1932

Abstract

Adeno-associated virus (AAV) is a small, nonenveloped virus that was adapted 30 years ago for use as a gene transfer vehicle. It is capable of transducing a wide range of species and tissues in vivo with no evidence of toxicity, and it generates relatively mild innate and adaptive immune responses. We review the basic biology of AAV, the history of progress in AAV vector technology, and some of the clinical and research applications where AAV has shown success.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-virology-031413-085355
2014-09-29
2024-04-21
Loading full text...

Full text loading...

/deliver/fulltext/virology/1/1/annurev-virology-031413-085355.html?itemId=/content/journals/10.1146/annurev-virology-031413-085355&mimeType=html&fmt=ahah

Literature Cited

  1. Ganem D, Nussbaum AL, Davoli D, Fareed GC. 1.  1976. Propagation of a segment of bacteriophage lamda-DNA in monkey cells after covalent linkage to a defective simian virus 40 genome. Cell 7:349–59 [Google Scholar]
  2. Goff SP, Berg P. 2.  1976. Construction of hybrid viruses containing SV40 and lambda phage DNA segments and their propagation in cultured monkey cells. Cell 9:695–705 [Google Scholar]
  3. Muzyczka N. 3.  1980. Construction of an SV40-derived cloning vector. Gene 11:63–77 [Google Scholar]
  4. Shimotohno K, Temin HM. 4.  1981. Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus. Cell 26:67–77 [Google Scholar]
  5. Wei CM, Gibson M, Spear PG, Scolnick EM. 5.  1981. Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1. J. Virol. 39:935–44 [Google Scholar]
  6. Solnick D. 6.  1981. Construction of an adenovirus-SV40 recombinant producing SV40 T antigen from an adenovirus late promoter. Cell 24:135–43 [Google Scholar]
  7. Hermonat PL, Muzyczka N. 7.  1984. Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl. Acad. Sci. USA 81:6466–70 [Google Scholar]
  8. Spaete RR, Frenkel N. 8.  1982. The herpes simplex virus amplicon: a new eucaryotic defective-virus cloning-amplifying vector. Cell 30:295–304 [Google Scholar]
  9. Bryant LM, Christopher DM, Giles AR, Hinderer C, Rodriguez JL. 9.  et al. 2013. Lessons learned from the clinical development and market authorization of Glybera. Hum. Gene Ther. Clin. Dev. 24:55–64 [Google Scholar]
  10. Berns KI, Parrish CR. 10.  2007. Parvoviridae. Fields Virology DM Knipe, PM Howley 2437–77 New York: Lippincott Williams & Wilkins [Google Scholar]
  11. Srivastava A, Lusby EW, Berns KI. 11.  1983. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J. Virol. 45:555–64 [Google Scholar]
  12. Atchison RW, Casto BC, Hammon W. 12.  1965. Adenovirus-associated defective virus particles. Science 149:754–56 [Google Scholar]
  13. Calcedo R, Morizono H, Wang L, McCarter R, He J. 13.  et al. 2011. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin. Vaccine Immunol. 18:1586–88 [Google Scholar]
  14. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. 14.  2009. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199:381–90 [Google Scholar]
  15. Zhou X, Zeng X, Fan Z, Li C, McCown T. 15.  et al. 2008. Adeno-associated virus of a single-polarity DNA genome is capable of transduction in vivo. Mol. Ther. 16:494–99 [Google Scholar]
  16. Zhong L, Zhou X, Li Y, Qing K, Xiao X. 16.  et al. 2008. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: mechanism of transduction. Mol. Ther. 16:290–95 [Google Scholar]
  17. Samulski RJ, Chang LS, Shenk T. 17.  1987. A recombinant plasmid from which an infectious adeno-associated virus genome can be excised in vitro and its use to study viral replication. J. Virol. 61:3096–101 [Google Scholar]
  18. Sonntag F, Schmidt K, Kleinschmidt JA. 18.  2010. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc. Natl. Acad. Sci. USA 107:10220–25 [Google Scholar]
  19. McLaughlin SK, Collis P, Hermonat PL, Muzyczka N. 19.  1988. Adeno-associated virus general transduction vectors: analysis of proviral structures. J. Virol. 62:1963–73 [Google Scholar]
  20. Hauswirth WW, Berns KI. 20.  1977. Origin and termination of adeno-associated virus DNA replication. Virology 78:488–99 [Google Scholar]
  21. Samulski RJ, Chang LS, Shenk T. 21.  1989. Helper-free stocks of recombinant adeno-associated viruses: Normal integration does not require viral gene expression. J. Virol. 63:3822–28 [Google Scholar]
  22. Pereira DJ, McCarty DM, Muzyczka N. 22.  1997. The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection. J. Virol. 71:1079–88 [Google Scholar]
  23. Haberman RP, McCown TJ, Samulski RJ. 23.  2000. Novel transcriptional regulatory signals in the adeno-associated virus terminal repeat A/D junction element. J. Virol. 74:8732–39 [Google Scholar]
  24. Flotte TR, Afione SA, Solow R, Drumm ML, Markakis D. 24.  et al. 1993. Expression of the cystic fibrosis transmembrane conductance regulator from a novel adeno-associated virus promoter. J. Biol. Chem. 268:3781–90 [Google Scholar]
  25. Afione SA, Conrad CK, Kearns WG, Chunduru S, Adams R. 25.  et al. 1996. In vivo model of adeno-associated virus vector persistence and rescue. J. Virol. 70:3235–41 [Google Scholar]
  26. Buller RM, Janik JE, Sebring ED, Rose JA. 26.  1981. Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication. J. Virol. 40:241–47 [Google Scholar]
