54.
131. Brantly ML, Chulay JD, Wang L, et al. Sustained transgene expressiondespite T lymphocyte responses in a clinical trial ofrAAV1-AAT gene therapy. Proc Natl Acad Sci U S A 2009; 106: 16363-8.
132. Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, et al. Limbgirdlemuscular dystrophy type 2D gene therapy restores alphasarcoglycanand associated proteins. Ann Neurol 2009; 66: 290-7.
133. Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administrationof AAV1-lipoprotein lipase S447X lowers triglyceridesin lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol 2008; 28: 2303-4.
134. Mingozzi F, Meulenberg JJ, Hui DJ, et al. AAV-1-mediated genetransfer to skeletal muscle in humans results in dose-dependent activationof capsid-specific T cells. Blood 2009; 114: 2077-86.
135. 2+ ATPase as a therapeutic target for heartfailure. Exp Opin Biol Ther 2010; 10: 29-41.
136. Limberis MP, Vandenberghe LH, Zhang L, Pickles RJ, Wilson JM. Transduction efficiencies of novel AAV vectors in mouse airwayepithelium in vivo and human ciliated airway epithelium in vitro. Mol Ther 2008; 17: 294-301.
137. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAVserotypes 1-9 mediated gene expression and tropism in mice aftersystemic injection. Mol Ther 2008; 16: 1073-80.
138. Cooper M, Nayak S, Hoffman BE, Terhorst C, Cao O, Herzog RW. Improved induction of immune tolerance to factor ix by hepaticaav-8 gene transfer. Hum Gene Ther 2009; 20: 767-76.
139. Sondhi D, Hackett NR, Peterson DA, et al. Enhanced survival ofthe LINCL mouse following CLN2 gene transfer using the rh.10rhesus macaque-derived adeno-associated virus vector. Mol Ther 2006; 15: 481-91.
140. Mingozzi F, Maus MV, Hui DJ, et al. CD8+ T-cell responses toadeno-associated virus capsid in humans. Nat Med 2007; 13: 419-22.
141. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors forhuman gene therapy. Proc Natl Acad Sci U S A 2002; 99: 11854-9.
142. Bantel-Schaal U, zur Hausen H. Characterization of the DNA of adefective human parvovirus isolated from a genital site. Virology 1984; 134: 52-63.
143. Grimm D, Kay MA, Kleinschmidt JA. Helper virus-free, opticallycontrollable, and two-plasmid-based production of adenoassociatedvirus vectors of serotypes 1 to 6. Mol Ther 2003; 7: 839-50.
144. Mori S, Wang L, Takeuchi T, Kanda T. Two novel adenoassociatedviruses from cynomolgus monkey: pseudotyping characterizationof capsid protein. Virology 2004; 330: 375-83.
145. Rutledge EA, Halbert CL, Russell DW. Infectious clones and vectorsderived from adeno-associated virus (AAV) serotypes otherthan AAV type 2. J Virol 1998; 72: 309-19.
146. Schmidt M, Grot E, Cervenka P, Wainer S, Buck C, Chiorini JA. Identification and characterization of novel adeno-associated virusisolates in ATCC virus stocks. J Virol 2006; 80: 5082-5.
147. Grimm D, Kay MA. From virus evolution to vector revolution: useof naturally occurring serotypes of adeno-associated virus (AAV)as novel vectors for human gene therapy. Curr Gene Ther 2003; 3: 281-304.
148. Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, Walsh CE. Severallog increase in therapeutic transgene delivery by distinctadeno-associated viral serotype vectors. Mol Ther 2000; 2: 619-23.
149. Blankinship MJ, Gregorevic P, Allen JM, et al. Efficient transductionof skeletal muscle using vectors based on adeno-associated virusserotype 6. Mol Ther 2004; 10: 671-8.
150. Gregorevic P, Blankinship MJ, Allen JM, et al. Systemic deliveryof genes to striated muscles using adeno-associated viral vectors. Nat Med 2004; 10: 828-34.
151. Pacak CA, Mah CS, Thattaliyath BD, et al. Recombinant adenoassociatedvirus serotype 9 leads to preferential cardiac transductionin vivo. Circ Res 2006; 99: e3-9.
152. Mori S, Takeuchi T, Enomoto Y, et al. Tissue distribution of cynomolgusadeno-associated viruses AAV10, AAV11, andAAVcy.7 in naturally infected monkeys. Arch Virol 2008; 153: 375-80.
