Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tailoring the AAV vector capsid for gene therapy

Abstract

A number of preclinical studies have shown the adeno-associated virus (AAV) to be an efficient vehicle for gene therapy. Clinical studies successfully demonstrated its potential for in vivo gene transfer. The complexity of host–vector interactions when progressing from small to large animal models, and eventually to humans, has impeded translation of AAV technology to the clinic. One approach to address this complexity has been to explore the biological characteristics of variations in AAV capsid structure. Initial strategies characterized the naturally occurring capsid variants from mammalian species. The structural and functional knowledge gathered on these natural AAV variants as vectors has led to the first series of second-generation vectors that aim at specifically improving certain properties by rational design of the capsid. A third exciting approach uses directed evolution to isolate vectors that are able to overcome selective pressures applied in the laboratory and thereby steer the capsid to evolve toward improved functionality.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  1. Fields BN, Knipe DM, Howley PM . Fields’ virology, 5th edn. Wolters kluwer/Lippincott Williams & Wilkins: Philadelphia, 2007.

    Google Scholar 

  2. Gao G, Vandenberghe LH, Wilson JM . New recombinant serotypes of AAV vectors. Curr Gene Ther 2005; 5: 285–297.

    CAS  PubMed  Article  Google Scholar 

  3. Samulski RJ, Berns KI, Tan M, Muzyczka N . Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc Natl Acad Sci USA 1982; 79: 2077–2081.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Grieger JC, Choi VW, Samulski RJ . Production and characterization of adeno-associated viral vectors. Nat Protoc 2006; 1: 1412–1428.

    CAS  PubMed  Article  Google Scholar 

  5. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791–801.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Auricchio A, Kobinger G, Anand V, Hildinger M, O’Connor E, Maguire AM et al. Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model. Hum Mol Genet 2001; 10: 3075–3081.

    CAS  Article  PubMed  Google Scholar 

  7. Nakai H, Thomas CE, Storm TA, Fuess S, Powell S, Wright JF et al. A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J Virol 2002; 76: 11343–11349.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Zabner J, Seiler M, Walters R, Kotin RM, Fulgeras W, Davidson BL et al. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J Virol 2000; 74: 3852–3858.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Grimm D, Pandey K, Nakai H, Storm TA, Kay MA . Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J Virol 2006; 80: 426–439.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Rolling F, Le Meur G, Stieger K, Smith AJ, Weber M, Deschamps JY et al. Gene therapeutic prospects in early onset of severe retinal dystrophy: restoration of vision in RPE65 Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Bull Mem Acad R Med Belg 2006; 161: 497–508; discussion 508-499.

    CAS  PubMed  Google Scholar 

  11. Limberis MP, Wilson JM . Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered. Proc Natl Acad Sci USA 2006; 103: 12993–12998.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Halbert CL, Allen JM, Miller AD . Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J Virol 2001; 75: 6615–6624.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Wang Z, Zhu T, Qiao C, Zhou L, Wang B, Zhang J et al. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat Biotechnol 2005; 23: 321–328.

    CAS  Article  PubMed  Google Scholar 

  14. Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG et al. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 2004; 10: 828–834.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Inagaki K, Fuess S, Storm TA, Gibson GA, McTiernan CF, Kay MA et al. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 2006; 14: 45–53.

    CAS  Article  PubMed  Google Scholar 

  16. Scallan CD, Jiang H, Liu T, Patarroyo-White S, Sommer JM, Zhou S et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 2006; 107: 1810–1817.

    CAS  PubMed  Article  Google Scholar 

  17. Lin J, Calcedo R, Vandenberghe LH, Figueredo JM, Wilson JM . Impact of preexisting vector immunity on the efficacy of adeno-associated virus-based HIV-1 Gag vaccines. Hum Gene Ther 2008; 19: 663–669.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM . Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 2008 (accepted for publication).