  27. Urabe M, Nakakura T, Xin KQ, Obara Y, Mizukami H. 27.  et al. 2006. Scalable generation of high-titer recombinant adeno-associated virus type 5 in insect cells. J. Virol. 80:1874–85 [Google Scholar]
  28. Nash K, Chen W, Muzyczka N. 28.  2008. Complete in vitro reconstitution of adeno-associated virus DNA replication requires the minichromosome maintenance complex proteins. J. Virol. 82:1458–64 [Google Scholar]
  29. Ni TH, McDonald WF, Zolotukhin I, Melendy T, Waga S. 29.  et al. 1998. Cellular proteins required for adeno-associated virus DNA replication in the absence of adenovirus coinfection. J. Virol. 72:2777–87 [Google Scholar]
  30. Ward P, Dean FB, O'Donnell ME, Berns KI. 30.  1998. Role of the adenovirus DNA-binding protein in in vitro adeno-associated virus DNA replication. J. Virol. 72:420–27 [Google Scholar]
  31. Carter BJ, Antoni BA, Klessig DF. 31.  1992. Adenovirus containing a deletion of the early region 2A gene allows growth of adeno-associated virus with decreased efficiency. Virology 191:473–76 [Google Scholar]
  32. Janik JE, Huston MM, Rose JA. 32.  1981. Locations of adenovirus genes required for the replication of adenovirus-associated virus. Proc. Natl. Acad. Sci. USA 78:1925–29 [Google Scholar]
  33. Straus SE, Ginsberg HS, Rose JA. 33.  1975. DNA-minus temperature-sensitive mutants of adenovirus type 5 help adenovirus-associated virus replication. J. Virol. 17:140–48 [Google Scholar]
  34. Chang LS, Shenk T. 34.  1990. The adenovirus DNA-binding protein stimulates the rate of transcription directed by adenovirus and adeno-associated virus promoters. J. Virol. 64:2103–9 [Google Scholar]
  35. Shi Y, Seto E, Chang LS, Shenk T. 35.  1991. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell 67:377–88 [Google Scholar]
  36. Chang LS, Shi Y, Shenk T. 36.  1989. Adeno-associated virus P5 promoter contains an adenovirus E1A-inducible element and a binding site for the major late transcription factor. J. Virol. 63:3479–88 [Google Scholar]
  37. Pereira DJ, Muzyczka N. 37.  1997. The adeno-associated virus type 2 p40 promoter requires a proximal Sp1 interaction and a p19 CArG-like element to facilitate Rep transactivation. J. Virol. 71:4300–9 [Google Scholar]
  38. Pereira DJ, Muzyczka N. 38.  1997. The cellular transcription factor SP1 and an unknown cellular protein are required to mediate Rep protein activation of the adeno-associated virus p19 promoter. J. Virol. 71:1747–56 [Google Scholar]
  39. Lackner DF, Muzyczka N. 39.  2002. Studies of the mechanism of transactivation of the adeno-associated virus p19 promoter by Rep protein. J. Virol. 76:8225–35 [Google Scholar]
  40. Hörer M, Weger S, Butz K, Hoppe-Seyler F, Geisen C, Kleinschmidt JA. 40.  1995. Mutational analysis of adeno-associated virus Rep protein-mediated inhibition of heterologous and homologous promoters. J. Virol. 69:5485–96 [Google Scholar]
  41. Berk AJ. 41.  2007. Adenoviridae: the viruses and their replication. Fields Virology DM Knipe, PM Howley 2355–94 New York: Lippincott Williams & Wilkins [Google Scholar]
  42. Samulski RJ, Shenk T. 42.  1988. Adenovirus E1B 55-Mr polypeptide facilitates timely cytoplasmic accumulation of adeno-associated virus mRNAs. J. Virol. 62:206–10 [Google Scholar]
  43. Ferrari FK, Samulski T, Shenk T, Samulski RJ. 43.  1996. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J. Virol. 70:3227–34 [Google Scholar]
  44. Carson CT, Schwartz RA, Stracker TH, Lilley CE, Lee DV, Weitzman MD. 44.  2003. The Mre11 complex is required for ATM activation and the G2/M checkpoint. EMBO J. 22:6610–20 [Google Scholar]
  45. Cathomen T, Weitzman MD. 45.  2000. A functional complex of adenovirus proteins E1B-55kDa and E4orf6 is necessary to modulate the expression level of p53 but not its transcriptional activity. J. Virol. 74:11407–12 [Google Scholar]
  46. Schwartz RA, Palacios JA, Cassell GD, Adam S, Giacca M, Weitzman MD. 46.  2007. The Mre11/Rad50/Nbs1 complex limits adeno-associated virus transduction and replication. J. Virol. 81:12936–45 [Google Scholar]
  47. Huang MM, Hearing P. 47.  1989. Adenovirus early region 4 encodes two gene products with redundant effects in lytic infection. J. Virol. 63:2605–15 [Google Scholar]
  48. Slanina H, Weger S, Stow ND, Kuhrs A, Heilbronn R. 48.  2006. Role of the herpes simplex virus helicase-primase complex during adeno-associated virus DNA replication. J. Virol. 80:5241–50 [Google Scholar]
  49. Weindler FW, Heilbronn R. 49.  1991. A subset of herpes simplex virus replication genes provides helper functions for productive adeno-associated virus replication. J. Virol. 65:2476–83 [Google Scholar]
  50. Alazard-Dany N, Nicolas A, Ploquin A, Strasser R, Greco A. 50.  et al. 2009. Definition of herpes simplex virus type 1 helper activities for adeno-associated virus early replication events. PLOS Pathog. 5:e1000340 [Google Scholar]
  51. Toublanc E, Benraiss A, Bonnin D, Blouin V, Brument N. 51.  et al. 2004. Identification of a replication-defective herpes simplex virus for recombinant adeno-associated virus type 2 (rAAV2) particle assembly using stable producer cell lines. J. Gene Med. 6:555–64 [Google Scholar]
  52. Myers MW, Carter BJ. 52.  1981. Adeno-associated virus replication: the effect of l-canavanine or a helper virus mutation on accumulation of viral capsids and progeny single-stranded DNA. J. Biol. Chem. 256:567–70 [Google Scholar]