153. Rabinowitz JE, Bowles DE, Faust SM, Ledford JG, Cunningham SE, Samulski RJ. Cross-dressing the virion: the transcapsidation ofadeno-associated virus serotypes functionally defines subgroups. JVirol 2004; 78: 4421-32.
154. Rabinowitz JE, Rolling F, Li C, et al. Cross-packaging of a singleadeno-associated virus (AAV) type 2 vector genome into multipleAAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791-801.
155. Lerch TF, Xie Q, Ongley HM, Hare J, Chapman MS. Twinnedcrystals of adeno-associated virus serotype 3b prove suitable forstructural studies. Acta Crystallogr Sect F Struct Biol Cryst Commun 2009; 65: 177-83.
156. O'Donnell J, Taylor KA, Chapman MS. Adeno-associated virus-2and its primary cellular receptor--Cryo-EM structure of a heparincomplex. Virology 2009; 385: 434-43.
157. Kern A, Schmidt K, Leder C, et al. Identification of a heparinbindingmotif on adeno-associated virus type 2 capsids. J Virol 2003; 77: 11072-81.
158. Shi X, Fang G, Shi W, Bartlett JS. Insertional mutagenesis at positions520 and 584 of adeno-associated virus type 2 (AAV2) capsidgene and generation of AAV2 vectors with eliminated heparinbindingability and introduced novel tropism. Hum Gene Ther 2006; 17: 353-61.
159. Girod A, Ried M, Wobus C, et al. Genetic capsid modificationsallow efficient re-targeting of adeno-associated virus type 2. Nat Med 1999; 5: 1438.
160. Grifman M, Trepel M, Speece P, et al. Incorporation of tumortargetingpeptides into recombinant adeno-associated virus capsids. Mol Ther 2001; 3: 964-75.
161. Shi W, Arnold GS, Bartlett JS. Insertional mutagenesis of theadeno-associated virus type 2 (AAV2) capsid gene and generationof AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther 2001; 12: 1697-711.
162. Asokan A, Conway JC, Phillips JL, et al. Reengineering a receptorfootprint of adeno-associated virus enables selective and systemicgene transfer to muscle. Nat Biotechnol 2010; 28: 79-82.
163. Petrs-Silva H, Dinculescu A, Li Q, et al. High-efficiency transductionof the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 2009; 17: 463-71.
164. Zhong L, Li B, Mah CS, et al. Next generation of adeno-associatedvirus 2 vectors: point mutations in tyrosines lead to high-efficiencytransduction at lower doses. Proc Natl Acad Sci U S A 2008; 105: 7827-32.
165. Zhang HG, Xie J, Dmitriev I, et al. Addition of six-His-taggedpeptide to the C terminus of adeno-associated virus VP3 does notaffect viral tropism or production. J Virol 2002; 76: 12023-31.
166. Zhong L, Li B, Jayandharan G, et al. Tyrosine-phosphorylation ofAAV2 vectors and its consequences on viral intracellular traffickingand transgene expression. Virology 2008; 381: 194-202.
167. Zhong L, Zhao W, Wu J, et al. A dual role of EGFR protein tyrosinekinase signaling in ubiquitination of AAV2 capsids and viralsecond-strand DNA synthesis. Mol Ther 2007; 15: 1323-30.
168. Yu CY, Yuan Z, Cao Z, et al. A muscle-targeting peptide displayedon AAV2 improves muscle tropism on systemic delivery. Gene Ther 2009; 16: 953-62.
169. Liqun Wang R, McLaughlin T, Cossette T, et al. Recombinant AAV serotype and capsid mutant comparison for pulmonary genetransfer of alpha-1-antitrypsin using invasive and noninvasive delivery. Mol Ther 2009; 17: 81-7.
170. Grimm D, Lee JS, Wang L, et al. In vitro and in vivo gene therapyvector evolution via multispecies interbreeding and retargeting ofadeno-associated viruses. J Virol 2008; 82: 5887-911.
171. White SJ, Nicklin SA, Buning H, et al. Targeted gene delivery tovascular tissue in vivo by tropism-modified adeno-associated virusvectors. Circulation 2004; 109: 513-9.
