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Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues

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Abstract

Traditional tissue engineering approaches to the restoration of orthopaedic tissues promise to be expensive and not well suited to treating large numbers of patients. Advances in gene transfer technology offer the prospect of developing expedited techniques in which all manipulations can be performed percutaneously or in a single operation. This rests on the ability of gene delivery to provoke the sustained synthesis of relevant gene products in situ without further intervention. Regulated gene expression is also possible, but its urgency is reduced by our ignorance of exactly what levels and periods of expression are needed for specific gene products. This review describes various strategies by which gene therapy can be used to expedite the repair and regeneration of orthopaedic tissues. Strategies include the direct injection of vectors into sites of injury, the use of genetically modified, allogeneic cell lines and the intra-operative harvest of autologous tissues that are quickly transduced and returned to the body, either intact or following rapid cell isolation. Data obtained from pre-clinical experiments in animal models have provided much encouragement that such approaches may eventually find clinical application in human and veterinary medicine.

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References

  1. Evans CH (2013) Advances in regenerative orthopedics. Mayo Clin Proc 88(11):1323–39

    Article  PubMed  Google Scholar 

  2. Evans CH, Robbins PD (1999) Genetically augmented tissue engineering of the musculoskeletal system. Clinical orthopaedics and related research. (367 Suppl):S410-8.

  3. Evans CH, Ghivizzani SC, The RPD (2003) Nicolas Andry Award. Orthop Genet Ther Clin Orthop Relat Res 2004(429):316–29

    Google Scholar 

  4. Evans CH, Robbins PD (1995) Possible orthopaedic applications of gene therapy. J bone Joint Surg Am Vol 77(7):1103–14

    CAS  Google Scholar 

  5. Evans CH, Palmer GD, Pascher A, Porter R, Kwong FN, Gouze E et al (2007) Facilitated endogenous repair: making tissue engineering simple, practical, and economical. Tissue Eng 13(8):1987–93

    Article  CAS  PubMed  Google Scholar 

  6. Sohier J, Moroni L, van Blitterswijk C, de Groot K, Bezemer JM (2008) Critical factors in the design of growth factor releasing scaffolds for cartilage tissue engineering. Expert Opin Drug Deliv 5(5):543–66

    Article  CAS  PubMed  Google Scholar 

  7. Moutsatsos IK, Turgeman G, Zhou S, Kurkalli BG, Pelled G, Tzur L et al (2001) Exogenously regulated stem cell-mediated gene therapy for bone regeneration. Mol Ther: J Am Soc Gene Ther 3(4):449–61

    Article  CAS  Google Scholar 

  8. Kimelman-Bleich N, Pelled G, Sheyn D, Kallai I, Zilberman Y, Mizrahi O et al (2009) The use of a synthetic oxygen carrier-enriched hydrogel to enhance mesenchymal stem cell-based bone formation in vivo. Biomaterials 30(27):4639–48

    Article  CAS  PubMed  Google Scholar 

  9. Vannucci L, Lai M, Chiuppesi F, Ceccherini-Nelli L, Pistello M (2013) Viral vectors: a look back and ahead on gene transfer technology. New Microbiol 36(1):1–22

    CAS  PubMed  Google Scholar 

  10. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (2013) Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med 15(2):65–77

    Article  CAS  PubMed  Google Scholar 

  11. Wang W, Li W, Ma N, Steinhoff G (2013) Non-viral gene delivery methods. Curr Pharm Biotechnol 14(1):46–60

    CAS  PubMed  Google Scholar 

  12. Lin CY, Lu CH, Luo WY, Chang YH, Sung LY, Chiu HY et al (2010) Baculovirus as a gene delivery vector for cartilage and bone tissue engineering. Curr Gene Ther 10(3):242–54

    Article  CAS  PubMed  Google Scholar 

  13. Lattermann C, Baltzer AW, Zelle BA, Whalen JD, Niyibizi C, Robbins PD et al (2004) Feasibility of percutaneous gene transfer to an atrophic nonunion in a rabbit. Clin Orthop Relat Res 425:237–43

    Article  PubMed  Google Scholar 

  14. Niyibizi C, Baltzer A, Lattermann C, Oyama M, Whalen JD, Robbins PD et al (1998) Potential role for gene therapy in the enhancement of fracture healing. Clinical orthopaedics and related research. (355 Suppl):S148-53.