  53. Bleker S, Sonntag F, Kleinschmidt JA. 53.  2005. Mutational analysis of narrow pores at the fivefold symmetry axes of adeno-associated virus type 2 capsids reveals a dual role in genome packaging and activation of phospholipase A2 activity. J. Virol. 79:2528–40 [Google Scholar]
  54. Dubielzig R, King JA, Weger S, Kern A, Kleinschmidt JA. 54.  1999. Adeno-associated virus type 2 protein interactions: formation of pre-encapsidation complexes. J. Virol. 73:8989–98 [Google Scholar]
  55. Kube DM, Ponnazhagan S, Srivastava A. 55.  1997. Encapsidation of adeno-associated virus type 2 Rep proteins in wild-type and recombinant progeny virions: Rep-mediated growth inhibition of primary human cells. J. Virol. 71:7361–71 [Google Scholar]
  56. Prasad KM, Trempe JP. 56.  1995. The adeno-associated virus Rep78 protein is covalently linked to viral DNA in a preformed virion. Virology 214:360–70 [Google Scholar]
  57. Weitzman MD, Kyöstiö SR, Carter BJ, Owens RA. 57.  1996. Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on AAV hairpin DNA. J. Virol. 70:2440–48 [Google Scholar]
  58. Weitzman MD, Kyöstiö SR, Kotin RM, Owens RA. 58.  1994. Adeno-associated virus (AAV) Rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc. Natl. Acad. Sci. USA 91:5808–12 [Google Scholar]
  59. Nony P, Chadeuf G, Tessier J, Moullier P, Salvetti A. 59.  2003. Evidence for packaging of rep-cap sequences into adeno-associated virus (AAV) type 2 capsids in the absence of inverted terminal repeats: a model for generation of rep-positive AAV particles. J. Virol. 77:776–81 [Google Scholar]
  60. Nony P, Tessier J, Chadeuf G, Ward P, Giraud A. 60.  et al. 2001. Novel cis-acting replication element in the adeno-associated virus type 2 genome is involved in amplification of integrated rep-cap sequences. J. Virol. 75:9991–94 [Google Scholar]
  61. Tessier J, Chadeuf G, Nony P, Avet-Loiseau H, Moullier P, Salvetti A. 61.  2001. Characterization of adenovirus-induced inverted terminal repeat-independent amplification of integrated adeno-associated virus rep-cap sequences. J. Virol. 75:375–83 [Google Scholar]
  62. King JA, Dubielzig R, Grimm D, Kleinschmidt JA. 62.  2001. DNA helicase-mediated packaging of adeno-associated virus type 2 genomes into preformed capsids. EMBO J. 20:3282–91 [Google Scholar]
  63. Samulski RJ, Berns KI, Tan M, Muzyczka N. 63.  1982. Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc. Natl. Acad. Sci. USA 79:2077–81 [Google Scholar]
  64. Hermonat PL, Labow MA, Wright R, Berns KI, Muzyczka N. 64.  1984. Genetics of adeno-associated virus: isolation and preliminary characterization of adeno-associated virus type 2 mutants. J. Virol. 51:329–39 [Google Scholar]
  65. Tratschin JD, Miller IL, Carter BJ. 65.  1984. Genetic analysis of adeno-associated virus: properties of deletion mutants constructed in vitro and evidence for an adeno-associated virus replication function. J. Virol. 51:611–19 [Google Scholar]
  66. Tratschin JD, West MH, Sandbank T, Carter BJ. 66.  1984. A human parvovirus, adeno-associated virus, as a eucaryotic vector: transient expression and encapsidation of the procaryotic gene for chloramphenicol acetyltransferase. Mol. Cell. Biol. 4:2072–81 [Google Scholar]
  67. Xiao X, Li J, Samulski RJ. 67.  1998. Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J. Virol. 72:2224–32 [Google Scholar]
  68. Matsushita T, Elliger S, Elliger C, Podsakoff G, Villarreal L. 68.  et al. 1998. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 5:938–45 [Google Scholar]
  69. Grimm D, Kern A, Rittner K, Kleinschmidt JA. 69.  1998. Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum. Gene Ther. 9:2745–60 [Google Scholar]
  70. Clark KR, Voulgaropoulou DM, Fraley DM, Johnson PR. 70.  1995. Cell lines for the production of recombinant adeno-associated virus. Hum. Gene Ther. 6:1329–41 [Google Scholar]
  71. Virag T, Cecchini S, Kotin RM. 71.  2009. Producing recombinant adeno-associated virus in foster cells: overcoming production limitations using a baculovirus–insect cell expression strategy. Hum. Gene Ther. 20:807–17 [Google Scholar]
  72. Clément N, Knop DR, Byrne BJ. 72.  2009. Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. Hum. Gene Ther. 20:796–806 [Google Scholar]
  73. Thorne BA, Takeya RK, Peluso RW. 73.  2009. Manufacturing recombinant adeno-associated viral vectors from producer cell clones. Hum. Gene Ther. 20:707–14 [Google Scholar]
  74. Wright JF. 74.  2009. Transient transfection methods for clinical adeno-associated viral vector production. Hum. Gene Ther. 20:698–706 [Google Scholar]
  75. Aucoin MG, Perrier M, Kamen AA. 75.  2008. Critical assessment of current adeno-associated viral vector production and quantification methods. Biotechnol. Adv. 26:73–88 [Google Scholar]
  76. Kotin RM. 76.  2011. Large-scale recombinant adeno-associated virus production. Hum. Mol. Genet. 20:R2–6 [Google Scholar]
  77. Thomas DL, Wang L, Niamke J, Liu J, Kang W. 77.  et al. 2009. Scalable recombinant adeno-associated virus production using recombinant herpes simplex virus type 1 coinfection of suspension-adapted mammalian cells. Hum. Gene Ther. 20:861–70 [Google Scholar]
  78. Kohlbrenner E, Aslanidi G, Nash K, Shklyaev S, Campbell-Thompson M. 78.  et al. 2005. Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system. Mol. Ther. 12:1217–25 [Google Scholar]