172. White K, Buning H, Kritz A, et al. Engineering adeno-associatedvirus 2 vectors for targeted gene delivery to atherosclerotic lesions. Gene Ther 2008; 15: 443-51.
173. Sellner L, Stiefelhagen M, Kleinschmidt JA, et al. Generation ofefficient human blood progenitor-targeted recombinant adenoassociatedviral vectors (AAV) by applying an AAV random peptidelibrary on primary human hematopoietic progenitor cells. Exp Hematol 2008; 36: 957-64.
174. Stiefelhagen M, Sellner L, Kleinschmidt JA, et al. Application of ahaematopoetic progenitor cell-targeted adeno-associated viral(AAV) vector established by selection of an AAV random peptidelibrary on a leukaemia cell line. Genet Vaccines Ther 2008; 6: 12.
175. Muller OJ, Kaul F, Weitzman MD, et al. Random peptide librariesdisplayed on adeno-associated virus to select for targeted genetherapy vectors. Nat Biotechnol 2003; 21: 1040-6.
176. Work LM, Buning H, Hunt E, et al. Vascular bed-targeted in vivogene delivery using tropism-modified adeno-associated viruses. Mol Ther 2006; 13: 683-93.
177. Nicklin SA, Buening H, Dishart KL, et al. Efficient and selectiveAAV2-mediated gene transfer directed to human vascular endothelialcells. Mol Ther 2001; 4: 174-81.
178. Loiler SA, Conlon TJ, Song S, et al. Targeting recombinant adenoassociatedvirus vectors to enhance gene transfer to pancreatic isletsand liver. Gene Ther 2003; 10: 1551-8.
179. Perabo L, Buning H, Kofler DM, et al. In vitro selection of viralvectors with modified tropism: the adeno-associated virus display. Mol Ther 2003; 8: 151-7.
180. Shi W, Bartlett JS. RGD inclusion in VP3 provides adenoassociatedvirus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism. Mol Ther 2003; 7: 515-25.
181. Wu P, Xiao W, Conlon T, et al. Mutational analysis of the adenoassociatedvirus type 2 (AAV2) capsid gene and construction ofAAV2 vectors with altered tropism. J Virol 2000; 74: 8635-47.
182. Hida K, Won SY, Di Pasquale G, Hanes J, Chiorini JA, Ostermeier M. Sites in the AAV5 capsid tolerant to deletions and tandem duplications. Arch Biochem Biophys 2010; 496(1): 1-8.
183. Boucas J, Lux K, Huber A, et al. Engineering adeno-associatedvirus serotype 2-based targeting vectors using a new insertion siteposition453-and single point mutations. J Gene Med 2009; 11: 1103-13.
184. Warrington KH, Jr., Gorbatyuk OS, Harrison JK, Opie SR, Zolotukhin S, Muzyczka N. Adeno-associated virus type 2 VP2 capsidprotein is nonessential and can tolerate large peptide insertions atits N terminus. J Virol 2004; 78: 6595-609.
185. Perabo L, Endell J, King S, et al. Combinatorial engineering of agene therapy vector: directed evolution of adeno-associated virus. JGene Med 2006; 8: 155-62.
186. Waterkamp DA, Muller OJ, Ying Y, Trepel M, Kleinschmidt JA. Isolation of targeted AAV2 vectors from novel virus display libraries. J Gene Med 2006; 8: 1307-19.
187. Michelfelder S, Lee MK, deLima-Hahn E, et al. Vectors selectedfrom adeno-associated viral display peptide libraries for leukemiacell-targeted cytotoxic gene therapy. Exp Hematol 2007; 35: 1766-76.
188. Michelfelder S, Kohlschutter J, Skorupa A, et al. Successful expansionbut not complete restriction of tropism of adeno-associated virusby in vivo biopanning of random virus display peptide libraries. PLo S One 2009; 4: e5122.
189. Hauck B, Chen L, Xiao W. Generation and characterization ofchimeric recombinant AAV vectors. Mol Ther 2003; 7: 419-25.
190. Gigout L, Rebollo P, Clement N, et al. Altering AAV tropism withmosaic viral capsids. Mol Ther 2005; 11: 856-65.
191. Stachler MD, Bartlett JS. Mosaic vectors comprised of modifiedAAV1 capsid proteins for efficient vector purification and targetingto vascular endothelial cells. Gene Ther 2006; 13: 926-31.
192. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolutionof adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 2006; 24: 198-204.
193. Stemmer WP. DNA shuffling by random fragmentation and reassembly:in vitro recombination for molecular evolution. Proc Natl Acad Sci U S A 1994; 91: 10747-51.
194. Crameri A, Raillard SA, Bermudez E, Stemmer WP. DNA shufflingof a family of genes from diverse species accelerates directedevolution. Nature 1998; 391: 288-91.
195. Li W, Asokan A, Wu Z, et al. Engineering and selection of shuffledAAV genomes: a new strategy for producing targeted biologicalnanoparticles. Mol Ther 2008; 16: 1252-60.
196. Koerber JT, Jang JH, Schaffer DV. DNA shuffling of adenoassociatedvirus yields functionally diverse viral progeny. Mol Ther 2008; 16: 1703-9.
197. Excoffon KJ, Koerber JT, Dickey DD, et al. Directed evolution ofadeno-associated virus to an infectious respiratory virus. Proc Natl Acad Sci U S A 2009; 106: 3865-70.
198. Li W, Zhang L, Johnson JS, et al. Generation of novel AAV variantsby directed evolution for improved CFTR delivery to humanciliated airway epithelium. Mol Ther 2009; 17: 2067-77.
199. Koerber JT, Klimczak R, Jang JH, Dalkara D, Flannery JG, Schaffer DV. Molecular evolution of adeno-associated virus for enhancedglial gene delivery. Mol Ther 2009; 17: 2088-95.
200. Maguire CA, Gianni D, Meijer DH, et al. Directed evolution ofadeno-associated virus for glioma cell transduction. J Neurooncol 2009; 96: 337-47.
201. Yang L, Jiang J, Drouin LM, et al. A myocardium tropic adenoassociatedvirus (AAV) evolved by DNA shuffling and in vivo selection. Proc Natl Acad Sci U S A 2009; 106: 3946-51.
202. Gray SJ, Blake BL, Criswell HE, Nicolson SC, Samulski RJ, McCown TJ. Directed Evolution of a Novel Adeno-associated Virus(AAV) Vector That Crosses the Seizure-compromised Blood-Brain Barrier (BBB). Mol Ther 2010; 18(3): 570-5.
203. Bartlett JS, Kleinschmidt J, Boucher RC, Samulski RJ. Targetedadeno-associated virus vector transduction of nonpermissive cellsmediated by a bispecific F(ab'gamma)2 antibody. Nat Biotechnol 1999; 17: 181-6.
204. Arnold GS, Sasser AK, Stachler MD, Bartlett JS. Metabolic biotinylationprovides a unique platform for the purification and targetingof multiple AAV vector serotypes. Mol Ther 2006; 14: 97-106.
205. Ponnazhagan S, Mahendra G, Kumar S, Thompson JA, Castillas M, Jr. Conjugate-based targeting of recombinant adeno-associatedvirus type 2 vectors by using avidin-linked ligands. J Virol 2002; 76: 12900-7.
206. Stachler MD, Chen I, Ting AY, Bartlett JS. Site-specific modificationof AAV vector particles with biophysical probes and targetingligands using biotin ligase. Mol Ther 2008; 16: 1467-73.
207. Carlisle RC, Benjamin R, Briggs SS, et al. Coating of adenoassociatedvirus with reactive polymers can ablate virus tropism, enable retargeting and provide resistance to neutralising antisera. JGene Med 2008; 10: 400-11.
208. Lee GK, Maheshri N, Kaspar B, Schaffer DV. PEG conjugationmoderately protects adeno-associated viral vectors against antibodyneutralization. Biotechnol Bioeng 2005; 92: 24-34.
209. Fein DE, Limberis MP, Maloney SF, Heath JM, Wilson JM, Diamond SL. Cationic lipid formulations alter the in vivo tropism ofAAV2/9 vector in lung. Mol Ther 2009; 17: 2078-87.
210. Sun X, Pawlyk B, Xu X, et al. Gene therapy with a promoter targetingboth rods and cones rescues retinal degeneration caused byAIPL1 mutations. Gene Ther 17: 117-31.
211. Li Q, Timmers AM, Guy J, Pang J, Hauswirth WW. Cone-specificexpression using a human red opsin promoter in recombinant AAV. Vision Res 2008; 48: 332-8.