  19. Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA . Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 2002; 76: 4580–4590.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Petry H, Brooks A, Orme A, Wang P, Liu P, Xie J et al. Effect of viral dose on neutralizing antibody response and transgene expression after AAV1 vector re-administration in mice. Gene Therapy 2008: 15: 54–60.

    CAS  PubMed  Article  Google Scholar 

  21. Vandenberghe LH, Wang L, Somanathan S, Zhi Y, Figueredo J, Calcedo R et al. Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nat Med 2006; 12: 967–971.

    CAS  Article  PubMed  Google Scholar 

  22. Herzog RW, Hagstrom JN, Kung SH, Tai SJ, Wilson JM, Fisher KJ et al. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94: 5804–5809.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Auricchio A, Hildinger M, O’Connor E, Gao GP, Wilson JM . Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step gravity-flow column. Hum Gene Ther 2001; 12: 71–76.

    CAS  PubMed  Article  Google Scholar 

  24. Kaludov N, Handelman B, Chiorini JA . Scalable purification of adeno-associated virus type 2, 4, or 5 using ion-exchange chromatography. Hum Gene Ther 2002; 13: 1235–1243.

    CAS  PubMed  Article  Google Scholar 

  25. Zolotukhin S, Potter M, Zolotukhin I, Sakai Y, Loiler S, Fraites Jr TJ et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 2002; 28: 158–167.

    CAS  PubMed  Article  Google Scholar 

  26. Wu Z, Asokan A, Samulski RJ . Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther 2006; 14: 316–327.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Schmidt M, Voutetakis A, Afione S, Zheng C, Mandikian D, Chiorini JA . Adeno-associated virus type 12 (AAV12): a novel AAV serotype with sialic acid- and heparan sulfate proteoglycan-independent transduction activity. J Virol 2008; 82: 1399–1406.

    CAS  Article  PubMed  Google Scholar 

  30. Schmidt M, Grot E, Cervenka P, Wainer S, Buck C, Chiorini JA . Identification and characterization of novel adeno-associated virus isolates in ATCC virus stocks. J Virol 2006; 80: 5082–5085.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Schnepp BC, Jensen RL, Chen CL, Johnson PR, Clark KR . Characterization of adeno-associated virus genomes isolated from human tissues. J Virol 2005; 79: 14793–14803.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Bossis I, Chiorini JA . Cloning of an avian adeno-associated virus (AAAV) and generation of recombinant AAAV particles. J Virol 2003; 77: 6799–6810.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Schmidt M, Katano H, Bossis I, Chiorini JA . Cloning and characterization of a bovine adeno-associated virus. J Virol 2004; 78: 6509–6516.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Isolation of a Close AAV5 Relative from Goat Tissues: Evidence of Host Promiscuity, ASGT 7th Annual Meeting; Minneapolis, MN, 2004a.

  35. Characterization of Novel Caprine and Bovine AAV Capsids with Unique Transduction and Neutralization Properties, Xth Parvovirus Workshop; St Petersburg, FL, 2004b.

  36. Grimm D, Kay MA . From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr Gene Ther 2003; 3: 281–304.

    CAS  PubMed  Article  Google Scholar 

  37. Arbetman AE, Lochrie M, Zhou S, Wellman J, Scallan C, Doroudchi MM et al. Novel caprine adeno-associated virus (AAV) capsid (AAV-Go.1) is closely related to the primate AAV-5 and has unique tropism and neutralization properties. J Virol 2005; 79: 15238–15245.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Gao G, Alvira MR, Somanathan S, Lu Y, Vandenberghe LH, Rux JJ et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci USA 2003; 100: 6081–6086.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Vandenberghe LH, Breous K, Nam HJ, Gao G, Xiao R, Shandu A et al. Naturally occurring singleton residues in AAV capsid impact vector performance and illustrate structural constraints. (submitted for publication).

