Skip to main content
SpringerLink
Log in

Gene Therapy in Cartilage Repair and Regeneration

  • Chapter
  • First Online:
Gene Therapy in Reconstructive and Regenerative Surgery

  • 315 Accesses

Abstract

Clinical and translational research for the treatment of articular cartilage disease and injury has demonstrated a continued need for the development of molecular approaches in the last decade. New technological breakthroughs in combining gene and cell therapy have revolutionized cartilage regeneration, resulting in advances never before thought possible. This review covers recent progress in recombinant adeno-associated viral (rAAV) vector-mediated approaches for gene and cell therapy in vivo and ex vivo. In particular, we will discuss the application of the AAV vector for in vivo gene therapy and AAV-based genetic modification of stem cells ex vivo. Moreover, we will also discuss the various approaches to clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Warrington KH Jr, Herzog RW. Treatment of human disease by adeno-associated viral gene transfer. Hum Genet. 2006;119(6):571–603.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang X, Godbey WT. Viral vectors for gene delivery in tissue engineering. Adv Drug Deliv Rev. 2006;58(4):515–34.

    Article  CAS  PubMed  Google Scholar 

  3. Dai J, Rabie AB. The use of recombinant adeno-associated virus for skeletal gene therapy. Orthod Craniofac Res. 2007;10(1):1–14.

    Article  PubMed  Google Scholar 

  4. Atchison RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science. 1965;149:754–6.

    Article  CAS  PubMed  Google Scholar 

  5. 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 U S A. 2002;99(16):10405–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weitzman MD, Kyostio SR, Kotin RM, Owens RA. Adeno-associated virus (AAV) rep proteins mediate complex formation between AAV DNA and its integration site in human DNA. Proc Natl Acad Sci U S A. 1994;91(13):5808–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Flotte TR, Afione SA, Zeitlin PL. Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol. 1994;11(5):517–21.

    Article  CAS  PubMed  Google Scholar 

  8. Cone RD, Mulligan RC. High-efficiency gene transfer into mammalian cells: generation of helper-free recombinant retrovirus with broad mammalian host range. Proc Natl Acad Sci U S A. 1984;81(20):6349–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Luk KD, Chen Y, Cheung KM, Kung HF, Lu WW, Leong JC. Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem Biophys Res Commun. 2003;308(3):636–45.

    Article  CAS  PubMed  Google Scholar 

  10. Ye X, Rivera VM, Zoltick P, Cerasoli F Jr, Schnell MA, Gao G, et al. Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer. Science. 1999;283(5398):88–91.

    Article  CAS  PubMed  Google Scholar 

  11. 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(4):1424–30. https://doi.org/10.1182/blood-2004-06-2501.

    Article  PubMed  CAS  Google Scholar 

  12. 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(4):281–304.

    Article  CAS  PubMed  Google Scholar 

  13. Mori S, Wang L, Takeuchi T, Kanda T. Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization of capsid protein. Virology. 2004;330(2):375–83.

    Article  CAS  PubMed  Google Scholar 

  14. Ding W, Zhang L, Yan Z, Engelhardt JF. Intracellular trafficking of adeno-associated viral vectors. Gene Ther. 2005;12(11):873–80.

    Article  CAS  PubMed  Google Scholar 

  15. Schaffer DV, Maheshri N. Directed evolution of AAV mutants for enhanced gene delivery. Conf Proc IEEE Eng Med Biol Soc. 2004;5:3520–3.

    PubMed  CAS  Google Scholar 

  16. Asuri P, Bartel MA, Vazin T, Jang JH, Wong TB, Schaffer DV. Directed evolution of adeno-associated virus for enhanced gene delivery and gene targeting in human pluripotent stem cells. Mol Ther. 2012;20(2):329–38. https://doi.org/10.1038/mt.2011.255.

    Article  PubMed  CAS  Google Scholar 

  17. 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 retargeting of adeno-associated viruses. J Virol. 2008;82(12):5887–911. https://doi.org/10.1128/JVI.00254-08.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Koerber JT, Jang JH, Schaffer DV. DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther. 2008;16(10):1703–9. https://doi.org/10.1038/mt.2008.167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Adachi K, Nakai H. A new recombinant adeno-associated virus (Aav)-based random peptide display library system: infection-defective Aav1.9-3 as a novel detargeted platform for vector evolution. Gene Ther Regul. 2010;5(1):31–55. https://doi.org/10.1142/S1568558610000197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Jang JH, Koerber JT, Kim JS, Asuri P, Vazin T, Bartel M, et al. An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells. Mol Ther. 2011;19(4):667–75. https://doi.org/10.1038/mt.2010.287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Zhang HG, Xie J, Yang P, Wang Y, Xu L, Liu D, et al. Adeno-associated virus production of soluble tumor necrosis factor receptor neutralizes tumor necrosis factor alpha and reduces arthritis. Hum Gene Ther. 2000;11(17):2431–42.

    Article  CAS  PubMed  Google Scholar 

  22. Pan RY, Chen SL, Xiao X, Liu DW, Peng HJ, Tsao YP. Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist. Arthritis Rheum. 2000;43(2):289–97.

