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La terapia genica nella riparazione cartilaginea

Gene therapy in cartilage damage

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Archivio di Ortopedia e Reumatologia

Abstract

Damaged cartilage has a limited power of regeneration. Although present surgical approaches are often effective, they can’t restore articular cartilage to its normal structure. Cartilage regeneration can be stimulated by gene transfer using vectors. Early studies show how gene therapy is a promising but feasible tool to repair cartilage damage.

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Bibliografia

  1. Evans CH, Robbins PD, Ghivizzani SC et al (1996) Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Hum Gene Ther 7:1261–1280

    Article  CAS  PubMed  Google Scholar 

  2. Evans CH, Robbins PD, Ghivizzani SC et al (2005) Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 102:8698–8703

    Article  CAS  PubMed  Google Scholar 

  3. Evans CH, Gouze JN, Gouze E et al (2004) Osteoarthritis gene therapy. Gene Ther 11:379–389

    Article  CAS  PubMed  Google Scholar 

  4. Ghivizzani SC, Lechman ER, Kang R et al (1998) Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci U S A 95:4613–4618

    Article  CAS  PubMed  Google Scholar 

  5. Trippel SB (1997) Growth factors as therapeutic agents. Instr Course Lect 46:473–476

    CAS  PubMed  Google Scholar 

  6. Lo YY, Cruz TF (1995) Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes. J Biol Chem 270:11727–11730

    Article  CAS  PubMed  Google Scholar 

  7. Shida J, Jingushi S, Izumi T et al (1996) Basic fibroblast growth factor stimulates articular cartilage enlargement in young rats in vivo. J Orthop Res 14:265–272

    Article  CAS  PubMed  Google Scholar 

  8. Trippel SB (1995) Growth factor actions on articular cartilage. J Rheumatol Suppl 43:129–132

    CAS  PubMed  Google Scholar 

  9. Nixon AJ, Fortier LA, Williams J et al (1999) Enhanced repair of extensive articular defects by insulin-like growth factor-I-laden fibrin composites. J Orthop Res 17:475–487

    Article  CAS  PubMed  Google Scholar 

  10. Joyce ME, Roberts AB, Sporn MB et al (1990) Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur. J Cell Biol 110:2195–2207

    Article  CAS  PubMed  Google Scholar 

  11. Hanada K, Solchaga LA, Caplan AI et al (2001) BMP-2 induction and TGF-beta 1 modulation of rat periosteal cell chondrogenesis. J Cell Biochem 81:284–294

    Article  CAS  PubMed  Google Scholar 

  12. Sellers RS, Peluso D, Morris EA (1997) The effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the healing of full-thickness defects of articular cartilage. J Bone Joint Surg Am 79:1452–1463

    CAS  PubMed  Google Scholar 

  13. Asahina I, Sampath TK, Hauschka PV (1996) Human osteogenic protein-1 induces chondroblastic, osteoblastic, and/or adipocytic differentiation of clonal murine target cells. Exp Cell Res 222:38–47

    Article  CAS  PubMed  Google Scholar 

  14. Klein-Nulend J, Louwerse RT, Heyligers IC et al (1998) Osteogenic protein (OP-1, BMP-7) stimulates cartilage differentiation of human and goat perichondrium tissue in vitro. J Biomed Mater Res 40:614–620

    Article  CAS  PubMed  Google Scholar 

  15. Gospodarowicz D (1974) Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 249:123–127

    Article  CAS  PubMed  Google Scholar 

  16. Jentzsch KD, Wellmitz G, Heder G et al (1980) A bovine brain fraction with fibroblast growth factor activity inducing articular cartilage regeneration in vivo. Acta Biol Med Ger 39:967–971

    CAS  PubMed  Google Scholar 

  17. Lotz M (2001) Cytokines in cartilage injury and repair. Clin Orthop 391[Suppl]:108–115

    Google Scholar 

  18. Hickey DG, Frenkel SR, Di Cesare PE (2003) Clinical applications of growth factors for articular cartilage repair. Am J Orthop 32:70–76

    PubMed  Google Scholar 

  19. Hotten GC, Matsumoto T, Kimura M et al (1996) Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs. Growth Factors 13:65–74