  15. Betz OB, Betz VM, Nazarian A, Egermann M, Gerstenfeld LC, Einhorn TA et al (2007) Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects. Gene Ther 14(13):1039–44

    Article  CAS  PubMed  Google Scholar 

  16. Betz VM, Betz OB, Glatt V, Gerstenfeld LC, Einhorn TA, Bouxsein ML et al (2007) Healing of segmental bone defects by direct percutaneous gene delivery: effect of vector dose. Hum Gene Ther 18(10):907–15

    Article  CAS  PubMed  Google Scholar 

  17. Betz OB, Betz VM, Nazarian A, Pilapil CG, Vrahas MS, Bouxsein ML et al (2006) Direct percutaneous gene delivery to enhance healing of segmental bone defects. J Bone Joint Surg Am Vol 88(2):355–65

  18. Southwood LL, Frisbie DD, Kawcak CE, Ghivizzani SC, Evans CH, McIlwraith CW (2004) Evaluation of Ad-BMP-2 for enhancing fracture healing in an infected defect fracture rabbit model. J Orthop Res: Off Publ Orthop Res Soc 22(1):66–72

  19. Baltzer AW, Lattermann C, Whalen JD, Braunstein S, Robbins PD, Evans CH (1999) A gene therapy approach to accelerating bone healing. Evaluation of gene expression in a New Zealand white rabbit model. Knee Surg Sports Traumatol Arthrosc: Off J ESSKA 7(3):197–202

    Article  CAS  Google Scholar 

  20. Baltzer AW, Lattermann C, Whalen JD, Wooley P, Weiss K, Grimm M et al (2000) Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther 7(9):734–9

    Article  CAS  PubMed  Google Scholar 

  21. Baltzer AW, Lattermann C, Whalen JD, Ghivizzani S, Wooley P, Krauspe R et al (2000) Potential role of direct adenoviral gene transfer in enhancing fracture repair. Clinical orthopaedics and related research. (379 Suppl):S120-5.

  22. Bertone AL, Pittman DD, Bouxsein ML, Li J, Clancy B, Seeherman HJ (2004) Adenoviral-mediated transfer of human BMP-6 gene accelerates healing in a rabbit ulnar osteotomy model. J Orthop Res: Off Publ Orthop Res Soc 22(6):1261–70

    Article  CAS  Google Scholar 

  23. Menendez MI, Clark DJ, Carlton M, Flanigan DC, Jia G, Sammet S et al (2011) Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthr Cartil / OARS, Osteoarthr Res Soc 19(8):1066–75

    Article  CAS  Google Scholar 

  24. Ishihara A, Zekas LJ, Weisbrode SE, Bertone AL (2010) Comparative efficacy of dermal fibroblast-mediated and direct adenoviral bone morphogenetic protein-2 gene therapy for bone regeneration in an equine rib model. Gene Ther 17(6):733–44

    Article  CAS  PubMed  Google Scholar 

  25. Ishihara A, Shields KM, Litsky AS, Mattoon JS, Weisbrode SE, Bartlett JS et al (2008) Osteogenic gene regulation and relative acceleration of healing by adenoviral-mediated transfer of human BMP-2 or −6 in equine osteotomy and ostectomy models. J Orthop Res: Off Publ Orthop Res Soc 26(6):764–71

    Article  CAS  Google Scholar 

  26. Egermann M, Baltzer AW, Adamaszek S, Evans C, Robbins P, Schneider E et al (2006) Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep. Hum Gene Ther 17(5):507–17

    Article  CAS  PubMed  Google Scholar 

  27. Egermann M, Lill CA, Griesbeck K, Evans CH, Robbins PD, Schneider E et al (2006) Effect of BMP-2 gene transfer on bone healing in sheep. Gene Ther 13(17):1290–9

    Article  CAS  PubMed  Google Scholar 

  28. Cucchiarini M, Madry H (2005) Gene therapy for cartilage defects. J Gene Med 7(12):1495–509

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Madry H, Cucchiarini M, Terwilliger EF, Trippel SB (2003) Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther 14(4):393–402

    Article  CAS  PubMed  Google Scholar 

  31. Watson RS, Broome TA, Levings PP, Rice BL, Kay JD, Smith AD (2013) scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints. Gene Ther 20(6):670–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Madry H, Cucchiarini M, Kaul G, Kohn D, Terwilliger EF, Trippel SB (2004) Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo. Am J Sports Med 32(8):1860–5

    Article  PubMed  Google Scholar 

  33. Goto H, Shuler FD, Lamsam C, Moller HD, Niyibizi C, Fu FH et al (1999) Transfer of lacZ marker gene to the meniscus. J Bone Joint Surg Am Vol 81(7):918–25