    Article  CAS  PubMed  Google Scholar 

  23. Tak PP, Gerlag DM, Aupperle KR, van de Geest DA, Overbeek M, Bennett BL, et al. Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum. 2001;44(8):1897–907.

    Article  CAS  PubMed  Google Scholar 

  24. Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, et al. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther. 2005;12(2):229–38.

    Article  CAS  PubMed  Google Scholar 

  25. Hiraide A, Yokoo N, Xin KQ, Okuda K, Mizukami H, Ozawa K, et al. Repair of articular cartilage defect by intraarticular administration of basic fibroblast growth factor gene, using adeno-associated virus vector. Hum Gene Ther. 2005;16(12):1413–21.

    Article  CAS  PubMed  Google Scholar 

  26. Ulrich-Vinther M, Stengaard C, Schwarz EM, Goldring MB, Soballe K. Adeno-associated vector mediated gene transfer of transforming growth factor-beta1 to normal and osteoarthritic human chondrocytes stimulates cartilage anabolism. Eur Cell Mater. 2005;10:40–50.

    Article  CAS  PubMed  Google Scholar 

  27. Izal I, Acosta CA, Ripalda P, Zaratiegui M, Ruiz J, Forriol F. IGF-1 gene therapy to protect articular cartilage in a rat model of joint damage. Arch Orthop Trauma Surg. 2008;128(2):239–47.

    Article  PubMed  Google Scholar 

  28. Bakker AC, Joosten LA, Arntz OJ, Helsen MM, Bendele AM, van de Loo FA, et al. Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum. 1997;40(5):893–900.

    Article  CAS  PubMed  Google Scholar 

  29. Kim JM, Jeong JG, Ho SH, Hahn W, Park EJ, Kim S, et al. Protection against collagen-induced arthritis by intramuscular gene therapy with an expression plasmid for the interleukin-1 receptor antagonist. Gene Ther. 2003;10(18):1543–50.

    Article  CAS  PubMed  Google Scholar 

  30. Cottard V, Mulleman D, Bouille P, Mezzina M, Boissier MC, Bessis N. Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. Gene Ther. 2000;7(22):1930–9.

    Article  CAS  PubMed  Google Scholar 

  31. Goater J, Muller R, Kollias G, Firestein GS, Sanz I, O'Keefe RJ, et al. Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. J Rheumatol. 2000;27(4):983–9.

    PubMed  CAS  Google Scholar 

  32. Saidenberg-Kermanac'h N, Bessis N, Deleuze V, Bloquel C, Bureau M, Scherman D, et al. Efficacy of interleukin-10 gene electrotransfer into skeletal muscle in mice with collagen-induced arthritis. J Gene Med. 2003;5(2):164–71.

    Article  CAS  PubMed  Google Scholar 

  33. Apparailly F, Millet V, Noel D, Jacquet C, Sany J, Jorgensen C. Tetracycline-inducible interleukin-10 gene transfer mediated by an adeno-associated virus: application to experimental arthritis. Hum Gene Ther. 2002;13(10):1179–88.

    Article  CAS  PubMed  Google Scholar 

  34. Handel ML, Girgis L. Transcription factors. Best Pract Res Clin Gastroenterol. 2001;15(5):657–75.

    Article  CAS  Google Scholar 

  35. Roshak AK, Callahan JF, Blake SM. Small-molecule inhibitors of NF-kappaB for the treatment of inflammatory joint disease. Curr Opin Pharmacol. 2002;2(3):316–21.

    Article  CAS  PubMed  Google Scholar 

  36. Tas SW, Adriaansen J, Hajji N, Bakker AC, Firestein GS, Vervoordeldonk MJ, et al. Amelioration of arthritis by intraarticular dominant negative Ikk beta gene therapy using adeno-associated virus type 5. Hum Gene Ther. 2006;17(8):821–32.

    Article  CAS  PubMed  Google Scholar 

  37. Firestein GS, Zvaifler NJ. Anticytokine therapy in rheumatoid arthritis. N Engl J Med. 1997;337(3):195–7.

    Article  CAS  PubMed  Google Scholar 

  38. Bessis N, Doucet C, Cottard V, Douar AM, Firat H, Jorgensen C, et al. Gene therapy for rheumatoid arthritis. J Gene Med. 2002;4(6):581–91.

    Article  CAS  PubMed  Google Scholar 

  39. Payne KA, Lee HH, Haleem AM, Martins C, Yuan Z, Qiao C, et al. Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees. Osteoarthr Cartil. 2011;19(8):1058–65. https://doi.org/10.1016/j.joca.2011.04.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Peng H, Huard J. Muscle-derived stem cells for musculoskeletal tissue regeneration and repair. Transpl Immunol. 2004;12(3–4):311–9. https://doi.org/10.1016/j.trim.2003.12.009.

    Article  PubMed  CAS  Google Scholar 

  41. Zheng B, Cao B, Crisan M, Sun B, Li G, Logar A, et al. Prospective identification of myogenic endothelial cells in human skeletal muscle. Nat Biotechnol. 2007;25(9):1025–34.