212. Khani SC, Pawlyk BS, Bulgakov OV, et al. AAV-mediated expressiontargeting of rod and cone photoreceptors with a humanrhodopsin kinase promoter. Invest Ophthalmol Vis Sci 2007; 48: 3954-61.
213. Glushakova LG, Timmers AM, Pang J, Teusner JT, Hauswirth WW. Human blue-opsin promoter preferentially targets reportergene expression to rat s-cone photoreceptors. Invest Ophthalmol Vis Sci 2006; 47: 3505-13.
214. Kyo S, Kanaya T, Takakura M, Tanaka M, Inoue M. Human telomerasereverse transcriptase as a critical determinant of telomeraseactivity in normal and malignant endometrial tissues. Int JCancer 1999; 80: 60-3.
215. Lin T, Huang X, Gu J, et al. Long-term tumor-free survival fromtreatment with the GFP-TRAIL fusion gene expressed from thehTERT promoter in breast cancer cells. Oncogene 2002; 21: 8020-8.
216. Liu J, Zou WG, Lang MF, et al. Cancer-specific killing by the CDsuicide gene using the human telomerase reverse transcriptasepromoter. Int J Oncol 2002; 21: 661-6.
217. Wang Y, Huang F, Cai H, Zhong S, Liu X, Tan WS. Potent antitumoreffect of TRAIL mediated by a novel adeno-associated viralvector targeting to telomerase activity for human hepatocellularcarcinoma. J Gene Med 2008; 10: 518-26.
218. Zhang Y, Ma H, Zhang J, Liu S, Liu Y, Zheng D. AAV-mediatedTRAIL gene expression driven by hTERT promoter suppressedhuman hepatocellular carcinoma growth in mice. Life Sci 2008; 82: 1154-61.
219. He LF, Wang YG, Xiao T, et al. Suppression of cancer growth inmice by adeno-associated virus vector-mediated IFN-beta expressiondriven by hTERT promoter. Cancer Lett 2009; 286: 196-205.
220. Sieger S, Jiang S, Kleinschmidt J, et al. Tumor-specific gene expression using regulatory elements of the glucose transporter isoform 1 gene. Cancer Gene Ther 2004; 11: 41-51.
221. Muller OJ, Leuchs B, Pleger ST, et al. Improved cardiac genetransfer by transcriptional and transductional targeting of adenoassociatedviral vectors. Cardiovasc Res 2006; 70: 70-8.
222. Aldrich WA, Ren C, White AF, et al. Enhanced transduction ofmouse bone marrow-derived dendritic cells by repetitive infectionwith self-complementary adeno-associated virus 6 combined withimmunostimulatory ligands. Gene Ther 2006; 13: 29-39.
223. Herzog RW, Hagstrom JN, Kung SH, et al. Stable gene transferand expression of human blood coagulation factor IX after intramuscularinjection of recombinant adeno-associated virus. Proc Natl Acad Sci U S A 1997; 94: 5804-9.
224. Herzog RW, Mount JD, Arruda VR, High KA, Lothrop CD, Jr. Muscle-directed gene transfer and transient immune suppressionresult in sustained partial correction of canine hemophilia B causedby a null mutation. Mol Ther 2001; 4: 192-200.
225. Liu Y, Chiriva-Internati M, You C, et al. Use and specificity ofbreast cancer antigen/milk protein BA46 for generating anti-selfcytotoxicT lymphocytes by recombinant adeno-associated virusbasedgene loading of dendritic cells. Cancer Gene Ther 2005; 12: 304-12.
226. Sarukhan A, Camugli S, Gjata B, von Boehmer H, Danos O, Jooss K. Successful interference with cellular immune responses to immunogenicproteins encoded by recombinant viral vectors. J Virol 2001; 75: 269-77.
227. Sarukhan A, Soudais C, Danos O, Jooss K. Factors influencingcross-presentation of non-self antigens expressed from recombinantadeno-associated virus vectors. J Gene Med 2001; 3: 260-70.
228. Veron P, Allo V, Riviere C, Bernard J, Douar AM, Masurier C. Major subsets of human dendritic cells are efficiently transducedby self-complementary adeno-associated virus vectors 1 and 2. JVirol 2007; 81: 5385-94.