  79. Mietzsch M, Grasse S, Zurawski C, Weger S, Bennett A. 79.  et al. 2014. OneBac: platform for scalable and high-titer production of adeno-associated virus serotype 1–12 vectors for gene therapy. Hum. Gene Ther. 25:212–22 [Google Scholar]
  80. Zhang X, De Alwis M, Hart SL, Fitzke FW, Inglis SC. 80.  et al. 1999. High-titer recombinant adeno-associated virus production from replicating amplicons and herpes vectors deleted for glycoprotein H. Hum. Gene Ther. 10:2527–37 [Google Scholar]
  81. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M. 81.  et al. 1999. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 6:973–85 [Google Scholar]
  82. Zolotukhin S, Potter M, Zolotukhin I, Sakai Y, Loiler S. 82.  et al. 2002. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 28:158–67 [Google Scholar]
  83. Auricchio A, O'Connor E, Hildinger M, Wilson JM. 83.  2001. A single-step affinity column for purification of serotype-5 based adeno-associated viral vectors. Mol. Ther. 4:372–74 [Google Scholar]
  84. Smith RH, Levy JR, Kotin RM. 84.  2009. A simplified baculovirus-AAV expression vector system coupled with one-step affinity purification yields high-titer rAAV stocks from insect cells. Mol. Ther. 17:1888–96 [Google Scholar]
  85. Grimm D, Kern A, Pawlita M, Ferrari FK, Samulski RJ, Kleinschmidt JA. 85.  1999. Titration of AAV-2 particles via a novel capsid ELISA: Packaging of genomes can limit production of recombinant AAV-2. Gene Ther. 6:1322–30 [Google Scholar]
  86. Loch M, Alvira MR, Wilson JM. 86.  2012. Analysis of particle content of recombinant adeno-associated virus sertoype 8 vectors by ion-exchange chromatography. Hum. Gene Ther. Methods 23:56–64 [Google Scholar]
  87. Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ. 87.  et al. 2014. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl. Med. 5:194ra92 [Google Scholar]
  88. Chulay JD, Ye GJ, Thomas DL, Knop DR, Benson JM. 88.  et al. 2011. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum. Gene Ther. 22:155–65 [Google Scholar]
  89. Conrad CK, Allen SS, Afione SA, Reynolds TC, Beck SE. 89.  et al. 1996. Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther. 3:658–68 [Google Scholar]
  90. McCown TJ, Xiao X, Li J, Breese GR, Samulski RJ. 90.  1996. Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res. 713:99–107 [Google Scholar]
  91. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW. 91.  et al. 1994. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat. Genet. 8:148–54 [Google Scholar]
  92. Kessler PD, Podsakoff GM, Chen X, McQuiston SA, Colosi PC. 92.  et al. 1996. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl. Acad. Sci. USA 93:14082–87 [Google Scholar]
  93. Xiao X, Li J, Samulski RJ. 93.  1996. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol. 70:8098–108 [Google Scholar]
  94. Flannery JG, Zolotukhin S, Vaquero MI, LaVail MM, Muzyczka N, Hauswirth WW. 94.  1997. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc. Natl. Acad. Sci. USA 94:6916–21 [Google Scholar]
  95. Peel AL, Zolotukhin S, Schrimsher GW, Muzyczka N, Reier PJ. 95.  1997. Efficient transduction of green fluorescent protein in spinal cord neurons using adeno-associated virus vectors containing cell type-specific promoters. Gene Ther. 4:16–24 [Google Scholar]
  96. Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O. 96.  et al. 1997. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat. Genet. 16:270–6 [Google Scholar]
  97. Snyder RO, Spratt SK, Lagarde C, Bohl D, Kaspar B. 97.  et al. 1997. Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. Hum. Gene Ther. 8:1891–900 [Google Scholar]
  98. Mandel RJ, Spratt SK, Snyder RO, Leff SE. 98.  1997. Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats. Proc. Natl. Acad. Sci. USA 94:14083–8 [Google Scholar]
  99. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV. 99.  et al. 2005. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol. Ther. 12:1072–82 [Google Scholar]
  100. Nonnenmacher M, Weber T. 100.  2012. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther. 19:649–58 [Google Scholar]
  101. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. 101.  2002. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl. Acad. Sci. USA 99:11854–59 [Google Scholar]
  102. Dismuke DJ, Gray S, Hirxch ML, Samulski RJ, Muzyczka N. 102.  2010. Viral vectors for gene therapy. Structural Virology Monograph M Agbandje-McKenna 338–57 London: RSC [Google Scholar]
  103. Agbandje-McKenna M, Kuhn R. 103.  2011. Current opinion in virology: structural virology. Curr. Opin. Virol. 1:81–83 [Google Scholar]
  104. Nonnenmacher M, Weber T. 104.  2011. Adeno-associated virus 2 infection requires endocytosis through the CLIC/GEEC pathway. Cell Host Microbe 10:563–76 [Google Scholar]
  105. Sonntag F, Bleker S, Leuchs B, Fischer R, Kleinschmidt JA. 105.  2006. Adeno-associated virus type 2 capsids with externalized VP1/VP2 trafficking domains are generated prior to passage through the cytoplasm and are maintained until uncoating occurs in the nucleus. J. Virol. 80:11040–54 [Google Scholar]
  106. Johnson JS, Samulski RJ. 106.  2009. Enhancement of adeno-associated virus infection by mobilizing capsids into and out of the nucleolus. J. Virol. 83:2632–44 [Google Scholar]
