The Marshall R. Urist Young Investigator Award. Orthopaedic applications of gene therapy. From concept to clinic.

Gene therapy offers new possibilities for the clinical management of orthopaedic conditions that are difficult to treat by traditional surgical or medical means. To bring the potential of this novel technology into the clinic, a research program was initiated that aimed to identify orthopaedically useful genes and develop methods for delivering them to suitable sites under conditions in which gene expression remains at therapeutic levels for the appropriate periods of time; this program is now 10 years old. Rheumatoid arthritis was selected as the lead disease. Preclinical studies evaluating the local and systemic delivery of numerous different genes by in vivo and ex vivo methods in murine and lapin models led to the development of a human gene therapy protocol for arthritis. In this protocol, a gene encoding the human interleukin-1 receptor antagonist protein is transferred to the metacarpophalangeal joints of female patients with rheumatoid arthritis. The first patient was treated this way in July 1996. This is not only the first orthopaedic application of human gene therapy, but also the first use of gene therapy approved for a nonlethal disease. In addition to providing additional therapeutic options for the treatment of rheumatoid arthritis, the experimental data from this study suggest that gene transfer approaches may improve the treatment of osteoarthritis, the repair of cartilage, ligaments, tendons, menisci, intervertebral discs and bone, and the management of disorders such as osteoporosis and osteogenesis imperfecta. They also show promise as a means for developing novel and improved animal models of orthopaedic diseases. If the current rate of progress continues, wide clinical application of gene therapy in various orthopaedic indications should occur within the next 5 to 10 years.

[1]  Y. Kaneda,et al.  Transient introduction of a foreign gene into healing rat patellar ligament. , 1996, The Journal of clinical investigation.

[2]  Christian Lattermann,et al.  A gene therapy approach to accelerating bone healing Evaluation of gene expression in a New Zealand white rabbit model , 1999, Knee Surgery, Sports Traumatology, Arthroscopy.

[3]  P. Robbins,et al.  Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study. , 1997, Osteoarthritis and cartilage.

[4]  J. Lou,et al.  In vivo gene transfer and overexpression of focal adhesion kinase (pp125 FAK) mediated by recombinant adenovirus‐induced tendon adhesion formation and epitenon cell change , 1997, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[5]  R. Class,et al.  Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  P. Wooley,et al.  The effect of an interleukin-1 receptor antagonist protein on type II collagen-induced arthritis and antigen-induced arthritis in mice. , 1993, Arthritis and rheumatism.

[7]  P. Robbins,et al.  A 1998 status report on orthopedic gene therapy , 1998 .

[8]  J. Woody,et al.  Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis , 1994, The Lancet.

[9]  P. Robbins,et al.  Prolonged systemic expression of human IL-1 receptor antagonist (hIL-1ra) in mice reconstituted with hematopoietic cells transduced with a retrovirus carrying the hIL-1ra cDNA. , 1995, Gene therapy.

[10]  T Ochi,et al.  A comparison of in vivo gene delivery methods for antisense therapy in ligament healing , 1998, Gene Therapy.

[11]  B. O’Malley,et al.  Gene transfer to synovial cells by intra-articular administration of plasmid DNA. , 1995, Human gene therapy.

[12]  P. Robbins,et al.  Genetically augmented tissue engineering of the musculoskeletal system. , 1999, Clinical orthopaedics and related research.

[13]  Simon C Watkins,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. , 1996, Human gene therapy.

[14]  J. Pelletier,et al.  In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. , 1997, Arthritis and rheumatism.

[15]  P. Robbins,et al.  Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. , 1994, Gene therapy.

[16]  E. Lechman,et al.  Direct retrovirus-mediated gene transfer to the synovium of the rabbit knee: implications for arthritis gene therapy , 1997, Gene Therapy.

[17]  M. Aoki,et al.  Adenovirus‐mediated gene transfer into tendon and tendon sheath , 1996, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[18]  P. Robbins,et al.  Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective. , 1997, Journal of immunology.

[19]  P. Robbins,et al.  Blocking cytokines with genes , 1998, Journal of leukocyte biology.

[20]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[21]  E. Lechman,et al.  Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. , 1999, Journal of immunology.

[22]  P. Robbins,et al.  Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. , 1999, Journal of immunology.

[23]  P. Tak,et al.  Gene therapy in rheumatic diseases. , 2001, Best practice & research. Clinical rheumatology.

[24]  G. Bandara,et al.  Gene transfer to synoviocytes: prospects for gene treatment of arthritis. , 1992, DNA and cell biology.