229. Wuensch SA, Pierce RH, Crispe IN. Local intrahepatic CD8+ Tcell activation by a non-self-antigen results in full functional differentiation. J Immunol 2006; 177: 1689-97.
230. Zhang TP, Jin DY, Wardrop RM, et al. Transgene expression levelsand kinetics determine risk of humoral immune response modeledin factor IX knockout and missense mutant mice. Gene Ther 2007; 14: 429-40.
231. Blacklow NR, Hoggan MD, Rowe WP. Serologic evidence forhuman infection with adenovirus-associated viruses. J Natl Cancer Inst 1968; 40: 319-27.
232. Mayor HD, Drake S, Stahmann J, Mumford DM. Antibodies toadeno-associated satellite virus and herpes simplex in sera fromcancer patients and normal adults. Am J Obstet Gynecol 1976; 126: 100-4.
233. Halbert CL, Miller AD, McNamara S, et al. Prevalence of neutralizingantibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: Implications forgene therapy using AAV vectors. Hum Gene Ther 2006; 17: 440-7.
234. Tobiasch E, Rabreau M, Geletneky K, et al. Detection of adenoassociatedvirus DNA in human genital tissue and in material fromspontaneous abortion. J Med Virol 1994; 44: 215-22.
235. Erles K, Sebokova P, Schlehofer JR. Update on the prevalence ofserum antibodies (Ig G and Ig M) to adeno-associated virus (AAV). J Med Virol 1999; 59: 406-11.
236. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwideepidemiology of neutralizing antibodies to adeno-associatedviruses. J Infect Dis 2009; 199: 381-90.
237. Sprecher-Goldberger S, Thiry L, Lefebvre N, Dekegel D, deHalleux F. Complement-fixation antibodies to adenovirusassociatedviruses, cytomegaloviruses and herpes simplex virusesin patients with tumors and in control individuals. Am J Epidemiol 1971; 94: 351-8.
238. Mingozzi F, Maus MV, Hui DJ, et al. CD8(+) T-cell responses toadeno-associated virus capsid in humans. Nat Med 2007; 13: 419-22.
239. Pulendran B, Ahmed R. Translating innate immunity into immunologicalmemory: implications for vaccine development. Cell 2006; 124: 849-63.
240. Zaiss AK, Cotter MJ, White LR, et al. Complement is an essentialcomponent of the immune response to adeno-associated virus vectors. J Virol 2008; 82: 2727-40.
241. Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA. Differential activation of innate immune responses by adenovirusand adeno-associated virus vectors. J Virol 2002; 76: 4580-90.
242. Zhu J, Huang X, Yang Y. The TLR9-My D88 pathway is critical foradaptive immune responses to adeno-associated virus gene therapyvectors in mice. J Clin Invest 2009; 119: 2388-98.
243. Moskalenko M, Chen L, van Roey M, et al. Epitope mapping ofhuman anti-adeno-associated virus type 2 neutralizing antibodies:implications for gene therapy and virus structure. J Virol 2000; 74: 1761-6.
244. Wobus CE, Hugle-Dorr B, Girod A, Petersen G, Hallek M, Kleinschmidt JA. Monoclonal antibodies against the adeno-associatedvirus type 2 (AAV-2) capsid: epitope mapping and identification ofcapsid domains involved in AAV-2-cell interaction and neutralizationof AAV-2 infection. J Virol 2000; 74: 9281-93.
245. Sabatino DE, Mingozzi F, Hui DJ, et al. Identification of mouseAAV capsid-specific CD8+ T cell epitopes. Mol Ther 2005; 12: 1023-33.
246. Mays LE, Wilson JM. Identification of the murine AAVrh32.33capsid-specific CD8+ T cell epitopes. J Gene Med 2009; 11: 1095-102.
247. Chen J, Wu Q, Yang P, Hsu HC, Mountz JD. Determination ofspecific CD4 and CD8 T cell epitopes after AAV2-and AAV8-hF. IX gene therapy. Mol Ther 2006; 13: 260-9.
248. Murphy SL, Li H, Mingozzi F, et al. Diverse Ig G subclass responsesto adeno-associated virus infection and vector administration. J Med Virol 2009; 81: 65-74.
249. Madsen D, Cantwell ER, O'Brien T, Johnson PA, Mahon BP. Adeno-associated virus serotype 2 induces cell-mediated immuneresponses directed against multiple epitopes of the capsid proteinVP1. J Gen Virol 2009; 90: 2622-33.