    Article  CAS  PubMed  Google Scholar 

  42. Salgado AJ, Oliveira JT, Pedro AJ, Reis RL. Adult stem cells in bone and cartilage tissue engineering. Curr Stem Cell Res Ther. 2006;1(3):345–64.

    Article  CAS  PubMed  Google Scholar 

  43. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. 2007;13(10):1219–27. https://doi.org/10.1038/nm1630.

    Article  PubMed  CAS  Google Scholar 

  44. Korbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med. 2003;349(6):570–82. https://doi.org/10.1056/NEJMra022361.

    Article  PubMed  Google Scholar 

  45. Hall VJ, Stojkovic P, Stojkovic M. Using therapeutic cloning to fight human disease: a conundrum or reality? Stem Cells. 2006;24(7):1628–37. https://doi.org/10.1634/stemcells.2005-0592.

    Article  PubMed  Google Scholar 

  46. Kimelman N, Pelled G, Helm GA, Huard J, Schwarz EM, Gazit D. Review: gene- and stem cell-based therapeutics for bone regeneration and repair. Tissue Eng. 2007;13(6):1135–50.

    Article  CAS  PubMed  Google Scholar 

  47. Yokoo N, Saito T, Uesugi M, Kobayashi N, Xin KQ, Okuda K, et al. Repair of articular cartilage defect by autologous transplantation of basic fibroblast growth factor gene-transduced chondrocytes with adeno-associated virus vector. Arthritis Rheum. 2005;52(1):164–70. https://doi.org/10.1002/art.20739.

    Article  PubMed  CAS  Google Scholar 

  48. Pagnotto MR, Wang Z, Karpie JC, Ferretti M, Xiao X, Chu CR. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 2007;14(10):804–13.

    Article  CAS  PubMed  Google Scholar 

  49. Frisch J, Venkatesan JK, Rey-Rico A, Schmitt G, Madry H, Cucchiarini M. Influence of insulin-like growth factor I overexpression via recombinant adeno-associated vector gene transfer upon the biological activities and differentiation potential of human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 2014;5(4):103. https://doi.org/10.1186/scrt491.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Tang Y, Wang B. Gene- and stem cell-based therapeutics for cartilage regeneration and repair. Stem Cell Res Ther. 2015;6:78. https://doi.org/10.1186/s13287-015-0058-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Moutsatsos IK, Turgeman G, Zhou S, Kurkalli BG, Pelled G, Tzur L, et al. Exogenously regulated stem cell-mediated gene therapy for bone regeneration. Mol Ther. 2001;3(4):449–61. https://doi.org/10.1006/mthe.2001.0291.

    Article  PubMed  CAS  Google Scholar 

  52. Allay JA, Sleep S, Long S, Tillman DM, Clark R, Carney G, et al. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial. Hum Gene Ther. 2011;22(5):595–604. https://doi.org/10.1089/hum.2010.202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Anklesaria P, Heald EA, Mease JP. Intra-articular administration of a recombinant adeno-associated vector containing a TNF antagonist gene was safe, well tolerated and demonstrated trend in clinical response in subjects with inflammatory arthritis. In: 11th American Society of Gene Therapy annual meeting; May 28–June 1; Boston, MA, US; 2008.

    Google Scholar 

  54. Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, et al. Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis. 2009;68(8):1247–54. https://doi.org/10.1136/ard.2008.089375.

    Article  PubMed  CAS  Google Scholar 

  55. Kaiser J. Clinical research. Death prompts a review of gene therapy vector. Science. 2007;317(5838):580. https://doi.org/10.1126/science.317.5838.580.

    Article  PubMed  CAS  Google Scholar 

  56. Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy's first death. Arthritis Res Ther. 2008;10(3):110. https://doi.org/10.1186/ar2411.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, et al. Investigation of the cause of death in a gene-therapy trial. N Engl J Med. 2009;361(2):161–9.

    Article  CAS  PubMed  Google Scholar 

  58. Evans CH, Ghivizzani SC, Robbins PD. Getting arthritis gene therapy into the clinic. Nat Rev Rheumatol. 2011;7(4):244–9. https://doi.org/10.1038/nrrheum.2010.193.

    Article  PubMed  CAS  Google Scholar 

  59. Evans CH, Ghivizzani SC, Gouze E, Rediske JJ, Schwarz EM, Robbins PD. The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics. Arthritis Res Ther. 2005;7(6):273–8.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge Ms. Anna T. Dzuricky, University of Pittsburgh Swanson School of Engineering, for reviewing and editing this manuscript.

Author information

Authors and Affiliations

  1. University of Pittsburgh, Pittsburgh, PA, USA

    Sheri Wang

  2. Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Bing Wang

Authors
  1. Sheri Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bing Wang .

Editor information

Editors and Affiliations

  1. Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Giorgio Giatsidis

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wang, S., Wang, B. (2018). Gene Therapy in Cartilage Repair and Regeneration. In: Giatsidis, G. (eds) Gene Therapy in Reconstructive and Regenerative Surgery. Springer, Cham. https://doi.org/10.1007/978-3-319-78957-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78957-6_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-78956-9

  • Online ISBN: 978-3-319-78957-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation