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Physikalische Medizin, Rehabilitationsmedizin, Kurortmedizin 2007; 17(1): 12-19
DOI: 10.1055/s-2007-958633
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Gentherapie für traumatische Defekte des Gelenkknorpels

Gene Therapy of Articular Cartilage defectsH. Madry 1 , P. Wilmes 1 , D. Kohn 1 , M. Cucchiarini 1
  • 1Labor für Experimentelle Orthopädie, Klinik für Orthopädie und Orthopädische Chirurgie, Universitütsklinikum des Saarlandes, Homburg
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Publication History

eingegangen: 12. Juli 2006

angenommen: 21. September 2006

Publication Date:
09 March 2007 (online)

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Zusammenfassung

Traumatische fokale Defekte des hyalinen Gelenkknorpels stellen ein ungelöstes Problem in der klinischen Orthopädie dar. Keine der derzeit verwendeten Therapien führt zu einer kompletten und dauerhaften Knorpelregeneration. Obwohl das Konzept einer Gentherapie für Knorpelschäden elegant erscheint, zeigt die gegenwärtige Forschung, dass die verwendeten Gentransfertechniken an das Problem eines umschriebenen Knorpeldefektes angepasst werden müssen. Insbesondere eine örtlich begrenzte Übertragung der therapeutischen Genkonstrukte in den Defekt ist wünschenswert. Gegenwärtige Strategien sind bestrebt, Signalwege der Knorpelheilung im Defekt zu modulieren. Sie umfassen entweder die Anregung der Zellproliferation, -reifung und der Matrixsynthese über einen direkten Transfer oder durch die Methode der Zelltransplantation. Unter den meistuntersuchten Kandidaten sind es die Polypeptidwachstumfaktoren, die die strukturelle Qualität des Reparaturgewebes verbessert haben. Erst ein besseres Verständnis der grundlegenden wissenschaftlichen Aspekte der Knorpeldefektreparatur, zusammen mit der Identifizierung von zusätzlichen molekularen Zielen und der Entwicklung von verbesserten Gentransfertechniken, kann eine klinische Anwendung der Gentherapie für Knorpeldefekte erlauben. Die ersten experimentellen Ergebnisse geben Anlass zu vorsichtigem Optimismus.

Abstract

Recent advances in gene transfer technology have provided novel tools for its therapeutic use in the regeneration of focal articular cartilage defects. Current strategies aiming at improving chondrogenic pathways in the new repair tissue that fills such defects include the stimulation of chondrocyte proliferation and maturation as well as the stimulation of matrix synthesis via direct or ex vivo approaches. To target gene vectors to cartilage defects, a localized intraarticular delivery into the defect of therapeutic gene constructs is necessary. This review outlines the basic scientific aspects of cartilage defect repair, defines the regenerative options that might be applied, summarizes the progress that has been made to date, and analyses some of the unique obstacles that need to be resolved before a clinical translation of gene therapy for cartilage defects may be considered.