250. Mingozzi F, High KA. Immune responses to AAV in clinical trials. Curr Gene Ther 2007; 7: 316-24.
251. Li C, Hirsch M, Asokan A, et al. Adeno-associated virus type 2(AAV2) capsid-specific cytotoxic T lymphocytes eliminate onlyvector-transduced cells coexpressing the AAV2 capsid in vivo. JVirol 2007; 81: 7540-7.
252. Wang Z, Allen JM, Riddell SR, et al. Immunity to adenoassociatedvirus-mediated gene transfer in a random-bred caninemodel of Duchenne muscular dystrophy. Hum Gene Ther 2007; 18: 18-26.
253. Mount JD, Herzog RW, Tillson DM, et al. Sustained phenotypiccorrection of hemophilia B dogs with a factor IX null mutation byliver-directed gene therapy. Blood 2002; 99: 2670-6.
254. Nathwani AC, Davidoff AM, Hanawa H, et al. Sustained highlevelexpression of human factor IX (hFIX) after liver-targeted deliveryof recombinant adeno-associated virus encoding the hFIXgene in rhesus macaques. Blood 2002; 100: 1662-9.
255. Le HT, Yu QC, Wilson JM, Croyle MA. Utility of PEGylatedrecombinant adeno-associated viruses for gene transfer. J Control Release 2005; 108: 161-77.
256. Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM. Gene therapy vectors based on adeno-associated virus type 1. JVirol 1999; 73: 3994-4003.
257. Halbert CL, Rutledge EA, Allen JM, Russell DW, Miller AD. Repeat transduction in the mouse lung by using adeno-associatedvirus vectors with different serotypes. J Virol 2000; 74: 1524-32.
258. Hildinger M, Auricchio A, Gao G, Wang L, Chirmule N, Wilson JM. Hybrid vectors based on adeno-associated virus serotypes 2and 5 for muscle-directed gene transfer. J Virol 2001; 75: 6199-203.
259. Riviere C, Danos O, Douar AM. Long-term expression and repeatedadministration of AAV type 1, 2 and 5 vectors in skeletalmuscle of immunocompetent adult mice. Gene Ther 2006; 13: 1300-8.
260. Sandalon Z, Bruckheimer EM, Lustig KH, Rogers LC, Peluso RW, Burstein H. Secretion of a TNFR:Fc fusion protein following pulmonaryadministration of pseudotyped adeno-associated virus vectors. J Virol 2004; 78: 12355-65.
261. Vandendriessche T, Thorrez L, Acosta-Sanchez A, et al. Efficacyand safety of adeno-associated viral vectors based on serotype 8and 9 vs. lentiviral vectors for hemophilia B gene therapy. JThromb Haemost 2007; 5: 16-24.
262. Mays LE, Vandenberghe LH, Xiao R, et al. Adeno-associated viruscapsid structure drives CD4-dependent CD8+ T cell response tovector encoded proteins. J Immunol 2009; 182: 6051-60.
263. Huttner NA, Girod A, Perabo L, et al. Genetic modifications of theadeno-associated virus type 2 capsid reduce the affinity and theneutralizing effects of human serum antibodies. Gene Ther 2003; 10: 2139-47.
264. Maersch S, Huber A, Buning H, Hallek M, Perabo L. Optimizationof stealth adeno-associated virus vectors by randomization of immunogenicepitopes. Virology 2010; 397: 167-75.
265. Vandenberghe LH, Wang L, Somanathan S, et al. Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nat Med 2006; 12: 967-71.
266. Li C, Goudy K, Hirsch M, et al. Cellular immune response to crypticepitopes during therapeutic gene transfer. Proc Natl Acad Sci US A 2009; 106: 10770-4.
267. Brockstedt DG, Podsakoff GM, Fong L, Kurtzman G, Mueller-Ruchholtz W, Engleman EG. Induction of immunity to antigensexpressed by recombinant adeno-associated virus depends on theroute of administration. Clin Immunol 1999; 92: 67-75.
268. Xiao W, Chirmule N, Schnell MA, Tazelaar J, Hughes JV, Wilson JM. Route of administration determines induction of T-cellindependenthumoral responses to adeno-associated virus vectors. Mol Ther 2000; 1: 323-9.