    Article  CAS  PubMed  Google Scholar 

  20. Bi W, Deng JM, Zhang Z et al (1999) Sox9 is required for cartilage formation. Nat Genet 22:85–89

    Article  CAS  PubMed  Google Scholar 

  21. Inada M, Yasui T, Nomura S et al (1999) Maturational disturbance of chondrocytes in Cbfa1deficient mice. Dev Dyn 214:279–290

    Article  CAS  PubMed  Google Scholar 

  22. Zhao GQ, Eberspaecher H, Seldin MF et al (1994) The gene for the homeodomain-containing protein Cart-1 is expressed in cells that have a chondrogenic potential during embryonic development. Mech Dev 48:245–254

    Article  CAS  PubMed  Google Scholar 

  23. Sumarsono SH, Wilson TJ, Tymms MJ et al (1996) Down’s syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379:534–537

    Article  CAS  PubMed  Google Scholar 

  24. Hoffmann A, Gross G (2001) BMP signaling pathways in cartilage and bone formation. Crit Rev Eukaryot Gene Expr 11:23–45

    CAS  PubMed  Google Scholar 

  25. Mackie EJ, Thesleff I, Chiquet-Ehrismann R (1987) Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro. J Cell Biol 105:2569–2579

    Article  CAS  PubMed  Google Scholar 

  26. Moser M, Bosserhoff AK, Hunziker EB et al (2002) Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice. Mol Cell Biol 22:1438–1445

    Article  CAS  PubMed  Google Scholar 

  27. Blanco FJ, Ochs RL, Schwarz H et al (1995) Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 146:75–85

    CAS  PubMed  Google Scholar 

  28. Stadler J, Stefanovic-Racic M, Billiar TR et al (1991) Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol 147:3915–3920

    CAS  PubMed  Google Scholar 

  29. Pelletier JP, DiBattista JA, Roughley P et al (1993) Cytokines and inflammation in cartilage degradation. Rheum Dis Clin North Am 19:545–568

    CAS  PubMed  Google Scholar 

  30. Arai Y, Kubo T, Kobayashi K et al (1997) Adenovirus vectormediated gene transduction to chondrocytes: in vitro evaluation of therapeutic efficacy of transforming growth factor-beta 1 and heat shock protein 70 gene transduction. J Rheumatol 24:1787–1795

    CAS  PubMed  Google Scholar 

  31. Bakker AC, Joosten LA, Arntz OJ et al (1997) 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 40:893–900

    Article  CAS  PubMed  Google Scholar 

  32. Bandara G, Mueller GM, Galea-Lauri J et al (1993) Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A 90:10764–10768

    Article  CAS  PubMed  Google Scholar 

  33. Baragi VM, Renkiewicz RR, Jordan H et al (1995) Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest 96:2454–2460

    Article  CAS  PubMed  Google Scholar 

  34. Fleischmann RM, Schechtman J, Bennett R et al (2003) Anakinra, a recombinant human interleukin-1 receptor antagonist [rmetHuIL-1ra], in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48:927–934

    Article  CAS  PubMed  Google Scholar 

  35. Gouze E, Pawliuk R, Pilapil C et al (2002) In vivo gene delivery to synovium by lentiviral vectors. Mol Ther 5:397–404

    Article  CAS  PubMed  Google Scholar 

  36. Gouze E, Pawliuk R, Gouze JN et al (2003) Lentiviral-mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation. Mol Ther 7:460–466

    Article  CAS  PubMed  Google Scholar 

  37. Gouze JN, Gouze E, Palmer GD et al (2003) A comparative study of the inhibitory effects of interleukin-1 receptor antagonist following administration as a recombinant protein or by gene transfer. Arthritis Res Ther 5:301–309

    Article  Google Scholar 

  38. Haupt JL, Frisbie DD, McIlwraith CW et al (2005) Dual transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model. J Orthop Res 23:118–126