Schlüsselwörter

Gentherapie - Knorpelschaden - Wachstumsfaktoren

Key words

gene therapy - cartilage defects - growth factors

Literatur

  • 1 Adachi N, Sato K, Usas A, Fu FH, Ochi M, Han CW, Niyibizi C, Huard J. Muscle derived, cell based ex vivo gene therapy for treatment of full thickness articular cartilage defects.  J Rheumatol. 2002;  29 ((9)) 1920-1930
    PubMedGoogle Scholar
  • 2 Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC. Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation.  J Cell Biol. 1994;  126 ((6)) 1611-1623
    CrossrefPubMedGoogle Scholar
  • 3 Asahina I, Sampath TK, Hauschka PV. Human osteogenic protein-1 induces chondroblastic, osteoblastic, and/or adipocytic differentiation of clonal murine target cells.  Exp Cell Res. 1996;  222 ((1)) 38-47
    CrossrefPubMedGoogle Scholar
  • 4 Baragi VM, Renkiewicz RR, Qiu L, Brammer D, Riley JM, Sigler RE, Frenkel SR, Amin A, Abramson SB, Roessler BJ. Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo.  Osteoarthritis Cartilage. 1997;  5 ((4)) 275-282
    CrossrefPubMedGoogle Scholar
  • 5 Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation.  Nat Genet. 1999;  22 ((1)) 85-89
    PubMedGoogle Scholar
  • 6 Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation.  N Engl J Med. 1994;  331 ((14)) 889-895
    CrossrefPubMedGoogle Scholar
  • 7 Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation.  Instr Course Lect. 1998;  47 487-504
    PubMedGoogle Scholar
  • 8 Cucchiarini M, Madry H. Gene therapy for cartilage defects.  J Gene Med. 2005;  7 ((12)) 1495-1509
    CrossrefPubMedGoogle Scholar
  • 9 Cucchiarini M, Madry H, Ma C, Thurn T, Zurakowski D, Menger MD, Kohn D, Trippel SB, Terwilliger EF. Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2.  Mol Ther. 2005;  12 ((2)) 229-238
    CrossrefPubMedGoogle Scholar
  • 10 Czitrom AA, Langer F, McKee N, Gross AE. Bone and cartilage allotransplantation. A review of 14 years of research and clinical studies.  Clin Orthop. 1986;  ((208)) 141-145
    PubMedGoogle Scholar
  • 11 Erlacher L, Ng CK, Ullrich R, Krieger S, Luyten FP. Presence of cartilage-derived morphogenetic proteins in articular cartilage and enhancement of matrix replacement in vitro.  Arthritis Rheum. 1998;  41 ((2)) 263-273
    CrossrefPubMedGoogle Scholar
  • 12 Evans CH, Robbins PD, Ghivizzani SC, Herndon JH, Kang R, Bahnson AB, Barranger JA, Elders EM, Gay S, Tomaino MM, Wasko MC, Watkins SC, Whiteside TL, Glorioso JC, Lotze MT, Wright TM. 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. 1996;  7 ((10)) 1261-1280
    PubMedGoogle Scholar
  • 13 Gelse K, Jiang QJ, Aigner T, Ritter T, Wagner K, Poschl E, von der Mark K, Schneider H. Fibroblast-mediated delivery of growth factor complementary DNA into mouse joints induces chondrogenesis but avoids the disadvantages of direct viral gene transfer.  Arthritis Rheum. 2001;  44 ((8)) 1943-1953
    CrossrefPubMedGoogle Scholar
  • 14 Gelse K, von der Mark K, Aigner T, Park J, Schneider H. Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells.  Arthritis Rheum. 2003;  48 ((2)) 430-441
    CrossrefPubMedGoogle Scholar
  • 15 Ghivizzani SC, Lechman ER, Tio C, Mule KM, Chada S, McCormack JE, Evans CH, Robbins PD. Direct retrovirus-mediated gene transfer to the synovium of the rabbit knee: implications for arthritis gene therapy.  Gene Ther. 1997;  4 ((9)) 977-982
    CrossrefPubMedGoogle Scholar
  • 16 Gies T. Ueber Heilung von Knorpelwunden.  Deutsche Zeitschrift für Chirurgie. 1883;  18 8-34
    PubMedGoogle Scholar
  • 17 Goomer RS, Deftos LJ, Terkeltaub R, Maris T, Lee MC, Harwood FL, Amiel D. High-efficiency non-viral transfection of primary chondrocytes and perichondrial cells for ex-vivo gene therapy to repair articular cartilage defects.  Osteoarthritis Cartilage. 2001;  9 ((3)) 248-256
    CrossrefPubMedGoogle Scholar
  • 18 Gouze E, Pawliuk R, Pilapil C, Gouze JN, Fleet C, Palmer GD, Evans CH, Leboulch P, Ghivizzani SC. In vivo gene delivery to synovium by lentiviral vectors.  Mol Ther. 2002;  5 ((4)) 397-404
    CrossrefPubMedGoogle Scholar
  • 19 Grande DA, Mason J, Light E, Dines D. Stem cells as platforms for delivery of genes to enhance cartilage repair.  J Bone Joint Surg Am. 2003;  85-A ((Suppl 2)) 111-116
    PubMedGoogle Scholar
  • 20 Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7.  J Orthop Res. 2003;  21 ((4)) 573-583
    CrossrefPubMedGoogle Scholar
  • 21 Hirschmann F, Verhoeyen E, Wirth D, Bauwens S, Hauser H, Rudert M. Vital marking of articular chondrocytes by retroviral infection using green fluorescence protein.  Osteoarthritis Cartilage. 2002;  10 ((2)) 109-118
    CrossrefPubMedGoogle Scholar
  • 22 Hotten GC, Matsumoto T, Kimura M, Bechtold RF, Kron R, Ohara T, Tanaka H, Satoh Y, Okazaki M, Shirai T, Pan H, Kawai S, Pohl JS, Kudo A. Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs.  Growth Factors. 1996;  13 ((1-2)) 65-74
    CrossrefPubMedGoogle Scholar
  • 23 Hunziker EB, Michel M, Studer D. Ultrastructure of adult human articular cartilage matrix after cryotechnical processing.  Microsc Res Tech. 1997;  37 ((4)) 271-284
    CrossrefPubMedGoogle Scholar
  • 24 Ikeda T, Kubo T, Arai Y, Nakanishi T, Kobayashi K, Takahashi K, Imanishi J, Takigawa M, Hirasawa Y. Adenovirus mediated gene delivery to the joints of guinea pigs.  J Rheumatol. 1998;  25 ((9)) 1666-1673
    PubMedGoogle Scholar
  • 25 Ikeda T, Kubo T, Nakanishi T, Arai Y, Kobayashi K, Mazda O, Ohashi S, Takahashi K, Imanishi J, Takigawa M, Hirasawa Y. Ex vivo gene delivery using an adenovirus vector in treatment for cartilage defects.  J Rheumatol. 2000;  27 ((4)) 990-996
    PubMedGoogle Scholar
  • 26 Jentzsch KD, Wellmitz G, Heder G, Petzold E, Buntrock P, Oehme P. A bovine brain fraction with fibroblast growth factor activity inducing articular cartilage regeneration in vivo.  Acta Biol Med Ger. 1980;  39 ((8-9)) 967-971
    PubMedGoogle Scholar
  • 27 Kang R, Marui T, Ghivizzani SC, Nita IM, Georgescu HI, Suh JK, Robbins PD, Evans CH. Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study.  Osteoarthritis Cartilage. 1997;  5 ((2)) 139-143
    CrossrefPubMedGoogle Scholar
  • 28 Katayama R, Wakitani S, Tsumaki N, Morita Y, Matsushita I, Gejo R, Kimura T. Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow.  Rheumatology (Oxford). 2004;  43 ((8)) 980-985
    CrossrefPubMedGoogle Scholar
  • 29 Kaul G, Cucchiarini M, Arntzen D, Zurakowski D, Menger MD, Kohn D, Trippel SB, Madry H. Local stimulation of articular cartilage repair by transplantation of encapsulated chondrocytes overexpressing human fibroblast growth factor 2 (FGF-2) in vivo.  J Gene Med. 2006;  8 ((1)) 100-111
    CrossrefPubMedGoogle Scholar
  • 30 Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grontvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen O. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial.  J Bone Joint Surg Am. 2004;  86-A ((3)) 455-464
    PubMedGoogle Scholar
  • 31 Kobayashi N, Koshino T, Uesugi M, Yokoo N, Xin KQ, Okuda K, Mizukami H, Ozawa K, Saito T. Gene marking in adeno-associated virus vector infected periosteum derived cells for cartilage repair.  J Rheumatol. 2002;  29 ((10)) 2176-2180
    PubMedGoogle Scholar
  • 32 Lo YY, Cruz TF. Involvement of reactive oxygen species in cytokine and growth factor induction of c-fos expression in chondrocytes.  J Biol Chem. 1995;  270 ((20)) 11727-11730
    CrossrefPubMedGoogle Scholar
  • 33 Madry H, Cucchiarini M, Stein U, Remberger K, Menger MD, Kohn D, Trippel SB. Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid-mediated gene transfer in a gel suspension delivery system.  J Gene Med. 2003;  5 ((6)) 502-509