269. Ge Y, Powell S, Van Roey M, McArthur JG. Factors influencingthe development of an anti-factor IX (FIX) immune response followingadministration of adeno-associated virus-FIX. Blood 2001; 97: 3733-7.
270. Wang L, Cao O, Swalm B, Dobrzynski E, Mingozzi F, Herzog RW. Major role of local immune responses in antibody formationto factor IX in AAV gene transfer. Gene Ther 2005; 12: 1453-64.
271. Wang L, Dobrzynski E, Schlachterman A, Cao O, Herzog RW. Systemic protein delivery by muscle-gene transfer is limited by alocal immune response. Blood 2005; 105: 4226-34.
272. Cao O, Dobrzynski E, Wang L, et al. Induction and role of regulatoryCD4+CD25+ T cells in tolerance to the transgene product followinghepatic in vivo gene transfer. Blood 2007; 110: 1132-40.
273. Dobrzynski E, Mingozzi F, Liu YL, et al. Induction of antigenspecificCD4+ T-cell anergy and deletion by in vivo viral genetransfer. Blood 2004; 104: 969-77.
274. Gross DA, Leboeuf M, Gjata B, Danos O, Davoust J. CD4+CD25+regulatory T cells inhibit immune-mediated transgene rejection. Blood 2003; 102: 4326-8.
275. Lin SW, Hensley SE, Tatsis N, Lasaro MO, Ertl HC. Recombinantadeno-associated virus vectors induce functionally impaired transgeneproduct-specific CD8+ T cells in mice. J Clin Invest 2007; 117: 3958-70.
276. Mingozzi F, Liu YL, Dobrzynski E, et al. Induction of immunetolerance to coagulation factor IX antigen by in vivo hepatic genetransfer. J Clin Invest 2003; 111: 1347-56.
277. Velazquez VM, Bowen DG, Walker CM. Silencing of T lymphocytesby antigen-driven programmed death in recombinant adenoassociatedvirus vector-mediated gene therapy. Blood 2009; 113: 538-45.
278. Li Q, Miller R, Han PY, et al. Intraocular route of AAV2 vectoradministration defines humoral immune response and therapeuticpotential. Mol Vis 2008; 14: 1760-9.
279. Mastakov MY, Baer K, Symes CW, Leichtlein CB, Kotin RM, During MJ. Immunological aspects of recombinant adenoassociatedvirus delivery to the mammalian brain. J Virol 2002; 76: 8446-54.
280. Peden CS, Manfredsson FP, Reimsnider SK, et al. Striatal readministrationof rAAV vectors reveals an immune response againstAAV2 capsids that can be circumvented. Mol Ther 2009; 17: 524-37.
281. Sabatino DE, Mackenzie TC, Peranteau W, et al. Persistent expressionof hF. IX After tolerance induction by in utero or neonatal administrationof AAV-1-F. IX in hemophilia B mice. Mol Ther 2007; 15: 1677-85.
282. Halbert CL, Standaert TA, Wilson CB, Miller AD. Successfulreadministration of adeno-associated virus vectors to the mouselung requires transient immunosuppression during the initial exposure. J Virol 1998; 72: 9795-805.
283. Manning WC, Zhou S, Bland MP, Escobedo JA, Dwarki V. Transientimmunosuppression allows transgene expression followingreadministration of adeno-associated viral vectors. Hum Gene Ther 1998; 9: 477-85.
284. Wang Z, Kuhr CS, Allen JM, et al. Sustained AAV-mediated dystrophinexpression in a canine model of Duchenne muscular dystrophywith a brief course of immunosuppression. Mol Ther 2007; 15: 1160-6.
285. Hirsch ML, Agbandje-McKenna M, Samulski RJ. Little vector, biggene transduction: fragmented genome reassembly of adenoassociatedvirus. Mol Ther 2010; 18: 6-8.
286. Hewitt FC, Li C, Gray SJ, Cockrell S, Washburn M, Samulski RJ. Reducing the risk of adeno-associated virus (AAV) vector mobilizationwith AAV type 5 vectors. J Virol 2009; 83: 3919-29.
287. Reddy VS, Natarajan P, Okerberg B, et al. Virus Particle Explorer(VIPER), a website for virus capsid structures and their computationalanalyses. J Virol 2001; 75: 11943-7.