Gentherapie von Knorpelgewebe

Zusammenfassung

Ziel: Weder die Spontanheilung noch die derzeit klinisch angewandten operativen Behandlungskonzepte führen bei Knorpelschäden in tragenden Gelenkabschnitten zu einem befriedigenden Heilungsergebnis mit einem dauerhaft belastbaren hyalinem Knorpelregenerat. Methode: Eine der aussichtsreichsten neuen Techniken zur Ergänzung und Modifikation bestehender Behandlungsmethoden bei Gelenkknorpelläsionen stellt die Gentherapie dar. Autogene Zellen synthetisieren und exprimieren über längere Zeit nach Einschleusen entsprechender Gensegmente vermehrt Wachstumsfaktoren, so dass eine gewebetypische Differenzierung induziert werden kann. Ergebnisse: Die am längsten anhaltende Expression von transferierten Genen, nämlich bis zu einem Jahr nach der Injektion, wurde bisher in Nucleus Pulposus Zellen von Zwischenwirbelscheiben beobachtet. Neuere Untersuchungen zeigen, dass nicht nur Knorpelzellen sondern auch aus Skelettmuskulatur isolierte Zellen in der Lage sind therapeutische Gene zur Knorpelregeneration aufzunehmen und spezifische Faktoren zu exprimieren. Pluripotente mesenchymale Stammzellen aus Skelettmuskulatur isoliert und ex vivo vermehrt können unter dem Einfluss von Faktoren zu hyalinem Knorpel differenzieren und Knorpeldefekte in Kombination mit biokompatiblen Trägermaterialien auffüllen. Schlussfolgerung: Die klinische Anwendung dieser erfolgversprechenden Techniken ist in der nächsten Dekade zu erwarten. Es wird daher der derzeitige Stand des Gentransfers und die Ansätze zur Fortentwicklung mit den Auswirkungen auf die rekonstruktive Gelenkchirurgie dargestellt.

Abstract

Aim: Articular cartilage has very limited intrinsic healing capacity. Although numerous attempts to repair full-thickness articular cartilage defects have been conducted, no methods have successfully regenerated long-lasting hyaline cartilage. One of the most promising procedures for cartilage repair is tissue engineering accompanied by gene therapy. Method: With gene therapy, genes encoding for therapeutic growth factors can be expressed at a high level in the injured site for an extended period of time. Chondrocytes have been intensively studied for cell transplantation in articular cartilage defects. Results: However, recent studies have shown that chondrocytes are not the only candidate for cartilage repair. Muscle-derived cells have been found capable of delivering genes and represent a good vehicle to deliver therapeutic genes to improve cartilage repair. More importantly, recent studies have suggested the presence of pluripotent stem cells in muscle-derived cells. Conclusion: New techniques of cell therapy and molecular medicine for the treatment of cartilage lesions are currently undergoing clinical trials. This paper will summarize the current status of gene therapy for cartilage repair and its future application.

Schlüsselwörter

Gentherapie - Knorpel - Arthrose - Stammzellen

Key words

Gene therapy - Cartilage - Arthritis - Stem cells - Muscle-derived cells

Literatur

• 1 Jackson D W, Halbrecht J, Proctor C, Van Sickle D, Simon T M. Assessment of donor cell and matrix survival in fresh articular cartilage allografts in a goat model.  J Orthop Res. 1996;  14: 255-264
• 2 Altman R D, Kates J, Chun L E, Dean D D, Eyre D. Preliminary observations of chondral abrasion in a canine model.  Ann Rheum Dis. 1992;  51: 1056-1062
• 3 Friedman M J, Berasi C C, Fox J M, Del Pizzo W, Snyder S J, Ferkel R D. Preliminary results with abrasion arthroplasty in the osteoarthritic knee.  Clin Orthop. 1984;  200-205
• 4 Bentley G, Greer R B. Homotransplantation of isolated epiphyseal and articular cartilage chondrocytes into joint surfaces of rabbits.  Nature. 1971;  230: 385-388
• 5 Ficat R P, Ficat C, Gedeon P, Toussaint J B. Spongialization: a new treatment for diseased patellae.  Clin Orthop. 1979;  74-83
• 6 Breinan H A, Minas T, Hsu H P, Nehrer S, Sledge C B, Spector M. Effect of cultured autologous chondrocytes on repair of chondral defects in a canine model.  J Bone Joint Surg Am. 1997;  79: 1439-1451
• 7 Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte Transplantation [see comments].  N Engl J Med. 1994;  331: 889-895
• 8 Brittberg M, Nilsson A, Lindahl A, Ohlsson C, Peterson L. Rabbit articular cartilage defects treated with autologous cultured chondrocytes.  Clin Orthop. 1996;  270-283
• 9 Grande D A, Pitman M I, Peterson L, Menche D, Klein M. The repair of experimentally produced defects in rabbit articular cartilage by autologous chondrocyte Transplantation.  J Orthop Res. 1989;  7: 208-218
• 10 Mont M A, Jones L C, Vogelstein B N, Hungerford D S. Evidence of Inappropriate Application of Autologous Cartilage Transplantation Therapy in an Uncontrolled Environment [(GENERIC) Ref Type: Magazine Article].  Am J Sports Med. 1999;  27 (5): 617-620
• 11 Horas U, Schnettler R, Pelinkovic D, Herr G, Aigner T. Knorpelknochentransplantation versus autologer Knorpeltransplantation.  Chirurg. 2000;  71: 1090-1097
• 12 O’Driscoll S W, Keeley F W, Salter R B. The chondrogenic potential of free autogenous periosteal grafts for biological resurfacing of major full-thickness defects in joint surfaces under the influence of continuous passive motion. An experimental investigation in the rabbit.  J Bone Joint Surg Am. 1986;  68: 1017-1035
• 13 Delaney J P, O’Driscoll S W, Salter R B. Neochondrogenesis in free intraarticular periosteal autografts in an immobilized and paralyzed limb. An experimental investigation in the rabbit.  Clin Orthop. 1989;  278-282
• 14 Homminga G N, Bulstra S K, Kuijer R, van der Linden A J. Repair of sheep articular cartilage defects with a rabbit costal perichondrial graft.  Acta Orthop Scand. 1991;  62: 415-418
• 15 Chu C R, Convery F R, Akeson W H, Meyers M, Amiel D. Articular cartilage Transplantation. Clinical results in the knee.  Clin Orthop. 1999;  159-168
• 16 Garrett J C. Fresh osteochondral allografts for treatment of articular defects in osteochondritis dissecans of the lateral femoral condyle in adults.  Clin Orthop. 1994;  33-37
• 17 Ghazavi M T, Pritzker K P, Davis A M, Gross A E. Fresh osteochondral allografts for post-traumatic osteochondral defects of the knee.  J Bone Joint Surg Br. 1997;  79: 1008-1013
• 18 Meyers M H, Akeson W, Convery F R. Resurfacing the knee with fresh osteochondral allograft.  J Bone Joint Surg Am. 1989;  71-A: 704-713
• 19 Morales T I, Roberts A B. Transforming growth factor beta regulates the metabolism of proteoglycans in bovine cartilage organ cultures.  J Biol Chem. 1988;  263: 12 828-12 831
• 20 Redini F, Galera P, Mauviel A, Loyau G, Pujol J P. Transforming growth factor beta stimulates collagen and glycosaminoglycan biosynthesis in cultured rabbit articular chondrocytes.  FEBS Lett. 1988;  234: 172-176
• 21 Humbel R E. Insulin-like growth factors I and II.  Eur J Biochem. 1990;  190: 445-462
• 22 Tyler J A. Insulin-like growth factor I can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines.  Biochem J. 1989;  260: 543-548
• 23 Pelletier J P, Caron J P, Evans C, Robbins P D, Georgescu H I, Jovanovic D, Fernandes J C, Martel-Pelletier J. In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy.  Am J Pathol. 1997;  40: 1012-1019
• 24 van Beuningen H M, van der Kraan P M, Arntz O J, van den Berg W B. Transforming growth factor-beta 1 stimulates articular chondrocyte proteoglycan synthesis and induces osteophyte formation in the murine knee joint.  Lab Invest. 1994;  71: 279-290
• 25 Allen J B, Manthey C L, Hand A R, Ohura K, Ellingsworth L, Wahl S M. Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta.  J Exp Med. 1990;  171: 231-247
• 26 Nita I, Ghivizzani S C, Galea-Lauri J, Bandara G, Georgescu H I, Robbins P D, Evans C H. Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo.  Arthritis Rheum. 1996;  39: 820-828
• 27 Evans C H, Robbins P D. Possible orthopaedic applications of gene therapy.  J Bone Joint Surg Am. 1995;  77: 1103-1114
• 28 Felgner P L, Gadek T R, Holm M, Roman R, Chan H W, Wenz M, Northrop J P, Ringold G M, Danielsen M. Lipofection: a highly effizient, lipid-mediated DNA-transfection procedure.  Proc Natl Acad Sci USA. 1987;  84: 7413-7417
• 29 Madry H, Trippel S B. Efficient lipid-mediated gene transfer to articular chondrocytes.  Gene Ther. 2000;  7: 286-291
• 30 Yang N S, Burkholder J, Roberts B, Martinell B, McCabe D. In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment.  Proc Natl Acad Sci USA. 1990;  87: 9568-9572
• 31 Tomita T, Hashimoto H, Tomita N, Morishita R, Lee S B, Hayashida K, Nakamura N, Yonenobu K, Kaneda Y, Ochi T. In vivo direct gene transfer into articular cartilage by intraarticular injection mediated by HVJ (Sendai virus) and liposomes.  Arthritis Rheum. 1997;  40: 901-906
• 32 lkeda T, Kubo T, Nakanishi T, Arai Y, Kobayashi K, Mazda O, Ohashi S, Takahashi K, lmanishi J, Takigawa M, Hirasawa Y. Ex vivo gene delivery using an adenovirus vector in treatment for cartilage defects.  J Rheumatol. 2000;  28: 330-336
• 33 Kang R, Marui T, Ghivizzani S C, Nita I M, Georgescu H I, Suh J K, Robbins P D, Evans C H. Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study.  Osteoarthritis Cartilage. 1997;  5: 139-143
• 34 Baragi V M, Renkiewicz R R, Jordan H, Bonadio J, Hartman J W, Roessler B J. Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation.  J Clin lnvest. 1995;  96: 2454-2460
• 35 Lee J Y, Hall R, Pelinkovic D, Cassinelli Z, Usas A, Gilbertson L, Huard J, Kang J. New Use of a Three-Dimensional Pellet Culture System for Human Intervertebral Disc Cells: lnitial Characterization and Potential Use for Tissue Engineering.  Spine. 2001;  26: 2316-2322
• 36 Moon S H, Gilbertson L G, Nishida K, Knaub M, Muzzonigro T, Robbins P D, Evans C H, Kang J D. Human intervertebral disc cells are genetically modifiable by adenovirus-mediated gene transfer: implications for the clinical management of intervertebral disc disorders.  Spine. 2000;  10 (Oct. 15, 25): 2573-2579
• 37 Nishida K, Gilbertson L G, Robbins P D, Evans C H, Kang J D. Potential applications of gene therapy to the treatment of intervertebral disc disorders.  Clin Orthop. 2000;  10 (379 Suppl.): 234-241
