Acta Chir Orthop Traumatol Cech. 2006; 73(2):115-122 | DOI: 10.55095/achot2006/016
Current Concepts in Gene Therapy of the Musculoskeletal SystemCurrent concepts review
- 1 Department of Orthopaedic Surgery, School of Medicine University of Zagreb, Croatia
- 2 Department of Orthopaedic Surgery, Medical University of Graz, Austria
- 3 Clinical Hospital for Traumatology, Zagreb, Croatia
The purpose of this article is to review the remarkable progress in the field of musculoskeletal system gene therapy. Since the introduction of this concept 15 years much of the preclinical and clinical data have emerged. The original target, rheumatoid arthritis, has been subjected to clinical phase II efficacy protocol, and osteoarthritis gene therapy efficacy is being thoroughly investigated in various animal models. The most promising area of research in this field however, is the tissue repair, because it doesn't require prolonged period of gene expression, local delivery is reasonably simple and it avoids substantial risk associated with systemic delivery, and levels of gene expression don't need to be so finely regulated. Gene transfer is successfully being used to aid the repair and regeneration of bone, cartilage, ligament tendon, meniscus and intervertebral disc. Other potential applications of gene therapy in musculoskeletal system include osteoporosis, aseptic loosening, genetic diseases and tumors. Highly encouraging data gained from these studies have confirmed that gene therapy is a promising therapeutic solution to treat various musculoskeletal system disorders.
Keywords: gene therapy, regeneration, repair, musculoskeletal system, rheumatoid arthritis, bone, cartilage
Accepted: February 13, 2006; Published: April 1, 2006 Show citation
ACS | AIP | APA | ASA | Harvard | Chicago | Chicago Notes | IEEE | ISO690 | MLA | NLM | Turabian | Vancouver |
References
- BALTZER, A. W., WHALEN, J. D., WOOLEY, P., LATTERMAN, C., TRUCHAN, L. M., ROBBINS, P. D. et al.: Gene therapy for osteoporosis: evaluation in a murine ovariectomy model. Gene Ther., 8:1770-1776, 2001.
Go to original source...
Go to PubMed...
- BALTZER, A. W., LIEBERMAN, J. R.: Regional gene therapy to enhance bone repair. Gene Ther., 11:344-350, 2004.
Go to original source...
Go to PubMed...
- CARMODY, E. E., SCHWARZ, E. M., PUZAS, J. E., ROSIER, R. N., O'KEEFE, R. J.: Viral interleukin-10 gene inhibition of inflammation, osteoclastogenesis, and bone resorption in response to titanium particles. Arthritis Rheum., 46:1298-1308, 2002.
Go to original source...
Go to PubMed...
- DJAPIC, T., KUSEC, V., JELIC, M., VUKICEVIC, S., PECINA, M.: Compressed homologous cancellous bone and bone morphogenetic protein (BMP)-7 or bone marrow accelerate healing of long-bone critical defects. Int. Orthop., 27:326-330, 2003.
Go to original source...
Go to PubMed...
- EVANS, C. H., ROBBINS, P. D.: Possible orthopaedic applications of gene therapy. J. Bone Jt Surg., 77:1103-1114, 1995.
Go to original source...
Go to PubMed...
- EVANS, C. H., ROBBINS, P. D., GHIVIZZANI, S. C., HERNDON, J. H., KANG, R., BAHNSON, A. B. et al.: 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, 1996.
Go to original source...
Go to PubMed...
- EVANS, C. H., ROBBINS, P. D.: Gene therapy of arthritis. Intern Med., 38:233-239, 1999.
Go to original source...
Go to PubMed...
- EVANS, C. H., GHIVIZZANI, S. C., HERNDON, J. H., WASKO, M.C., REINECKE, J., WEHLING, P., et al.: Clinical trials in the gene therapy of arthritis. Clin. Orthop., 379:S300-S307, 2000.
Go to original source...
Go to PubMed...