  107. Douar AM, Poulard K, Stockholm D, Danos O. 107.  2001. Intracellular trafficking of adeno-associated virus vectors: routing to the late endosomal compartment and proteasome degradation. J. Virol. 75:1824–33 [Google Scholar]
  108. Hansen J, Qing K, Srivastava A. 108.  2001. Adeno-associated virus type 2-mediated gene transfer: Altered endocytic processing enhances transduction efficiency in murine fibroblasts. J. Virol. 75:4080–90 [Google Scholar]
  109. Bartlett JS, Wilcher R, Samulski RJ. 109.  2000. Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. J. Virol. 74:2777–85 [Google Scholar]
  110. Girod A, Wobus CE, Zádori Z, Ried M, Leike K. 110.  et al. 2002. The VP1 capsid protein of adeno-associated virus type 2 is carrying a phospholipase A2 domain required for virus infectivity. J. Gen. Virol. 83:973–78 [Google Scholar]
  111. Hansen J, Qing K, Srivastava A. 111.  2001. Infection of purified nuclei by adeno-associated virus 2. Mol. Ther. 4:289–96 [Google Scholar]
  112. Xiao PJ, Samulski RJ. 112.  2012. Cytoplasmic trafficking, endosomal escape, and perinuclear accumulation of adeno-associated virus type 2 particles are facilitated by microtubule network. J. Virol. 86:10462–73 [Google Scholar]
  113. Grieger JC, Johnson JS, Gurda-Whitaker B, Agbandje-McKenna M, Samulski RJ. 113.  2007. Surface-exposed adeno-associated virus Vp1-NLS capsid fusion protein rescues infectivity of noninfectious wild-type Vp2/Vp3 and Vp3-only capsids but not that of fivefold pore mutant virions. J. Virol. 81:7833–43 [Google Scholar]
  114. Nakai H, Storm TA, Kay MA. 114.  2000. Recruitment of single-stranded recombinant adeno-associated virus vector genomes and intermolecular recombination are responsible for stable transduction of liver in vivo. J. Virol. 74:9451–63 [Google Scholar]
  115. Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R. 115.  et al. 2011. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. Hum. Gene Ther. 22:1239–47 [Google Scholar]
  116. McCarty DM. 116.  2008. Self-complementary AAV vectors; advances and applications. Mol. Ther. 16:1648–56 [Google Scholar]
  117. McCarty DM, Monahan PE, Samulski RJ. 117.  2001. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 8:1248–54 [Google Scholar]
  118. Kotin RM, Siniscalco M, Samulski RJ, Zhu XD, Hunter L. 118.  et al. 1990. Site-specific integration by adeno-associated virus. Proc. Natl. Acad. Sci. USA 87:2211–15 [Google Scholar]
  119. Samulski RJ, Zhu V, Xiao X, Brook JD, Housman DE. 119.  et al. 1991. Targeted integration of adeno-associated virus (AAV) in human chromosome 19. EMBO J. 10:3941–50 [Google Scholar]
  120. Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. 120.  2001. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J. Virol. 75:6969–76 [Google Scholar]
  121. Clark KR, Sferra TJ, Lo W, Qu G, Chen R, Johnson PR. 121.  1999. Gene transfer into the CNS using recombinant adeno-associated virus: analysis of vector DNA forms resulting in sustained expression. J. Drug Target. 7:269–83 [Google Scholar]
  122. Schnepp BC, Clark KR, Klemanski DL, Pacak CA, Johnson PR. 122.  2003. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J. Virol. 77:3495–504 [Google Scholar]
  123. Schnepp BC, Jensen RL, Clark KR, Johnson PR. 123.  2009. Infectious molecular clones of adeno-associated virus isolated directly from human tissues. J. Virol. 83:1456–64 [Google Scholar]
  124. Song S, Laipis PJ, Berns KI, Flotte TR. 124.  2001. Effect of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle. Proc. Natl. Acad. Sci. USA 98:4084–88 [Google Scholar]
  125. Flotte TR, Afione SA, Zeitlin PL. 125.  1994. Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am. J. Respir. Cell Mol. Biol. 11:517–21 [Google Scholar]
  126. Penaud-Budloo M, Le Guiner C, Nowrouzi A, Toromanoff A, Chérel Y. 126.  et al. 2008. Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J. Virol. 82:7875–85 [Google Scholar]
  127. Vincent-Lacaze N, Snyder RO, Gluzman R, Bohl D, Lagarde C, Danos O. 127.  1999. Structure of adeno-associated virus vector DNA following transduction of the skeletal muscle. J. Virol. 73:1949–55 [Google Scholar]
  128. Inagaki K, Lewis SM, Wu X, Ma C, Munroe DJ. 128.  et al. 2007. DNA palindromes with a modest arm length of greater, similar 20 base pairs are a significant target for recombinant adeno-associated virus vector integration in the liver, muscles, and heart in mice. J. Virol. 81:11290–303 [Google Scholar]
  129. Li J, Sun W, Wang B, Xiao X, Liu XQ. 129.  2008. Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy. Hum. Gene Ther. 19:958–64 [Google Scholar]
  130. Nakai H, Storm TA, Kay MA. 130.  2000. Increasing the size of rAAV-mediated expression cassettes in vivo by intermolecular joining of two complementary vectors. Nat. Biotechnol. 18:527–32 [Google Scholar]
  131. Dyka FM, Boye SL, Hiodo VA, Hauswirth WW, Boye SE. 131.  2014. Dual adeno-associated virus vectors result in efficient in vitro and in vivo expression of an oversized gene. MYO7A Hum. Gene Ther. 25:166–77 [Google Scholar]
  132. Rutledge EA, Halbert CL, Russell DW. 132.  1998. Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J. Virol. 72:309–19 [Google Scholar]