  40. Grimm D, Zhou S, Nakai H, Thomas CE, Storm TA, Fuess S et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood 2003; 102: 2412–2419.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  42. Kern A, Schmidt K, Leder C, Muller OJ, Wobus CE, Bettinger K et al. Identification of a heparin-binding motif on adeno-associated virus type 2 capsids. J Virol 2003; 77: 11072–11081.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Wu Z, Asokan A, Grieger JC, Govindasamy L, Agbandje-McKenna M, Samulski RJ . Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes. J Virol 2006; 80: 11393–11397.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Girod A, Ried M, Wobus C, Lahm H, Leike K, Kleinschmidt J et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat Med 1999; 5: 1052–1056.

    CAS  PubMed  Article  Google Scholar 

  45. Bleker S, Sonntag F, Kleinschmidt JA . 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 2005; 79: 2528–2540.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Opie SR, Warrington Jr KH, Agbandje-McKenna M, Zolotukhin S, Muzyczka N . Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J Virol 2003; 77: 6995–7006.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. DiPrimio N, Asokan A, Govindasamy L, Agbandje-McKenna M, Samulski RJ . Surface loop dynamics in adeno-associated virus capsid assembly. J Virol 2008; 82: 5178–5189.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 10405–10410.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Nam HJ, Lane MD, Padron E, Gurda B, McKenna R, Kohlbrenner E et al. Structure of adeno-associated virus serotype 8, a gene therapy vector. J Virol 2007; 81: 12260–12271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Padron E, Bowman V, Kaludov N, Govindasamy L, Levy H, Nick P et al. Structure of adeno-associated virus type 4. J Virol 2005; 79: 5047–5058.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Buning H, Ried MU, Perabo L, Gerner FM, Huttner NA, Enssle J et al. Receptor targeting of adeno-associated virus vectors. Gene Therapy 2003; 10: 1142–1151.

    CAS  PubMed  Article  Google Scholar 

  52. Zhang HG, Xie J, Dmitriev I, Kashentseva E, Curiel DT, Hsu HC et al. Addition of six-His-tagged peptide to the C terminus of adeno-associated virus VP3 does not affect viral tropism or production. J Virol 2002; 76: 12023–12031.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Rabinowitz JE, Bowles DE, Faust SM, Ledford JG, Cunningham SE, Samulski RJ . Cross-dressing the virion: the transcapsidation of adeno-associated virus serotypes functionally defines subgroups. J Virol 2004; 78: 4421–4432.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Hauck B, Xu RR, Xie J, Wu W, Ding Q, Sipler M et al. Efficient AAV1-AAV2 hybrid vector for gene therapy of hemophilia. Hum Gene Ther 2006; 17: 46–54.

    CAS  PubMed  Article  Google Scholar 

  55. Muller OJ, Leuchs B, Pleger ST, Grimm D, Franz WM, Katus HA et al. Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors. Cardiovasc Res 2006; 70: 70–78.

    PubMed  Article  CAS  Google Scholar 

  56. Perabo L, Goldnau D, White K, Endell J, Boucas J, Humme S et al. Heparan sulfate proteoglycan binding properties of adeno-associated virus retargeting mutants and consequences for their in vivo tropism. J Virol 2006; 80: 7265–7269.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Perabo L, Huber A, Marsch S, Hallek M, Buning H . Artificial evolution with adeno-associated viral libraries. Comb Chem High Throughput Screen 2008; 11: 118–126.

    CAS  PubMed  Article  Google Scholar 

  58. Perabo L, Buning H, Kofler DM, Ried MU, Girod A, Wendtner CM et al. In vitro selection of viral vectors with modified tropism: the adeno-associated virus display. Mol Ther 2003; 8: 151–157.

    CAS  PubMed  Article  Google Scholar 

  59. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV . Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 2006; 24: 198–204.

    CAS  PubMed  Article  Google Scholar 

  60. Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and re-targeting of adeno-associated viruses. J Virol 2008; 82: 5887–5911.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Li W, Asokan A, Wu Z, Van Dyke T, DiPrimio N, Johnson JS et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther 2008; 16: 1252–1260.

    CAS  PubMed  Article  Google Scholar 

  62. Muller OJ, Kaul F, Weitzman MD, Pasqualini R, Arap W, Kleinschmidt JA et al. Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors. Nat Biotechnol 2003; 21: 1040–1046.

    Article  CAS  PubMed  Google Scholar 

  63. Wu Z, Miller E, Agbandje-McKenna M, Samulski RJ . Alpha2,3 and alpha2,6 N-linked sialic acids facilitate efficient binding and transduction by adeno-associated virus types 1 and 6. J Virol 2006; 80: 9093–9103.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Flotte TR, Conlon TJ, Poirier A, Campbell-Thompson M, Byrne BJ . Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites. Hum Gene Ther 2007; 18: 245–256.

    CAS  PubMed  Article  Google Scholar 

  65. Ross CJ, Twisk J, Bakker AC, Miao F, Verbart D, Rip J et al. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum Gene Ther 2006; 17: 487–499.

    CAS  PubMed  Article  Google Scholar 

  66. Arruda VR, Schuettrumpf J, Herzog RW, Nichols TC, Robinson N, Lotfi Y et al. Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood 2004; 103: 85–92.

    CAS  Article  PubMed  Google Scholar 

  67. Rivera VM, Gao GP, Grant RL, Schnell MA, Zoltick PW, Rozamus LW et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 2005; 105: 1424–1430.

    CAS  PubMed  Article  Google Scholar 

  68. Flotte TR, Brantly ML, Byrne B, Humphries M, Washer S, Wilkorson P . Discussion of human gene transfer protocol #0404-638: a phase I trial of intramuscular 6 injection of a recombinant adeno-associated virus 1-alpha 1-antitrypsin (rAAV1-CB-hAAT) gene vector to AAT-deficient adults. NIH RAC 2004; http://www4.od.nih.gov/oba/RAC/minutes/RAC_Minutes_06-04.pdf.

  69. Meulenberg A . Immune responses in a lipoprotein lipase deficiency study using AAV-1-LPLS447X. NIH RAC AAV Safety Symposium 2007; http://www4.od.nih.gov/oba/RAC/minutes/RAC_minutes_06_19_07.pdf.

  70. Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D et al. Gene therapy for lipoprotein lipase deficiency: working toward clinical application. Hum Gene Ther 2005; 16: 1276–1286.

    CAS  PubMed  Article  Google Scholar 

  71. Koeberl DD, Pinto C, Sun B, Li S, Kozink DM, Benjamin Jr DK et al. AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Mol Ther 2008; 16: 665–672.

    CAS  Article  PubMed  Google Scholar 

  72. Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E et al. Local delivery of a recombinant adeno-associated vector containing a tumor necrosis factor-{alpha} antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis 2008.

  73. Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A et al. Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. J Card Fail 2008; 14: 355–367.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  77. Akache B, Grimm D, Pandey K, Yant SR, Xu H, Kay MA . The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J Virol 2006; 80: 9831–9836.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Rubenstein RC, McVeigh U, Flotte TR, Guggino WB, Zeitlin PL . CFTR gene transduction in neonatal rabbits using an adeno-associated virus (AAV) vector. Gene Therapy 1997; 4: 384–392.

    CAS  PubMed  Article  Google Scholar 

  79. Conrad CK, Allen SS, Afione SA, Reynolds TC, Beck SE, Fee-Maki M et al. Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Therapy 1996; 3: 658–668.

    CAS  PubMed  Google Scholar 

  80. Beck SE, Laube BL, Barberena CI, Fischer AC, Adams RJ, Chesnut K et al. Deposition and expression of aerosolized rAAV vectors in the lungs of Rhesus macaques. Mol Ther 2002; 6: 546–554.