- EVANS, C. H., GHIVIZZANI, S. C., ROBBINS, P. D.: Orthopaedic gene therapy. Clin. Orthop. Relat. Res., 429:316-329, 2004.
Go to original source...
Go to PubMed...
- FERNANDES, J., TARDIF, G., MARTEL-PELLETIER, J., LASCAU-COMAN, V., DUPUIS, M., MOLDOVAN, F., et al.: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Amer. J. Pathol., 154:1159-1169, 1999.
Go to original source...
Go to PubMed...
- FRANCESCHI, R. T., YANG, S., RUTHERFORD, R. B., KREBSBACH, P. H., ZHAO, M., WANG, D.: Gene therapy approaches for bone regeneration. Cells Tissues Organs., 176:95-108, 2004.
Go to original source...
Go to PubMed...
- 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., 48:430-441, 2003.
Go to original source...
Go to PubMed...
- GERICH, T. G., KANG, R., FU, F. H., ROBBINS, P. D., EVANS, C. H.: Gene transfer to the patellar tendon. Knee Surg. Sports Traumatol. Arthrosc., 5:118-123, 1997.
Go to original source...
Go to PubMed...
- GOUZE, J. N., GOUZE, E., PALMER, G. D., LIEW, V. S., PASCHER, A., BETZ, O. B. et al.: 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. Epub., 5:R301-309, 2003.
Go to original source...
Go to PubMed...
- GRANDE, D. A., MASON, J., LIGHT, E., DINES, D.: Stem cells as platforms for delivery of genes to enhance cartilage repair. J. Bone Jt Surg., 85-A (suppl. 2):111-116, 2003.
Go to original source...
Go to PubMed...
- GUNTHER, M., WAGNER, E., OGRIS, M.: Specific targets in tumor tissue for the delivery of therapeutic genes. Curr Med Chem Anti-Canc Agents., 5:157-171, 2005.
Go to original source...
Go to PubMed...
- HELM, G. A., ALDEN, T. D., BERES, E. J., HUDSON, S. B., DAS, S., ENGH, J. A. et al.: Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. J. Neurosurg. Spine, 92:191-196, 2000.
Go to original source...
Go to PubMed...
- HILDEBRAND, K. A., DEIE, M., ALLEN, C. R., SMITH, D. W., GEORGESCU, H. I., EVANS, C. H. et al.: Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury. J. Orthop. Res. 17:37-42, 1999.
Go to original source...
Go to PubMed...
- JELIC, M., PECINA, M., HASPL, M., KOS, J., TAYLOR, K., MATICIC, D. et al.: Regeneration of articular cartilage chondral defects by osteogenic protein-1 (bone morphogenetic protein-7) in sheep. Growth Factors, 19:101-113, 2001.
Go to original source...
Go to PubMed...
- KANG, J. D., GEORGESCU, H. I., MCINTYRE-LARKIN, L., STEFANOVIC-RACIC, M., DONALDSON, W. F. 3rd, EVANS, C. H.: Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine, 21:271-277, 1996.
Go to original source...
Go to PubMed...
- KANG, R., MARUI, T., GHIVIZZANI, S. C., NITA, I. M., GEORGESCU, H. I., SUH, J. K. et al.: Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study. Osteoarthritis Cartilage, 5:139-143, 1997.
Go to original source...
Go to PubMed...
- KIM, D. J., MOON, S. H., KIM, H., KWON, U. H., PARK, M. S., HAN, K. J. et al.: Bone morphogenetic protein-2 facilitates expression of chondrogenic, not osteogenic, phenotype of human intervertebral disc cells. Spine, 28:2679-2684, 2003.
Go to original source...
Go to PubMed...
- KOOSTRA, N. A., VERMA, I. M.: Gene therapy with viral vectors. Ann. Rev. Pharmacol. Toxicol., 43:413-439, 2003.
Go to original source...
Go to PubMed...
- KOSTENUIK, P. J., BOLON, B., MORONY, S., DARIS, M., GENG, Z., CARTER, C. et al.: Gene therapy with human recombinant osteoprotegerin reverses established osteopenia in ovariectomized mice. Bone, 34:656-664, 2004.