  133. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R. 133.  et al. 2004. Clades of adeno-associated viruses are widely disseminated in human tissues. J. Virol. 76:6381–88 [Google Scholar]
  134. Agbandje-McKenna M, Kleinschmidt J. 134.  2011. AAV capsid and cell interactions. Adeno-Associated Virus: Methods and Protocols RO Snyder, P Moullier 47–92 Clifton, NJ: Humana [Google Scholar]
  135. Asokan A, Schaffer DV, Samuslki RJ. 135.  2012. The AAV vector toolkit: poised at the clinical crossroads. Mol. Ther. 4:699–708 [Google Scholar]
  136. Salganik M, Aydemir F, Nam HJ, McKenna R, Agbandje-McKenna M, Muzyczka N. 136.  2014. Adeno-associated virus capsid proteins may play a role in transcription and second-strand synthesis of recombinant genomes. J. Virol. 88:1071–79 [Google Scholar]
  137. Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M. 137.  et al. 2008. 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 105:7827–32 [Google Scholar]
  138. Petrs-Silva H, Dinculescu A, Li Q, Min SH, Chiodo V. 138.  et al. 2009. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol. Ther. 17:463–71 [Google Scholar]
  139. Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ. 139.  et al. 2012. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol. Ther. 20:443–55 [Google Scholar]
  140. Girod A, Ried M, Wobus C, Lahm H, Leike K. 140.  et al. 1999. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat. Med. 5:1052–56 [Google Scholar]
  141. Wu P, Xiao W, Conlon T, Hughes J, Agbandje-McKenna M. 141.  et al. 2000. Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism. J. Virol. 74:8635–47 [Google Scholar]
  142. Opie SR, Warrington KH Jr, Agbandje-McKenna M, Zolotukhin S, Muzyczka N. 142.  2003. Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J. Virol. 77:6995–7006 [Google Scholar]
  143. Kern A, Schmidt K, Leder C, Müller OJ, Wobus CE. 143.  et al. 2003. Identification of a heparin-binding motif on adeno-associated virus type 2 capsids. J. Virol. 77:11072–81 [Google Scholar]
  144. Müller OJ, Kaul F, Weitzman MD, Pasqualini F, Arap W. 144.  et al. 2003. Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors. Nat. Biotechnol. 21:1040–46 [Google Scholar]
  145. Waterkamp DA, Müller OJ, Ying Y, Trempel M, Kleinschmidt JA. 145.  2006. Isolation of targeted AAV2 vectors from novel virus display libraries. J. Gene Med. 8:1307–19 [Google Scholar]
  146. Warrington KH Jr, Gorbatyuk OS, Harrison JK, Opie SR, Zolotukhin S, Muzyczka N. 146.  2004. Adeno-associated virus type 2 VP2 capsid protein is nonessential and can tolerate large peptide insertion in its N terminus. J. Virol. 78:6595–609 [Google Scholar]
  147. Grimm D, Lee JS, Wang L, Desai T, Akache B. 147.  et al. 2008. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82:5887–911 [Google Scholar]
  148. Koerber JT, Maheshri N, Kaspar BK, Schaffer DV. 148.  2006. Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles. Nat. Protoc. 1:701–6 [Google Scholar]
  149. Li W, Asokan A, Wu Z, Van Dyke T, DiPrimio N. 149.  et al. 2008. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol. Ther. 16:1252–60 [Google Scholar]
  150. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. 150.  2006. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat. Biotechnol. 24:198–204 [Google Scholar]
  151. Bartel MA, Weinstein JR, Schaffer DV. 151.  2012. Directed evolution of novel adeno-associated viruses for therapeutic gene delivery. Gene Ther. 19:694–700 [Google Scholar]
  152. Komáromy AM, Alexander JJ, Cooper AE, Chiodo VA, Glushakova LG. 152.  et al. 2008. Targeting gene expression to cones with human cone opsin promoters in recombinant AAV. Gene Ther. 15:1049–55 [Google Scholar]
  153. Geisler A, Jungmann A, Kurreck J, Poller W, Katus HA. 153.  et al. 2011. microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Gene Ther. 18:199–209 [Google Scholar]
  154. Karali M, Manfredi A, Puppo A, Marrocco E, Gargiulo A. 154.  et al. 2011. MicroRNA-restricted transgene expression in the retina. PLOS ONE 6:e22166 [Google Scholar]
  155. Kay CN, Ryals RC, Aslanidi GV, Min SH, Ruan Q. 155.  et al. 2013. Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors. PLOS ONE 8:e62097 [Google Scholar]
  156. Majowicz A, Maczuga P, Kwikkers KL, van der Marel S, van Logtenstein R. 156.  et al. 2013. Mir-142-3p target sequences reduce transgene-directed immunogenicity following intramuscular adeno-associated virus 1 vector-mediated gene delivery. J. Gene Med. 15:219–32 [Google Scholar]
  157. Qiao C, Yuan Z, Li J, He B, Zheng H. 157.  et al. 2011. Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver. Gene Ther. 18:403–10 [Google Scholar]
  158. Rendahl KG, Leff SE, Otten GR, Spratt SK, Bohl D. 158.  et al. 1998. Regulation of gene expression in vivo following transduction by two separate rAAV vectors. Nat. Biotechnol. 16:757–61 [Google Scholar]
  159. Stieger K, Le Meur G, Lasne F, Weber M, Deschamps JY. 159.  et al. 2006. Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors. Mol. Ther. 13:967–75 [Google Scholar]
  160. Chen SJ, Johnston J, Sandhu A, Bish LT, Hovhannisyan R. 160.  et al. 2013. Enhancing the utility of adeno-associated virus gene transfer through inducible tissue-specific expression. Hum. Gene Ther. Methods 24:270–78 [Google Scholar]
  161. Su H, Joho S, Huang Y, Barcena A, Arakawa-Hoyt J. 161.  et al. 2004. Adeno-associated viral vector delivers cardiac-specific and hypoxia-inducible VEGF expression in ischemic mouse hearts. Proc. Natl. Acad. Sci. USA 101:16280–85 [Google Scholar]