    Article  CAS  PubMed  Google Scholar 

  39. Mi Z, Ghivizzani SC, Lechman ER et al (2000) Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum 43:2563–2570

    Article  CAS  PubMed  Google Scholar 

  40. Makarov SS, Olsen JC, Johnston WN et al (1996) Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A 93:402–406

    Article  CAS  PubMed  Google Scholar 

  41. Nixon AJ, Haupt JL, Frisbie DD et al (2005) Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy. Gene Ther 12:177–186

    Article  CAS  PubMed  Google Scholar 

  42. Oligino TJ, Ghivizzani SC, Wolfe D et al (1999) Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis. Gene Ther 6:1713–1720

    Article  CAS  PubMed  Google Scholar 

  43. Pelletier JP, Caron JP, Evans C et al (1997) In vivo suppression of early experimental osteoarthritis by interleukin- 1 receptor antagonist using gene therapy. Arthritis Rheum 40:1012–1019

    Article  CAS  PubMed  Google Scholar 

  44. Rudolphi K, Gerwin N, Verzijl N et al (2003) Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 11:738–746

    Article  CAS  PubMed  Google Scholar 

  45. Robbins PD, Evans CH, Chernajovsky Y (2003) Gene therapy for arthritis. Gene Ther 10:902–911

    Article  CAS  PubMed  Google Scholar 

  46. Dayer JM (2002) Interleukin 1 or tumor necrosis factor-alpha: which is the real target in rheumatoid arthritis? J Rheumatol Suppl 65:10–15

    CAS  PubMed  Google Scholar 

  47. Conway JG, Andrews RC, Beaudet B et al (2001) Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alphaconverting enzyme and matrix metalloproteinases. J Pharmacol Exp Ther 298:900–908

    CAS  PubMed  Google Scholar 

  48. Chernajovsky Y, Adams G, Podhajcer OL et al (1995) Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. Gene Ther 2:731–735

    CAS  PubMed  Google Scholar 

  49. D’Lima DD, Hashimoto S, Chen PC et al (2001) Impact of mechanical trauma on matrix and cells. Clin Orthop 391[Suppl]:90–99

    Google Scholar 

  50. D’Lima DD, Hashimoto S, Chen PC et al (2001) Cartilage injury induces chondrocyte apoptosis. J Bone Joint Surg Am 83[Suppl. 2]:19–21

    PubMed  Google Scholar 

  51. D’Lima DD, Hashimoto S, Chen PC et al (2001) Prevention of chondrocyte apoptosis. J Bone Joint Surg Am 83[Suppl. 2]:25–32

    PubMed  Google Scholar 

  52. Holler N, Kataoka T, Bodmer JL et al (2000) Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors. J Immunol Methods 237:159–173

    Article  CAS  PubMed  Google Scholar 

  53. Lotz M, Hashimoto S, Kuhn K (1999) Mechanisms of chondrocyte apoptosis. Osteoarthritis Cartilage 7:389–391

    Article  CAS  PubMed  Google Scholar 

  54. Miura T, Mattson MP, Rao MS (2004) Cellular lifespan and senescence signaling in embryonic stem cells. Aging Cell 3:333–343

    Article  CAS  PubMed  Google Scholar 

  55. Yao Q, Glorioso JC, Evans CH et al (2000) Adenoviral mediated delivery of FAS ligand to arthritic joints causes extensive apoptosis in the synovial lining. J Gene Med 2:210–219

    Article  CAS  PubMed  Google Scholar 

  56. Yao Q, Wang S, Gambotto A et al (2003) Intra-articular adenoviral-mediated gene transfer of trail induces apoptosis of arthritic rabbit synovium. Gene Ther 10:1055–1060

    Article  CAS  PubMed  Google Scholar 

  57. Imperiale MJ, Kochanek S (2004) Adenovirus vectors: biology, design, and production. Curr Top Microbiol Immunol 273:335–357

    CAS  PubMed  Google Scholar 

  58. Breyer B, Jiang W, Cheng H et al (2001) Adenoviral vector-mediated gene transfer for human gene therapy. Curr Gene Ther 1:149–162

    Article  CAS  PubMed  Google Scholar 

  59. Roy S, Gao G, Lu Y et al (2004) Characterization of a family of chimpanzee adenoviruses and development of molecular clones for gene transfer vectors. Hum Gene Ther 15:519–530