Go to original source...
Go to PubMed...
- LEE, D. K., CHOI, K. B., OH, I. S., SONG, S. U., HWANG, S., LIM, C. L. et al.: Continuous transforming growth factor beta1 secretion by cell-mediated gene therapy maintains chondrocyte redifferentiation. Tissue Eng., 11:310-308, 2005.
Go to original source...
Go to PubMed...
- LIEBERMAN, J. R., DALUISKI, A., STEVENSON, S., WU, L., MCALLISTER, P., LEE, Y. P. et al.: 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 Jt Surg., 81-A: 905-917, 1999.
Go to original source...
Go to PubMed...
- MADRY, H., CUCCHIARINI, M., KAUL, G., KOHN, D., TERWILLIGER, E. F., TRIPPEL, S. B.: Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo. Amer. J. Sports Med., 32:1860-1865, 2004.
Go to original source...
Go to PubMed...
- MARTINEK, V., LATTERMAN, C., USAS, A., ABRAMOWITCH, S., WOO, S. L., FU, F. H. et al.: Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study. J. Bone Jt Surg., 84-A:1123-1131, 2002.
Go to original source...
Go to PubMed...
- MI, Z., GHIVIZZANI, S. C., LECHMAN, E., GLORIOSO, J. C., EVANS, C. H., ROBBINS, P. D.: Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum., 43:2563-2570, 2000.
Go to original source...
- MIHELIC, R., PECINA, M., JELIC, M., ZORICIC, S., KUSEC, V., SIMIC, P. et al.: Bone morphogenetic protein-7 (osteogenic protein-1) promotes tendon graft integration in anterior cruciate ligament reconstruction in sheep. Amer. J. Sports Med., 32:1619-1625, 2004.
Go to original source...
Go to PubMed...
- NISHIDA, K., KANG, J. D., GILBERTSON, L. G., MOON, S. H., SUH, J.K., VOGT, M. T. et al.: Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine, 24:2419-2425, 1999.
Go to original source...
Go to PubMed...
- NISHIKAWA, M., HUANG, L.: Nonviral vectors in the new millennium: Delivery barriers in gene transfer. Hum. Gene Ther., 12:861-879, 2001.
Go to original source...
Go to PubMed...
- NITA, I., GHIVIZZANI, S. C., GALEA-LAURI, J., BANDARA, G., GEORGESCU, H. I., ROBBINS, P. D. et al.: Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum., 39:820-828, 1996.
Go to original source...
Go to PubMed...
- PASCHER, A., PALMER, G. D., STEINERT, A., OLIGINO, T., GOUZE, E., GOUZE, J. N., et al.: Gene delivery to cartilage defects using coagulated bone marrow aspirate. Gene Ther., 11:133-141, 2004.
Go to original source...
Go to PubMed...
- PASCHER, A., STEINERT, A. F., PALMER, G. D., BETZ, O., GOUZE, J. N., GOUZE, E. et al.: Enhanced repair of the anterior cruciate ligament by in situ gene transfer: evaluation in an in vitro model. Mol. Ther., 10:327-336, 2004.
Go to original source...
Go to PubMed...
- PAUL, R., HAYDON, R. C., CHENG, H., ISHIKAWA, A., NENADOVICH, N., JIANG, W. et al.: Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine, 28:755-763, 2003.
Go to original source...
Go to PubMed...
- PECINA, M., JELIC, M., MARTINOVIC, S., HASPL, M., VUKICEVIC, S.: Articular cartilage repair: the role of bone morphogenetic proteins. Int. Orthop., 26:131-136, 2002.
Go to original source...
Go to PubMed...
- PECINA, M., HASPL, M., JELIC, M., VUKICEVIC, S.: Repair of a resistant tibial non-union with a recombinant bone morphogenetic protein-7 (rh-BMP-7). Int. Orthop., 27:320-321, 2003.
Go to original source...
Go to PubMed...
- PELINKOVIC, D., LEE, J. Y., ADACHI, N., FU, F. H., HUARD, J.: Muscle-based gene therapy and tissue engineering. Crit. Rev. Eukaryot Gene Expr., 11:121-129, 2001.
Go to original source...
Go to PubMed...
- SHULER, F. D., GEORGESCU, H. I., NIYIBIZI, C., STUDER, R. K., MI, Z., JOHNSTONE, B. et al.: Increased matrix synthesis following adenoviral transfer of a transforming growth factor beta1 gene into articular chondrocytes. J. Orthop. Res., 18:585-592, 2000.
Go to original source...
Go to PubMed...
- STEINERT, A. F., PALMER, G. D., EVANS, C. H.: Gene therapy in the musculoskeletal system. Curr. Opin. Orthop., 15:318-324, 2004.
Go to original source...
- TAKEGAMI, K., THONAR, E. J., AN, H. S., KAMADA, H., MASUDA, K.: Osteogenic protein-1 enhances matrix replenishment by intervertebral disc cells previously exposed to interleukin-1. Spine, 27:1318-1325, 2002.
Go to original source...
Go to PubMed...
- TRIPPEL, S. B., GHIVIZZANI, S. C., NIXON, A. J.: Gene-based approaches for the repair of articular cartilage. Gene Ther., 11:351-359, 2004.
Go to original source...
Go to PubMed...
- ULRICH-VINTHER, M., CARMODY, E. E., GOATER, J. J., S BALLE, K., O'KEEFE, R. J., SCHWARZ, E. M.: Recombinant adenoassociated virus-mediated osteoprotegerin gene therapy inhibits wear debris - induced osteolysis. J. Bone Jt Surg., 84-A: 1405-1412, 2002.
Go to original source...
Go to PubMed...
- URIST, M.: Bone: formation by autoinduction. Science, 150:893-899, 1965.
Go to original source...
Go to PubMed...
- van der LAAN, W. H., QUAX, P. H., SEEMAYER, C. A., HUISMAN, L. G., PIETERMAN, E. J., GRIMBERGEN, J. M. et al.: Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3. Gene Ther., 10:234-242, 2003.
Go to original source...
Go to PubMed...
- VAN DE LOO, F. A., VAN DEN BERG, W. B.: Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators. Rheum. Dis. Clin. N. Amer., 28:127-149, 2002.
Go to original source...
Go to PubMed...
- VUKICEVIC, S., STAVLJENIC, A., PECINA, M.: Discovery and clinical applications of bone morphogenetic proteins. Europ. J. Clin. Chem. Clin. Biochem., 33:661-671, 1995.
Go to original source...
Go to PubMed...
- WALLACH, C. J., SOBAJIMA, S., WATANABE, Y., KIM, J. S., GEORGESCU, H. I., ROBBINS, P. et al.: Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine, 28:2331-2337, 2003.
Go to original source...
Go to PubMed...
- WALTHER, W., STEIN, U.: Viral vectors for gene transfer: a review of their use in the treatment of human diseases. Drugs, 60:249-271, 2000.
Go to original source...
Go to PubMed...
- WATANABE, S., IMAGAWA, T., BOIVIN, G. P., GAO, G., WILSON, J. M., HIRSCH, R.: Adeno associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium. Mol. Ther., 2:147-152, 2000.
Go to original source...
Go to PubMed...
- XIAO, X., LI, J., SAMULSKI, R. J.: Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J. Virol., 70:8098-8108, 1996.
Go to original source...
Go to PubMed...
- YANG, S. Y., MAYTON, L., WU, B., GOATER, J. J., SCHWARZ, E. M., WOOLEY, P. H.: Adeno-associated virus-mediated osteoprotegerin gene transfer protects against particulate polyethylene-induced osteolysis in a murine model. Arthritis Rheum., 46:2514-2523, 2002.
Go to original source...
Go to PubMed...
- ZHANG, X., MAO, Z., YU, C.: Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 receptor antagonist and interleukin-10. J. Orthop. Res., 22:742-750, 2004.
Go to original source...
Go to PubMed...