  162. Wang J, Voutetakis A, Papa M, Rivera VM, Clackson T. 162.  et al. 2006. Rapamycin control of transgene expression from a single AAV vector in mouse salivary glands. Gene Ther. 13:187–90 [Google Scholar]
  163. Manfredsson FP, Burger C, Rising AC, Zuobi-Hasona K, Sullivan LF. 163.  et al. 2009. Tight long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector. Mol. Ther. 17:1857–67 [Google Scholar]
  164. Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M. 164.  et al. 2009. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc. Natl. Acad. Sci. USA 106:16363–68 [Google Scholar]
  165. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J. 165.  et al. 2011. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N. Engl. J. Med. 365:2357–65 [Google Scholar]
  166. Daly TM, Vogler C, Levy B, Haskins ME, Sands MS. 166.  1999. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc. Natl. Acad. Sci. USA 96:2296–300 [Google Scholar]
  167. Embury JE, Charron CE, Martynyuk A, Zori AG, Liu B. 167.  et al. 2007. PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pahenu2 mice. Brain Res. 1127:136–50 [Google Scholar]
  168. Boye SE, Boye SL, Lewin AS, Hauswirth WW. 168.  2013. A comprehensive review of retinal gene therapy. Mol. Ther. 21:509–19 [Google Scholar]
  169. Naim C, Yerevanian A, Hajjar RJ. 169.  2013. Gene therapy for heart failure: Where do we stand?. Curr. Cardiol. Rep. 15:333 [Google Scholar]
  170. Bartus RT, Baumann TL, Brown L, Kruegel BR, Ostrove JM, Herzog CD. 170.  2013. Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson's disease. Neurobiol. Aging 34:35–61 [Google Scholar]
  171. Dayton RD, Wang DB, Klein RL. 171.  2012. The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin. Biol. Ther. 12:757–66 [Google Scholar]
  172. Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM. 172.  2011. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 19:1025–33 [Google Scholar]
  173. Sanftner LM, Sommer JM, Suzuki BM, Smith PH, Vijay S. 173.  et al. 2005. AAV2-mediated gene delivery to monkey putamen: evaluation of an infusion device and delivery parameters. Exp. Neurol. 194:476–83 [Google Scholar]
  174. Sun B, Li S, Bird A, Koeberl DD. 174.  2010. Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease. Gene Ther. 17:1500–5 [Google Scholar]
  175. Wagner JA, Messner AH, Moran ML, Daifuku R, Kouyama K. 175.  et al. 1999. Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 109:266–74 [Google Scholar]
  176. Flotte T, Carter B, Conrad C, Guggino W, Reynolds T. 176.  et al. 1996. A phase I study of an adeno-associated virus-CFTR gene vector in adult CF patients with mild lung disease. Hum. Gene Ther. 7:1145–59 [Google Scholar]
  177. Hauswirth W, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB. 177.  et al. 2008. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum. Gene Ther. 19:979–90 [Google Scholar]
  178. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F. 178.  et al. 2008. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358:2240–48 [Google Scholar]
  179. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R. 179.  et al. 2008. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358:2231–39 [Google Scholar]
  180. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S. 180.  et al. 2008. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl. Acad. Sci. USA 105:15112–17 [Google Scholar]
  181. Hasbrouck NC, High KA. 181.  2008. AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospects. Gene Ther. 15:870–75 [Google Scholar]
  182. Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ. 182.  et al. 2009. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73:1662–69 [Google Scholar]
  183. Mandel RJ. 183.  2010. CERE-110, an adeno-associated virus-based gene delivery vector expressing human nerve growth factor for the treatment of Alzheimer's disease. Curr. Opin. Mol. Ther. 12:240–47 [Google Scholar]
  184. Leone P, Shera D, McPhee SW, Francis JS, Kolodny EH. 184.  et al. 2012. Long-term follow-up after gene therapy for canavan disease. Sci. Transl. Med. 4:165ra63 [Google Scholar]
  185. Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA. 185.  et al. 2002. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol. Ther. 5:571–78 [Google Scholar]
  186. Zhu J, Huang X, Yang Y. 186.  2009. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J. Clin. Investig. 119:2388–98 [Google Scholar]
  187. Martino AT, Nayak S, Hoffman BE, Cooper M, Liao G. 187.  et al. 2009. Tolerance induction to cytoplasmic β-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity. PLOS ONE 4:e6376 [Google Scholar]
  188. Rogers GL, Martino AT, Aslanidi GV, Jayandharan GR, Srivastava A, Herzog RW. 188.  2011. Innate immune responses to AAV vectors. Front. Microbiol. 2:194 [Google Scholar]
  189. Hauck B, Murphy SL, Smith PH, Qu G, Liu X. 189.  et al. 2009. Undetectable transcription of cap in a clinical AAV vector: implications for preformed capsid in immune responses. Mol. Ther. 17:144–52 [Google Scholar]
  190. Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL. 190.  et al. 2012. AAV2 gene therapy readministration in three adults with congenital blindness. Sci. Transl. Med. 4:120ra15 [Google Scholar]