    Article  CAS  PubMed  Google Scholar 

  60. Goncalves MA (2005) Adenoassociated virus: from defective virus to effective vector. Virol J 2:43

    Article  PubMed  Google Scholar 

  61. Tenenbaum L, Lehtonen E, Monahan PE (2003) Evaluation of risks related to the use of adeno-associated virus-based vectors. Curr Gene Ther 3:545–565

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. Samulski RJ (2003) AAV vectors, the future workhorse of human gene therapy. Ernst Schering Res Found Workshop 43:25–40

    CAS  PubMed  Google Scholar 

  64. Burton EA, Bai Q, Goins WF, Glorioso JC (2002) Replication defective genomic herpes simplex vectors: design and production. Curr Opin Biotechnol 13:424–428

    Article  CAS  PubMed  Google Scholar 

  65. Goins WF, Wolfe D, Krisky DM et al (2004) Delivery using herpes simplex virus: an overview. Methods Mol Biol 246:257–299

    CAS  PubMed  Google Scholar 

  66. Glorioso JC, Fink DJ (2004) Herpes vector-mediated gene transfer in treatment of diseases of the nervous system. Annu Rev Microbiol 58:253–271

    Article  CAS  PubMed  Google Scholar 

  67. Dornburg R (2003) The history and principles of retroviral vectors. Front Biosci 8:d818–d835

    Article  CAS  PubMed  Google Scholar 

  68. Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–441

    Article  CAS  PubMed  Google Scholar 

  69. Hu WS, Pathak VK (2000) Design of retroviral vectors and helper cells for gene therapy. Pharmacol Rev 52:493–511

    CAS  PubMed  Google Scholar 

  70. ang Y, Vanin EF, Whitt MA et al (1995) Inducible, highlevel production of infectious murine leukemia retroviral vector particles pseudotyped with vesicular stomatitis virus G envelope protein. Hum Gene Ther 6:1203–1213

    Article  Google Scholar 

  71. Cone RD, Mulligan RC (1984) 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 81:6349–6353

    Article  CAS  PubMed  Google Scholar 

  72. Zufferey R, Dull T, Mandel RJ et al (1998) Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 72:9873–9880

    CAS  PubMed  Google Scholar 

  73. Spitzer D, Hauser H, Wirth D (1999) Complement-protected amphotropic retroviruses from murine packaging cells. Hum Gene Ther 10:1893–1902

    Article  CAS  PubMed  Google Scholar 

  74. Ulrich-Vinther M, Duch MR, Soballe K et al (2004) In vivo gene delivery to articular chondrocytes mediated by an adeno-associated virus vector. J Orthop Res 22:726–734

    Article  CAS  PubMed  Google Scholar 

  75. Ikeda T, Kubo T, Nakanishi T et al (2000) Ex vivo gene delivery using an adenovirus vector in treatment for cartilage defects. J Rheumatol 27:990–996

    CAS  PubMed  Google Scholar 

  76. Glover DJ, Lipps HJ, Jans DA (2005) Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet 6:299–310

    Article  CAS  PubMed  Google Scholar 

  77. Sato Y, Roman M, Tighe H et al (1996) Immunostimulatory DNA sequences necessary for effective intradermal gene immunization. Science 273:352–354

    Article  CAS  PubMed  Google Scholar 

  78. Tranchant I, Thompson B, Nicolazzi C et al (2004) Physicochemical optimisation of plasmid delivery by cationic lipids. J Gene Med 6[Suppl. 1]:24–35

    Article  Google Scholar 

  79. Thomas M, Klibanov AM (2003) Non-viral gene therapy: polycation-mediated DNA delivery. Appl Microbiol Biotechnol 62:27–34

    Article  CAS  PubMed  Google Scholar 

  80. Mehier-Humbert S, Guy RH (2005) Physical methods for gene transfer: improving the kinetics of gene delivery into cells. Adv Drug Deliv Rev 57:733–753