• 38 Reinecke J A, Wehling P, Robbins P, Evans C H, Sager M, Schulze-Allen G, Koch H. [In vitro transfer of genes in spinal tissue] In vitro Transfer von Genen in spinale Gewebe.  Z Orthop Ihre Grenzgeb. 1997;  135: 412-416
• 39 Evans C H, Robbins P D, Ghivizzani S C, Herndon J H, Kang R, Bahnson A B, Barranger J A, Elders E M, Gay S, Tomaino M M, Wasko M C, Watkins S C, Whiteside T L, Glorioso J C, Lotze M T, Wright T M. 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: 1261-1280
• 40 Whalen J D, Lechman E L, Carlos C A, Weiss K, Kovesdi I, Glorioso J C, Robbins P D, Evans C H. Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws.  J Immunol. 1999;  162: 3625-3632
• 41 Smith P, Shuler F D, Georgescu H I, Ghivizzani S C, Johnstone B, Niyibizi C, Robbins P D, Evans C H. Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1.  Arthritis Rheum. 2000;  43: 1156-1164
• 42 Pan R Y, Chen S L, Xiao X, Liu D W, Peng H J, Tsao Y P. Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist.  Arthritis Rheum. 2000;  43: 289-297
• 43 Arai Y, Kubo T, Fushiki S, Mazda O, Nakai H, lwaki Y, lmanishi J, Hirasawa Y. Gene delivery to human chondrocytes by an adeno associated virus vector.  J Rheumatol. 2000;  27: 979-982
• 44 Eming S A, Morgan J R, Berger A. Genetherapy for tissue repair: approaches and prospects.  Br J Plast Surg. 1997;  50: 491-500
• 45 Adachi N, Pelinkovic D, Lee C W, Fu F H, Huard J. Gene Therapy and Future of Cartilage Repair.  Operative Techniques in Orthopaedics. 2001;  351-358
• 46 Pridie K H. A Method of Resurfacing Osteoarthritic Knee Joints.  J Bone Joint Surg Br. 1959;  41: 618-619
• 47 Pelinkovic D, Lee J Y, Adachi N, Fu F H, Huard J. Muscle-based gene therapy and tissue engineering. Crit.  Rev Eukaryot Gene Expr. 2001;  11 (1.-3.): 121-129
• 48 Bosch P, Musgrave D, Shuler F, Ghivizzani S, Evans C, Robbins P, Huard J. Osteoprogenitor cells in skeletal muscle.  J Orthop Res. 2000;  18: 933-944
• 49 Huard J, Bouchard J P, Roy R, Malouin F, Dansereau G, Labrecque C, Albert N, Richards C L, Lemieux B, Tremblay J P. Human myoblast Transplantation: preliminary results of 4 cases.  Muscle Nerve. 1992;  15: 550-560
• 50 Kasemkijwattana C, Menetrey J, Somogyl G, Moreland M S, Fu F H, Buranapanitkit B, Watkins S C, Huard J. Development of approaches to improve the healing following muscle contusion.  Cell Transplant. 1998;  7: 585-598
• 51 Qu Z, Balkir L, van Deutekom J C, Robbins P D, Pruchnic R, Huard J. Development of approaches to improve cell survival in myoblast transfer therapy.  J Cell Biol. 1998;  142: 1257-1267
• 52 Day C S, Kasemkijwattana C, Menetrey J, Floyd S SJ, Booth D, Moreland M S, Fu F H, Huard J. Myoblast-mediated gene transfer to the joint.  J Orthop Res. 1997;  15: 894-903
• 53 Pelinkovic D, Martinek V, Engelhardt M, Lee J Y, Fu F, Huard J. [Tissue Engineering and Gene Therapy of the Musculoskeletal System with Muscle Derived Cells] Tissue Engineering und Gentherapie des Bewegungsapparates mit Muskelzellen.  Z Orthop Ihre Grenzgeb. 200;  9 (138): 402-406
• 54 Lee J Y, Qu-Petersen Z, Cao B, Kimura S, Jankowski R, Cummins J, Usas A, Gates C, Robbins P, Wernig A, Huard J. Clonal Isolation of Muscle-derived Cells Capable of Enhancing Muscle Regeneration and Bone Healing.  J Cell Biol. 2000;  150: 1085-1100
• 55 Gussoni E, Blau H M, Kunkel L M. The fate of individual myoblasts after Transplantation into muscles of DMD patients.  Nat Med. 1997;  3: 970-977
• 56 Webster C, Pavlath G K, Parks D R, Walsh F S, Blau H M. Isolation of human myoblasts with the fluorescence-activated cell sorter.  Exp Cell Res. 1988;  174: 252-265
• 57 Rando T A, Blau H M. Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy.  J Cell Biol. 1994;  125: 1275-1287