  191. Peden CS, Manfredsson FP, Reimsnider SK, Poirier AE, Burger C. 191.  et al. 2009. Striatal readministration of rAAV vectors reveals an immune response against AAV2 capsids that can be circumvented. Mol. Ther. 17:524–37 [Google Scholar]
  192. Tseng YS, Agbandje-McKenna M. 192.  2014. Mapping the AAV capsid host antibody response toward the development of second generation gene delivery vectors. Front. Immunol. 5:9 [Google Scholar]
  193. Donsante A, Miller DG, Li Y, Vogler C, Brunt EM. 193.  et al. 2007. AAV vector integration sites in mouse hepatocellular carcinoma. Science 317:477 [Google Scholar]
  194. Donsante A, Vogler C, Muzyczka N, Crawford JM, Barker J. 194.  et al. 2001. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther. 8:1343–46 [Google Scholar]
  195. Bell P, Moscioni AD, McCarter RJ, Wu D, Gao G. 195.  et al. 2006. Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. Mol. Ther. 14:34–44 [Google Scholar]
  196. Bell P, Wang L, Lebherz C, Flieder DB, Bove MS. 196.  et al. 2005. No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol. Ther. 12:299–306 [Google Scholar]
  197. Wu K, Li S, Bodhinathan K, Meyers C, Chen W. 197.  et al. 2012. Enhanced expression of Pctk1, Tcf12 and Ccnd1 in hippocampus of rats: impact on cognitive function, synaptic plasticity and pathology. Neurobiol. Learn. Mem. 97:69–80 [Google Scholar]
  198. Rosas LE, Grieves JL, Zaraspe K, La Perle KM, Fu H, McCarty DM. 198.  2012. Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol. Ther. 20:2098–110 [Google Scholar]
  199. Kirik D, Björklund A. 199.  2003. Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors. Trends Neurosci. 26:386–92 [Google Scholar]
  200. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Björklund A. 200.  2003. Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 100:2884–89 [Google Scholar]
  201. Gorbatyuk OS, Li S, Nash K, Gorbatyuk M, Lewin AS. 201.  et al. 2010. In vivo RNAi-mediated α-synuclein induces nigrostriatal degeneration. Mol. Ther. 8:1450–57 [Google Scholar]
  202. Gerstein H, Lindstrom MJ, Burger C. 202.  2013. Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging. Neurobiol. Aging 34:1963–70 [Google Scholar]
  203. Rex CS, Gavin CF, Rubio MD, Kramer EA, Chen LY. 203.  et al. 2010. Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation. Neuron 67:603–17 [Google Scholar]
  204. Fenno L, Yizhar O, Deisseroth K. 204.  2011. The development and application of optogenetics. Annu. Rev. Neurosci. 34:389–412 [Google Scholar]
  205. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T. 205.  et al. 2002. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc. Natl. Acad. Sci. USA 99:10405–10 [Google Scholar]
  206. Im DS, Muzyczka N. 206.  1990. The AAV origin binding protein Rep68 is an ATP-dependent site-specific endonuclease with DNA helicase activity. Cell 61:447–57 [Google Scholar]
  207. Im DS, Muzyczka N. 207.  1992. Partial purification of adeno-associated virus Rep78, Rep52, and Rep40 and their biochemical characterization. J. Virol. 66:1119–28 [Google Scholar]
  208. Smith RH, Kotin RM. 208.  1998. The Rep52 gene product of adeno-associated virus is a DNA helicase with 3′-to-5′ polarity. J. Virol. 72:4874–81 [Google Scholar]
  209. Grieger JC, Snowdy S, Samulski RJ. 209.  2006. Separate basic region motifs within the adeno-associated virus capsid proteins are essential for infectivity and assembly. J. Virol. 80:5199–210 [Google Scholar]
  210. Becerra SP, Koczot F, Fabisch P, Rose JA. 210.  1988. Synthesis of adeno-associated virus structural proteins requires both alternative mRNA splicing and alternative initiations from a single transcript. J. Virol. 62:2745–54 [Google Scholar]
  211. Lusby E, Fife KH, Berns KI. 211.  1980. Nucleotide sequence of the inverted terminal repetition in adeno-associated virus DNA. J. Virol. 34:402–9 [Google Scholar]
  212. Snyder RO, Im DS, Ni T, Xiao X, Samulski RJ, Muzyczka N. 212.  1993. Features of the adeno-associated virus origin involved in substrate recognition by the viral Rep protein. J. Virol. 67:6096–104 [Google Scholar]
  213. McCarty DM, Pereira DJ, Zolotukhin I, Zhou X, Ryan JH, Muzyczka N. 213.  1994. Identification of linear DNA sequences that specifically bind the adeno-associated virus Rep protein. J. Virol. 68:4988–97 [Google Scholar]
  214. Ryan JH, Zolotukhin S, Muzyczka N. 214.  1996. Sequence requirements for binding of Rep68 to the adeno-associated virus terminal repeats. J. Virol. 70:1542–53 [Google Scholar]
  215. Chiorini JA, Wiener SM, Owens RA, Kyöstiö SR, Kotin RM, Safer B. 215.  1994. Sequence requirements for stable binding and function of Rep68 on the adeno-associated virus type 2 inverted terminal repeats. J. Virol. 68:7448–57 [Google Scholar]
  216. Brister JR, Muzyczka N. 216.  1999. Rep-mediated nicking of the adeno-associated virus origin requires two biochemical activities, DNA helicase activity and transesterification. J. Virol. 73:9325–36 [Google Scholar]
  217. Brister JR, Muzyczka N. 217.  2000. Mechanism of Rep-mediated adeno-associated virus origin nicking. J. Virol. 74:7762–71 [Google Scholar]
/content/journals/10.1146/annurev-virology-031413-085355
Loading
/content/journals/10.1146/annurev-virology-031413-085355
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error