    CAS  Google Scholar 

  34. Nishida K, Kang JD, Suh JK, Robbins PD, Evans CH, Gilbertson LG (1998) Adenovirus-mediated gene transfer to nucleus pulposus cells. Implications Treat Intervertebral Disc Degener Spine 23(22):2437–42, discussion 43

    CAS  Google Scholar 

  35. Leckie SK, Bechara BP, Hartman RA, Sowa GA, Woods BI, Coelho JP et al (2012) Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J: Off J N Am Spine Soc 12(1):7–20

    Article  Google Scholar 

  36. Ren S, Liu Y, Ma J, Liu Y, Diao Z, Yang D et al (2013) Treatment of rabbit intervertebral disc degeneration with co-transfection by adeno-associated virus-mediated SOX9 and osteogenic protein-1 double genes in vivo. Int J Mol Med 32(5):1063–8

    CAS  PubMed  Google Scholar 

  37. Le Maitre CL, Hoyland JA, Freemont AJ (2007) Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study. Arthritis Res Ther 9(4):R83

    Article  PubMed Central  PubMed  Google Scholar 

  38. Evans C (2006) Potential biologic therapies for the intervertebral disc. J Bone Joint Surg Am Vol 88(Suppl 2):95–8

    Article  Google Scholar 

  39. Evans CH, Ghivizzani SC, Robbins PD (2013) Arthritis gene therapy and its tortuous path into the clinic. Transl Res:J Lab Clin Med 161(4):205–16

    Article  CAS  Google Scholar 

  40. Hildebrand KA, Frank CB, Hart DA (2004) Gene intervention in ligament and tendon: current status, challenges, future directions. Gene Ther 11(4):368–78

    Article  CAS  PubMed  Google Scholar 

  41. Docheva D, Mueller S, Majewski M, Evans CH (2014) Biologics for tendon repair. Advanced drug delivery reviews. ;In Press.

  42. Kang R, Marui T, Ghivizzani SC, Nita IM, Georgescu HI, Suh JK et al (1997) Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study. Osteoarthr Cartil / OARS, Osteoarthr Res Soc 5(2):139–43

    Article  CAS  Google Scholar 

  43. Baragi VM, Renkiewicz RR, Qiu L, Brammer D, Riley JM, Sigler RE et al (1997) Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. Osteoarthr Cartil / OARS, Osteoarthr Res Soc 5(4):275–82

    Article  CAS  Google Scholar 

  44. Brower-Toland BD, Saxer RA, Goodrich LR, Mi Z, Robbins PD, Evans CH et al (2001) Direct adenovirus-mediated insulin-like growth factor I gene transfer enhances transplant chondrocyte function. Hum Gene Ther 12(2):117–29

    Article  CAS  PubMed  Google Scholar 

  45. Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ (2007) Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg British Vol 89(5):672–85

    Article  CAS  Google Scholar 

  46. Nixon AJ, Brower-Toland BD, Bent SJ, Saxer RA, Wilke MJ, Robbins PD et al (2000) Insulinlike growth factor-I gene therapy applications for cartilage repair. Clinical orthopaedics and related research. (379 Suppl):S201-13.

  47. Madry H, Kaul G, Zurakowski D, Vunjak-Novakovic G, Cucchiarini M (2013) Cartilage constructs engineered from chondrocytes overexpressing IGF-I improve the repair of osteochondral defects in a rabbit model. Eur Cells Mater 25:229–47

    CAS  Google Scholar 

  48. Orth P, Kaul G, Cucchiarini M, Zurakowski D, Menger MD, Kohn D et al (2011) Transplanted articular chondrocytes co-overexpressing IGF-I and FGF-2 stimulate cartilage repair in vivo. Knee Surg Sports Traumatol Arthrosc:Off J ESSKA 19(12):2119–30

    Article  Google Scholar 

  49. Che JH, Zhang ZR, Li GZ, Tan WH, Bai XD, Qu FJ (2010) Application of tissue-engineered cartilage with BMP-7 gene to repair knee joint cartilage injury in rabbits. Knee Surg Sports Traumatol Arthrosc:Off J ESSKA 18(4):496–503

    Article  CAS  Google Scholar 

  50. Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ (2003) Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res: Off Publ Orthop Res Soc 21(4):573–83