    CAS  PubMed  Article  Google Scholar 

  81. Wagner JA, Nepomuceno IB, Messner AH, Moran ML, Batson EP, Dimiceli S et al. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther 2002; 13: 1349–1359.

    CAS  PubMed  Article  Google Scholar 

  82. Wagner JA, Messner AH, Moran ML, Daifuku R, Kouyama K, Desch JK et al. Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus. Laryngoscope 1999; 109: 266–274.

    CAS  PubMed  Article  Google Scholar 

  83. Herzog RW, Yang EY, Couto LB, Hagstrom JN, Elwell D, Fields PA et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 1999; 5: 56–63.

    CAS  Article  PubMed  Google Scholar 

  84. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000; 24: 257–261.

    CAS  PubMed  Article  Google Scholar 

  85. Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther 2004; 15: 93–128.

    PubMed  Article  CAS  Google Scholar 

  86. During MJ, Samulski RJ, Elsworth JD, Kaplitt MG, Leone P, Xiao X et al. In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Therapy 1998; 5: 820–827.

    CAS  PubMed  Article  Google Scholar 

  87. Bankiewicz KS, Forsayeth J, Eberling JL, Sanchez-Pernaute R, Pivirotto P, Bringas J et al. Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther 2006; 14: 564–570.

    CAS  PubMed  Article  Google Scholar 

  88. During MJ, Kaplitt MG, Stern MB, Eidelberg D . Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum Gene Ther 2001; 12: 1589–1591.

    CAS  PubMed  Google Scholar 

  89. Worgall S, Sondhi D, Hackett NR, Kosofsky B, Kekatpure MV, Neyzi N et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008; 19: 463–474.

    CAS  PubMed  Article  Google Scholar 

  90. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 2007; 369: 2097–2105.

    CAS  PubMed  Article  Google Scholar 

  91. Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 2008; 70: 1980–1983.

    CAS  PubMed  Article  Google Scholar 

  92. Bishop KM, Hofer EK, Mehta A, Ramirez A, Sun L, Tuszynski M et al. Therapeutic potential of CERE-110 (AAV2-NGF): targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons. Exp Neurol 2008; 211: 574–584.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Wang L, Nichols TC, Read MS, Bellinger DA, Verma IM . Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther 2000; 1: 154–158.

    CAS  Article  PubMed  Google Scholar 

  94. Gao G, Lu Y, Calcedo R, Grant RL, Bell P, Wang L et al. Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates. Mol Ther 2006; 13: 77–87.

    CAS  Article  PubMed  Google Scholar 

  95. Davidoff AM, Gray JT, Ng CY, Zhang Y, Zhou J, Spence Y et al. Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol Ther 2005; 11: 875–888.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  97. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28: 92–95.

    CAS  PubMed  Google Scholar 

  98. Bennett J, Maguire AM, Cideciyan AV, Schnell M, Glover E, Anand V et al. Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. Proc Natl Acad Sci USA 1999; 96: 9920–9925.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. Jacobson SG, Boye SL, Aleman TS, Conlon TJ, Zeiss CJ, Roman AJ et al. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther 2006; 17: 845–858.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  102. Hauswirth W, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L et al. Phase I trial of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results. Hum Gene Ther 2008.

  103. Kaludov N, Brown KE, Walters RW, Zabner J, Chiorini JA . Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J Virol 2001; 75: 6884–6893.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther 2003; 7: 774–781.

    CAS  PubMed  Article  Google Scholar 

  105. Di Pasquale G, Davidson BL, Stein CS, Martins I, Scudiero D, Monks A et al. Identification of PDGFR as a receptor for AAV-5 transduction. Nat Med 2003; 9: 1306–1312.

    CAS  PubMed  Article  Google Scholar 

  106. Wang Z, Kuhr CS, Allen JM, Blankinship M, Gregorevic P, Chamberlain JS et al. Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol Ther 2007; 15: 1160–1166.