    CrossrefPubMedGoogle Scholar
  • 34 Madry H, Cucchiarini M, Terwilliger EF, Trippel SB. Efficient and persistent gene transfer into articular cartilage using recombinant adeno-associated virus vectors in vitro and in vivo.  Human Gene Ther. 2003;  14 ((4)) 393-402
    CrossrefPubMedGoogle Scholar
  • 35 Madry H, Kaul G, Cucchiarini M, Stein U, Zurakowski D, Remberger K, Menger MD, Kohn D, Trippel SB. Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I).  Gene Ther. 2005;  12 ((14)) 1171-1179
    CrossrefPubMedGoogle Scholar
  • 36 Mason JM, Breitbart AS, Barcia M, Porti D, Pergolizzi RG, Grande DA. Cartilage and bone regeneration using gene-enhanced tissue engineering.  Clin Orthop. 2000;  ((379 Suppl)) 171-178
    PubMedGoogle Scholar
  • 37 Mason JM, Grande DA, Barcia M, Grant R, Pergolizzi RG, Breitbart AS. Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: potential utility in gene therapy for osteochondral repair.  Gene Ther. 1998;  5 ((8)) 1098-1104
    CrossrefPubMedGoogle Scholar
  • 38 Mi Z, Ghivizzani SC, Lechman E, Glorioso JC, Evans CH, Robbins PD. Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees.  Arthritis Res Ther. 2003;  5 ((3)) 132-139
    CrossrefPubMedGoogle Scholar
  • 39 Mi Z, Ghivizzani SC, Lechman ER, Jaffurs D, Glorioso JC, Evans CH, Robbins PD. Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints.  Arthritis Rheum. 2000;  43 ((11)) 2563-2570
    CrossrefPubMedGoogle Scholar
  • 40 Mierisch CM, Wilson HA, Turner MA, Milbrandt TA, Berthoux L, Hammarskjold ML, Rekosh D, Balian G, Diduch DR. Chondrocyte transplantation into articular cartilage defects with use of calcium alginate: the fate of the cells.  J Bone Joint Surg Am. 2003;  85-A ((9)) 1757-1767
    PubMedGoogle Scholar
  • 41 Nita I, Ghivizzani SC, Galea-Lauri J, Bandara G, Georgescu HI, Robbins PD, Evans CH. Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo.  Arthritis Rheum. 1996;  39 ((5)) 820-828
    CrossrefPubMedGoogle Scholar
  • 42 Noyes FR, Stabler CL. A system for grading articular cartilage lesions at arthroscopy.  Am J Sports Med. 1989;  17 ((4)) 505-513
    CrossrefPubMedGoogle Scholar
  • 43 Ochi M, Uchio Y, Kawasaki K, Wakitani S, Iwasa J. Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee.  J Bone Joint Surg Br. 2002;  84 ((4)) 571-578
    CrossrefPubMedGoogle Scholar
  • 44 O'Driscoll SW. The healing and regeneration of articular cartilage.  J Bone Joint Surg Am. 1998;  80 ((12)) 1795-1712
    PubMedGoogle Scholar
  • 45 O'Driscoll SW, Salter RB. The induction of neochondrogenesis in free intra-articular periosteal autografts under the influence of continuous passive motion. An experimental investigation in the rabbit.  J Bone Joint Surg [Am]. 1984;  66 ((8)) 1248-1257
    PubMedGoogle Scholar
  • 46 Pan RY, Xiao X, Chen SL, Li J, Lin LC, Wang HJ, Tsao YP. Disease-inducible transgene expression from a recombinant adeno-associated virus vector in a rat arthritis model.  J Virol. 1999;  73 ((4)) 3410-3417
    PubMedGoogle Scholar
  • 47 Pascher A, Palmer GD, Steinert A, Oligino T, Gouze E, Gouze JN, Betz O, Spector M, Robbins PD, Evans CH, Ghivizzani SC. Gene delivery to cartilage defects using coagulated bone marrow aspirate.  Gene Ther. 2004;  11 ((2)) 133-141
    CrossrefPubMedGoogle Scholar
  • 48 Perka C, Schultz O, Spitzer RS, Lindenhayn K. The influence of transforming growth factor beta1 on mesenchymal cell repair of full-thickness cartilage defects.  J Biomed Mater Res. 2000;  52 ((3)) 543-552
    PubMedGoogle Scholar
  • 49 Rahfoth B, Weisser J, Sternkopf F, Aigner T, von der Mark K, Brauer R. Transplantation of allograft chondrocytes embedded in agarose gel into cartilage defects of rabbits.  Osteoarthritis Cartilage. 1998;  6 ((1)) 50-65
    CrossrefPubMedGoogle Scholar
  • 50 Roessler BJ, Allen ED, Wilson JM, Hartman JW, Davidson BL. Adenoviral-mediated gene transfer to rabbit synovium in vivo.  J Clin Invest. 1993;  92 ((2)) 1085-1092
    PubMedGoogle Scholar
  • 51 Rogachefsky RA, Dean DD, Howell DS, Altman RD. Treatment of canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate.  Osteoarthritis Cartilage. 1993;  1 ((2)) 105-114
    CrossrefPubMedGoogle Scholar
  • 52 Salter RB. The biologic concept of continuous passive motion of synovial joints. The first 18 years of basic research and its clinical application.  Clin Orthop. 1989;  ((242)) 12-25
    PubMedGoogle Scholar
  • 53 Schaefer D, Martin I, Jundt G, Seidel J, Heberer M, Grodzinsky A, Bergin I, Vunjak-Novakovic G, Freed LE. Tissue-engineered composites for the repair of large osteochondral defects.  Arthritis Rheum. 2002;  46 ((9)) 2524-2534
    CrossrefPubMedGoogle Scholar
  • 54 Seggel R. Experimentelle Beiträge zur Anatomie und Pathologie des Gelenkknorpels. Studien über Knorpelwunden und Defekte.  Deutsche Zeitschrift für Chirurgie. 1904;  21 453-466
    PubMedGoogle Scholar
  • 55 Sellers RS, Peluso D, Morris EA. 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. 1997;  79 ((10)) 1452-1463
    CrossrefPubMedGoogle Scholar
  • 56 Sellers RS, Zhang R, Glasson SS, Kim HD, Peluso D, D'Augusta DA, Beckwith K, Morris EA. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2).  J Bone Joint Surg Am. 2000;  82 ((2)) 151-160
    CrossrefPubMedGoogle Scholar
  • 57 Shida J, Jingushi S, Izumi T, Iwaki A, Sugioka Y. Basic fibroblast growth factor stimulates articular cartilage enlargement in young rats in vivo.  J Orthop Res. 1996;  14 ((2)) 265-272
    CrossrefPubMedGoogle Scholar
  • 58 Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M. et al . Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation.  Lancet. 1994;  343 ((8903)) 950-951
    CrossrefPubMedGoogle Scholar
  • 59 Trippel SB. Growth factor actions on articular cartilage.  J Rheumatol. 1995;  ((Suppl 43)) 129-132
    PubMedGoogle Scholar
  • 60 Trippel SB. Growth factors as therapeutic agents.  Instr Course Lect. 1997;  46 473-476
    PubMedGoogle Scholar
  • 61 Trippel SB, Van Wyk JJ, Foster MB, Svoboda ME. Characterization of a specific somatomedin-c receptor on isolated bovine growth plate chondrocytes.  Endocrinology. 1983;  112 ((6)) 2128-2136
    PubMedGoogle Scholar
  • 62 Trippel SB, Wroblewski J, Makower AM, Whelan MC, Schoenfeld D, Doctrow SR. Regulation of growth-plate chondrocytes by insulin-like growth-factor I and basic fibroblast growth factor.  J Bone Joint Surg Am. 1993;  75 ((2)) 177-189
    PubMedGoogle Scholar
  • 63 Ueblacker P, Wagner B, Kruger A, Vogt S, DeSantis G, Kennerknecht E, Brill T, Hillemanns M, Salzmann GM, Imhoff AB, Plank C, Gansbacher B, Martinek V. Inducible nonviral gene expression in the treatment of osteochondral defects.  Osteoarthritis Cartilage. 2004;  12 ((9)) 711-719
    CrossrefPubMedGoogle Scholar
  • 64 Ulrich-Vinther M, Duch MR, Soballe K, O'Keefe RJ, Schwarz EM, Pedersen FS. In vivo gene delivery to articular chondrocytes mediated by an adeno-associated virus vector.  J Orthop Res. 2004;  22 ((4)) 726-734
    CrossrefPubMedGoogle Scholar
  • 65 Wakitani S, Kimura T, Hirooka A, Ochi T, Yoneda M, Yasui N, Owaki H, Ono K. Repair of rabbit articular surfaces with allograft chondrocytes embedded in collagen gel.  J Bone Joint Surg [Br]. 1989;  71 ((1)) 74-80
    PubMedGoogle Scholar
  • 66 Yokoo N, Saito T, Uesugi M, Kobayashi N, Xin KQ, Okuda K, Mizukami H, Ozawa K, Koshino T. 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)) 164-170
    CrossrefPubMedGoogle Scholar

Korrespondenzadresse

Priv.-Doz. Dr. H. Madry

Labor für Experimentelle Orthopädie

Klinik für Orthopädie und orthopädische Chirurgie

Universitätsklinkum des Saarlandes

66421 Homburg/Saar

Deutschland

Email: hmad@hotmail.com

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