    Article  CAS  Google Scholar 

  51. Ha CW, Noh MJ, Choi KB, Lee KH (2012) Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy 14(2):247–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP et al (1999) The effect of regional gene therapy with bone morphogenetic protein-2-producing bone-marrow cells on the repair of segmental femoral defects in rats. J Bone Joint Surg Am Vol 81(7):905–17

    CAS  Google Scholar 

  53. Lieberman JR, Le LQ, Wu L, Finerman GA, Berk A, Witte ON et al (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res: Off Publ Orthop Res Soc 16(3):330–9

    Article  CAS  Google Scholar 

  54. Tsuchida H, Hashimoto J, Crawford E, Manske P, Lou J (2003) Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats. J Orthop Res: Off Publ Orthop Res Soc 21(1):44–53

    Article  Google Scholar 

  55. Sonnet C, Simpson CL, Olabisi RM, Sullivan K, Lazard Z, Gugala Z et al (2013) Rapid healing of femoral defects in rats with low dose sustained BMP2 expression from PEGDA hydrogel microspheres. J Orthop Res: Off Publ Orthop Res Soc 31(10):1597–604

    Article  CAS  Google Scholar 

  56. Virk MS, Sugiyama O, Park SH, Gambhir SS, Adams DJ, Drissi H et al (2011) “Same day” ex-vivo regional gene therapy: a novel strategy to enhance bone repair. Mol Ther:J Am Soc Gene Ther 19(5):960–8

    Article  CAS  Google Scholar 

  57. Schinhan M, Mueller AM, Liu F, Shen Z, Porter RM, Windhager R et al (2012) Fibrin-encapsulated, genetically modified adipose-derived stem cells for use in tissue repair (abstract). J Tissue Eng Regen Med 6:265

    Google Scholar 

  58. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–7

    Article  CAS  PubMed  Google Scholar 

  59. Forsberg JA, Pepek JM, Wagner S, Wilson K, Flint J, Andersen RC et al (2009) Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors. J Bone Joint Surg Am Vol 91(5):1084–91

    Article  Google Scholar 

  60. Zeckey C, Hildebrand F, Frink M, Krettek C (2011) Heterotopic ossifications following implant surgery–epidemiology, therapeutical approaches and current concepts. Semin Immunopathol 33(3):273–86

    Article  PubMed  Google Scholar 

  61. Evans CH, Liu FJ, Glatt V, Hoyland JA, Kirker-Head C, Walsh A et al (2009) Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur Cells Mat 18:96–111

    CAS  Google Scholar 

  62. Pascher A, Palmer GD, Steinert A, Oligino T, Gouze E, Gouze JN et al (2004) Gene delivery to cartilage defects using coagulated bone marrow aspirate. Gene Ther 11(2):133–41

    Article  CAS  PubMed  Google Scholar 

  63. Neumann AJ, Schroeder J, Alini M, Archer CW, Stoddart MJ (2013) Enhanced adenovirus transduction of hMSCs using 3D hydrogel cell carriers. Mol Biotechnol 53(2):207–16

    Article  CAS  PubMed  Google Scholar 

  64. Ivkovic A, Pascher A, Hudetz D, Maticic D, Jelic M, Dickinson S et al (2010) Articular cartilage repair by genetically modified bone marrow aspirate in sheep. Gene Ther 17(6):779–89

    Article  CAS  PubMed  Google Scholar 

  65. Evans CH, Ghivizzani SC, Robbins PD (2012) Orthopedic gene therapy–lost in translation? J Cell Physiol 227(2):416–20

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Buning H (2013) Gene therapy enters the pharma market: the short story of a long journey. EMBO Mol Med 5(1):1–3

    Article  PubMed Central  PubMed  Google Scholar 

  67. Wehling P, Reinecke J, Baltzer AW, Granrath M, Schulitz KP, Schultz C et al (2009) Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum Gene Ther 20(2):97–101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Evans CH, Robbins PD, Ghivizzani SC, Wasko MC, Tomaino MM, Kang R et al (2005) Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 102(24):8698–703

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E et al (2009) 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 68(8):1247–54

    Article  CAS  PubMed  Google Scholar 

  70. Mease PJ, Wei N, Fudman EJ, Kivitz AJ, Schechtman J, Trapp RG et al (2010) Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study. J Rheumatol 37(4):692–703

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The author’s work in this area has been funded by the AO Foundation and NIH grant numbers R01AR50243 and AR 052809. Declan Devine, PhD is thanked for advice and discussion.

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Evans, C. Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues. International Orthopaedics (SICOT) 38, 1761–1769 (2014). https://doi.org/10.1007/s00264-014-2423-x

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