    CAS  PubMed  Article  Google Scholar 

  107. Bish LT, Sleeper MM, Brainard B, Cole S, Russell N, Withnall E et al. Percutaneous transendocardial delivery of self-complementary adeno-associated virus 6 achieves global Cardiac gene transfer in canines. Mol Ther 2008.

  108. Jiang H, Lillicrap D, Patarroyo-White S, Liu T, Qian X, Scallan CD et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood 2006; 108: 107–115.

    CAS  PubMed  Article  Google Scholar 

  109. Wang L, Calcedo R, Nichols TC, Bellinger DA, Dillow A, Verma IM et al. Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood 2005; 105: 3079–3086.

    CAS  PubMed  Article  Google Scholar 

  110. Sarkar R, Mucci M, Addya S, Tetreault R, Bellinger DA, Nichols TC et al. Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Hum Gene Ther 2006; 17: 427–439.

    CAS  Article  PubMed  Google Scholar 

  111. Nathwani AC, Gray JT, McIntosh J, Ng CY, Zhou J, Spence Y et al. Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 2007; 109: 1414–1421.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Nienhuis AW . Discussion of human gene transfer protocol 0707-864: an open-label dose-escalation study of a self-complementary adeno-associated viral vector (scAAV2/8-LPl-hFIXco) for gene therapy of hemophilia B. RAC NIH 2007; http://www4.od.nih.gov/oba/rac/meetings/Dec2007/final_RAC_agenda_dec07.pdf.

  113. Stieger K, Colle MA, Dubreil L, Mendes-Madeira A, Weber M, Le Meur G et al. Subretinal delivery of recombinant AAV serotype 8 vector in dogs results in gene transfer to neurons in the brain. Mol Ther 2008; 16: 916–923.

    CAS  Article  PubMed  Google Scholar 

  114. Mendell JR, Samulski RJ, Xiao X . Discussion of human gene transfer protocol 0410-679: phase I clinical trial of rAAV2.5-CMV-minidystrophin gene vector in duchenne muscular dystrophy. NIH RAC 2004; http://www4.od.nih.gov/oba/rac/minutes/RAC_minutes_12-04.pdf.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 2002; 99: 2670–2676.

    CAS  PubMed  Article  Google Scholar 

  118. Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 2006; 107: 2653–2661.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Nakai H, Fuess S, Storm TA, Muramatsu S, Nara Y, Kay MA . Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J Virol 2005; 79: 214–224.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Zaiss AK, Muruve DA . Immune responses to adeno-associated virus vectors. Curr Gene Ther 2005; 5: 323–331.

    CAS  PubMed  Article  Google Scholar 

  121. Vandenberghe LH, Wilson JM . AAV as an immunogen. Curr Gene Ther 2007; 7: 325–333.

    CAS  PubMed  Article  Google Scholar 

  122. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 2007; 13: 419–422.

    CAS  PubMed  Article  Google Scholar 

  123. Wang L, Figueredo J, Calcedo R, Lin J, Wilson JM . Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum Gene Ther 2007; 18: 185–194.

    CAS  Article  PubMed  Google Scholar 

  124. Li H, Murphy SL, Giles-Davis W, Edmonson S, Xiang Z, Li Y et al. Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol Ther 2007; 15: 792–800.

    CAS  PubMed  Article  Google Scholar 

  125. Li C, Hirsch M, Asokan A, Zeithaml B, Ma H, Kafri T et al. Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J Virol 2007; 81: 7540–7547.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank Maria P Limberis and Sadik Kassim for critical review of the paper. LHV, JMW and GPG hold several patents that are licensed to biotech and pharmaceutical companies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G Gao.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vandenberghe, L., Wilson, J. & Gao, G. Tailoring the AAV vector capsid for gene therapy. Gene Ther 16, 311–319 (2009). https://doi.org/10.1038/gt.2008.170

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.170

Keywords

  • adeno-associated virus
  • aav
  • serotype
  • capsid
  • vector

Further reading

Search

Quick links