    Article  CAS  PubMed  Google Scholar 

  81. Evans CH, Gouze E, Gouze JN et al (2006) Gene therapeutic approaches-transfer in vivo. Adv Drug Deliv Rev 58:243–258

    Article  CAS  PubMed  Google Scholar 

  82. Frisbie DD, Ghivizzani SC, Robbins PD et al (2002) Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 9:12–20

    Article  CAS  PubMed  Google Scholar 

  83. Cucchiarini M, Madry H, Ma C et al (2005) Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther 12:229–238

    Article  CAS  PubMed  Google Scholar 

  84. Gelse K, Jiang QJ, Aigner T et al (2001) Fibroblast-mediated delivery of growth factor complementary DNA into mouse joints induces chondrogenesis but avoids the disadvantages of direct viral gene transfer. Arthritis Rheum 44:1943–1953

    Article  CAS  PubMed  Google Scholar 

  85. Mi Z, Ghivizzani SC, Lechman E et al (2003) Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. Arthritis Res Ther 5:R132–R139

    Article  CAS  PubMed  Google Scholar 

  86. Pascher A, Palmer GD, Steinert AF et al (2004) Gene delivery to cartilage defects using coagulated bone marrow aspirate. Gene Ther 11:133–141

    Article  CAS  PubMed  Google Scholar 

  87. Evans CH, Pascher A, Betz O et al (2004] Genetically enhanced tissue engineering without cell culture or artificial scaffolds. In: Grodzinsky AJ, Sandell L (Eds.) Orthopaedic tissue engineering. AAOS, Rosemont, Ill.:389–394

    Google Scholar 

  88. Kuo CK, Li WJ, Mauck RL et al (2006) Cartilage tissue engineering: its potential and uses. Curr Opin Rheumatol 18:64–73

    Article  PubMed  Google Scholar 

  89. Shuler FD, Georgescu HI, Niyibizi C et al (2000) Increased matrix synthesis following adenoviral transfer of a transforming growth factor beta1 gene into articular chondrocytes. J Orthop Res 18:585–592

    Article  CAS  PubMed  Google Scholar 

  90. Smith P, Shuler FD, Georgescu HI et al (2000) Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1. Arthritis Rheum 43:1156–1164

    Article  CAS  PubMed  Google Scholar 

  91. Hidaka C, Goodrich LR, Chen CT et al (2003) Acceleration of cartilage repair by genetically modified chondrocytes overexpressing bone morphogenetic protein-7. J Orthop Res 21:573–583

    Article  CAS  PubMed  Google Scholar 

  92. Wakitani S, Mitsuoka T, Nakamura N et al (2004) Autologous bone marrow stromal cell transplantation for repair of fullthickness articular cartilage defects in human patellae: two case reports. Cell Transplant 13:595–600

    Article  PubMed  Google Scholar 

  93. Kuroda R, Ishida K, Matsumoto T et al (2007) Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthritis Cartilage 15:226–231

    Article  CAS  PubMed  Google Scholar 

  94. Hunziker EB (2002) Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage 10:432–463

    Article  CAS  PubMed  Google Scholar 

  95. Mason JM, Grande DA, Barcia M et al (1998) Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: potential utility in gene therapy for osteochondral repair. Gene Ther 5:1098–1104

    Article  CAS  PubMed  Google Scholar 

  96. Yoo JU, Barthel TS, Nishimura K et al (1998) The chondrogenic potential of human bone-marrow-derived mesenchymal progenitor cells. J Bone Joint Surg Am 80:1745–1757

    CAS  PubMed  Google Scholar 

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  1. Dipartimento di Chirurgia, Ortopedia, Traumatologia, Microchirurgia e Riabilitazione, Settore Funzionale di Artroscopia e Chirurgia del Ginocchio, Università degli Studi di Napoli “Federico II”, Napoli, Italy

    D. Rosa, C. D’Esposito, G. Matarazzo & G. Balato

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  1. D. Rosa
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  2. C. D’Esposito
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  3. G. Matarazzo
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  4. G. Balato
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Rosa, D., D’Esposito, C., Matarazzo, G. et al. La terapia genica nella riparazione cartilaginea. Arch Ortop Reumatol 120, 17–20 (2009). https://doi.org/10.1007/s10261-009-0044-5

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