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.

  • Review
  • Published:

Gene Therapy Progress and Prospects: Recombinant adeno-associated virus (rAAV) vectors

Gene Therapy volume 11, pages 805–810 (2004)Cite this article

  • Many new AAV serotypes have been discovered

  • Structural biology of AAV opens the door to new vector designs

  • Receptor-targeted capsid mutants and alternative serotypes broaden the host range for rAAV-mediated gene transfer

  • Postentry limitations to rAAV-mediated gene transfer have been identified, including proteasome-mediated vector degradation and limitations on transcriptional activation

  • New data on the mechanisms of rAAV persistence help define potential risks and benefits of rAAV-mediated transduction

  • Progress in rAAV production technology makes new applications feasible

  • Clinical trials utilizing rAAV are expanded

  • Barriers to rAAV-mediated gene transfer in the clinical setting are identified

  • Barriers to repeated dosing of rAAV

Many new AAV serotypes have been discovered

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Haberman RP, McCown TJ, Samulski RJ . Novel transcriptional regulatory signals in the adeno-associated virus terminal repeat A/D junction element. J Virol 2000; 74: 8732–8739.

    Article  CAS  Google Scholar 

  2. Gao G et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci USA 2003; 100: 6081–6086.

    Article  CAS  Google Scholar 

  3. Xie Q 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.

    Article  CAS  Google Scholar 

  4. Opie SR et al. 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.

    Article  CAS  Google Scholar 

  5. Wu P et al. Mutational analysis of the adeno-associated virus type 2 (AAV2) capsid gene and construction of AAV2 vectors with altered tropism [in process citation]. J Virol 2000; 74: 8635–8647.

    Article  CAS  Google Scholar 

  6. Zabner J 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.

    Article  CAS  Google Scholar 

  7. Kaludov N et al. 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.

    Article  CAS  Google Scholar 

  8. Grimm D et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood 2003; 102: 2412–2419.

    Article  CAS  Google Scholar 

  9. Chao H et al. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther 2000; 2: 619–623.

    Article  CAS  Google Scholar 

  10. Loiler SA et al. Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver. Gene Therapy 2003; 10: 1551–1558.

    Article  CAS  Google Scholar 

  11. Buning H et al. Receptor targeting of adeno-associated virus vectors. Gene Therapy 2003; 10: 1142–1151.

    Article  CAS  Google Scholar 

  12. Rabinowitz JE 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.

    Article  CAS  Google Scholar 

  13. Davidson BL et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000; 97: 3428–3432.

    Article  CAS  Google Scholar 

  14. Duan D et al. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest 2000; 105: 1573–1587.

    Article  CAS  Google Scholar 

  15. Hansen J et al. Impaired intracellular trafficking of adeno-associated virus type 2 vectors limits efficient transduction of murine fibroblasts. J Virol 2000; 74: 992–996.

    Article  CAS  Google Scholar 

  16. Srivastava A . Obstacles to human hematopoietic stem cell transduction by recombinant adeno-associated virus 2 vectors. J Cell Biochem Suppl 2002; 38: 39–45.

    Article  Google Scholar 

  17. Yan Z et al. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J Virol 2002; 76: 2043–2053.

    Article  CAS  Google Scholar 

  18. Bartlett JS, Wilcher R, Samulski RJ . Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. J Virol 2000; 74: 2777–2785.

    Article  CAS  Google Scholar 

  19. Qing K et al. Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression. J Virol 2001; 75: 8968–8976.

    Article  CAS  Google Scholar 

  20. McCarty DM, Monahan PE, Samulski RJ . Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Therapy 2001; 8: 1248–1254.

    Article  CAS  Google Scholar 

  21. Song S, Laipis PJ, Berns KI, Flotte TR . Effect of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle. Proc Natl Acad Sci USA 2001; 98: 4084–4088.

    Article  CAS  Google Scholar 

  22. Yan Z, Ritchie TC, Duan D, Engelhardt JF . Recombinant AAV-mediated gene delivery using dual vector heterodimerization. Methods Enzymol 2002; 346: 334–357.

    Article  CAS  Google Scholar 

  23. Sun L, Li J, Xiao X . Overcoming adeno-associated virus vector size limitation through viral DNA heterodimerization. Nat Med 2000; 6: 599–602.

    Article  CAS  Google Scholar 

  24. Reich SJ et al. Efficient trans-splicing in the retina expands the utility of adeno-associated virus as a vector for gene therapy. Hum Gene Ther 2003; 14: 37–44.

    Article  CAS  Google Scholar 

  25. Zolotukhin S et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods 2002; 28: 158–167.

    Article  CAS  Google Scholar 

  26. Potter M et al. Streamlined large-scale production of recombinant adeno-associated virus (rAAV) vectors. Methods Enzymol 2002; 346: 413–430.

    Article  CAS  Google Scholar 

  27. Gao G et al. Purification of recombinant adeno-associated virus vectors by column chromatography and its performance in vivo [in process citation]. Hum Gene Ther 2000; 11: 2079–2091.

    Article  CAS  Google Scholar 

  28. Beck SE et al. Deposition and expression of aerosolized rAAV vectors in the lungs of Rhesus macaques. Mol Ther 2002; 6: 546–554.

    Article  CAS  Google Scholar 

  29. Acland GM et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28: 92–95.

    CAS  PubMed  Google Scholar 

  30. Owen Rt et al. Gene therapy for pyruvate dehydrogenase E1alpha deficiency using recombinant adeno-associated virus 2 (rAAV2) vectors. Mol Ther 2002; 6: 394–399.

    Article  CAS  Google Scholar 

  31. Miao CH et al. Nonrandom transduction of recombinant adeno-associated virus vectors in mouse hepatocytes in vivo: cell cycling does not influence hepatocyte transduction. J Virol 2000; 74: 3793–3803.

    Article  CAS  Google Scholar 

  32. Nakai H et al. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol 2001; 75: 6969–6976.

    Article  CAS  Google Scholar 

  33. Nakai H 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.

    Article  CAS  Google Scholar 

  34. Song S et al. Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Therapy 2001; 8: 1299–1306.

    Article  CAS  Google Scholar 

  35. Xu L et al. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther 2001; 12: 563–573.

    Article  CAS  Google Scholar 

  36. Flotte TR et al. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum Gene Ther 2003; 14: 1079–1088.

    Article  CAS  Google Scholar 

  37. Wagner JA 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.

    Article  CAS  Google Scholar 

  38. Aitken ML et al. A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease. Hum Gene Ther 2001; 12: 1907–1916.

    Article  CAS  Google Scholar 

  39. Kay MA et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector [see comments]. Nat Genet 2000; 24: 257–261.

    Article  CAS  Google Scholar 

  40. Manno CS et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 2003; 101: 2963–2972.

    Article  CAS  Google Scholar 

  41. Virella-Lowell I et al. Inhibition of recombinant adeno-associated virus (rAAV) transduction by bronchial secretions from cystic fibrosis patients. Gene Therapy 2000; 7: 1783–1789.

    Article  CAS  Google Scholar 

  42. Rooney CP et al. Bronchoalveolar fluid is not a major hindrance to virus-mediated gene therapy in cystic fibrosis. J Virol 2002; 76: 10437–10443.

    Article  CAS  Google Scholar 

  43. Mah C et al. Improved method of recombinant AAV2 delivery for systemic targeted gene therapy. Mol Ther 2002; 6: 106–112.

    Article  CAS  Google Scholar 

  44. Halbert CL et al. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 2000; 74: 1524–1532.

    Article  CAS  Google Scholar 

  45. Rideout III WM et al. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 2002; 109: 17–27.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the NIH (RR16586, HL51811, HL59412, HL69877, EY13729, DK58327), the CF Foundation, the Alpha One Foundation, the Gold Coast CF Guild, the Berbecker Foundation, and Shands Hospital.

Author information

Authors and Affiliations

  1. Department of Pediatrics and the Powell Gene Therapy Center, University of Florida, Gainesville, FL, USA

    T R Flotte

Authors
  1. T R Flotte
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flotte, T. Gene Therapy Progress and Prospects: Recombinant adeno-associated virus (rAAV) vectors. Gene Ther 11, 805–810 (2004). https://doi.org/10.1038/sj.gt.3302233

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302233

Keywords

This article is cited by

Search

Advanced search

Quick links