[25]  L. Moreland,et al.  Biologic agents for treating rheumatoid arthritis. Concepts and progress. , 1997, Arthritis and rheumatism.

[26]  Leaf Huang,et al.  Lipidic vector systems for gene transfer. , 1997, Critical reviews in therapeutic drug carrier systems.

[27]  Simon C Watkins,et al.  Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis. , 1997, Journal of immunology.

[28]  P. Robbins,et al.  Increased matrix synthesis following adenoviral transfer of a transforming growth factor β1 gene into articular chondrocytes , 2000, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[29]  P. Robbins,et al.  Potential role for gene therapy in the enhancement of fracture healing. , 1998, Clinical orthopaedics and related research.

[30]  P. Robbins,et al.  Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing. , 1996, Gene therapy.

[31]  Freddie H. Fu,et al.  Gene therapy for meniscal injury: enhanced synthesis of proteoglycan and collagen by meniscal cells transduced with a TGFbeta(1)gene. , 2000, Osteoarthritis and cartilage.

[32]  G. Campion,et al.  Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. , 1996, Arthritis and rheumatism.

[33]  P. Robbins,et al.  Arthritis: is the cure in your genes? , 1999, The Journal of bone and joint surgery. American volume.

[34]  R. Gorczynski,et al.  Effect of interleukin-6 secreted by engineered human stromal cells on osteoclasts in human bone. , 1999, Bone.

[35]  K. Dolphin.  Complications of postenucleation/evisceration implants. , 1998, Current opinion in ophthalmology.

[36]  A. Baldwin,et al.  Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[37]  C. Evans,et al.  Nitric oxide and arthritis. , 1993, Arthritis and rheumatism.

[38]  G. Bandara,et al.  Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Greenberger,et al.  Effect of rhBMP-2 on the osteogenic potential of bone marrow stromal cells from an osteogenesis imperfecta mouse (oim). , 1997, Bone.

[40]  S. Abramson,et al.  Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. , 1997, Osteoarthritis and cartilage.

[41]  M. Mccarthy.  Gene therapy for rheumatoid arthritis starts clinical trials , 1996, The Lancet.

[42]  G. Bandara,et al.  Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. , 1996, Arthritis and rheumatism.

[43]  E. D. Wolf,et al.  High-velocity microprojectiles for delivering nucleic acids into living cells , 1987, Nature.

[44]  T Ochi,et al.  Early biological effect of in vivo gene transfer of platelet-derived growth factor (PDGF)-B into healing patellar ligament , 1998, Gene Therapy.

[45]  J. Kriegsmann,et al.  A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. , 1994, Arthritis and rheumatism.

[46]  P. Robbins,et al.  Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. , 1996, Journal of immunology.

[47]  P. Robbins,et al.  Potential treatment of osteoarthritis by gene therapy. , 1999, Rheumatic diseases clinics of North America.

[48]  Z Domljan,et al.  Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. , 1998, Arthritis and rheumatism.

[49]  L G Gilbertson,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. , 1999, Spine.

[50]  P. Robbins,et al.  Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. , 1999, Arthritis and rheumatism.

[51]  G. Finerman,et al.  Regional gene therapy with a BMP‐2‐producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[52]  W. B. van den Berg,et al.  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. , 1997, Arthritis and rheumatism.

[53]  K. Takeshita,et al.  Adenovirus vector-mediated gene transduction to chondrocytes: in vitro evaluation of therapeutic efficacy of transforming growth factor-beta 1 and heat shock protein 70 gene transduction. , 1997, The Journal of rheumatology.

[54]  P. Robbins,et al.  Gene therapy in orthopaedics. , 2000, Orthopedic Nursing.

[55]  S. Goldstein,et al.  Potential Role for Direct Gene Transfer in the Enhancement of Fracture Healing , 1998, Clinical orthopaedics and related research.

[56]  P. Robbins,et al.  Constitutive systemic expression of IL-1Ra or soluble TNF receptor by genetically modified hematopoietic cells suppresses LPS induction of IL-6 and IL-10 , 1997, Gene Therapy.

[57]  E. Lechman,et al.  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. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  J. Shiver,et al.  Heterologous and homologous protection against influenza A by DNA vaccination: optimization of DNA vectors. , 1993, DNA and cell biology.

[59]  T. Hardingham,et al.  The effect of recombinant human interleukin 1 receptor antagonist on the induction phase of antigen induced arthritis in the rabbit. , 1994, The Journal of rheumatology.

[60]  M Oyama,et al.  Retrovirally transduced bone marrow stromal cells isolated from a mouse model of human osteogenesis imperfecta (oim) persist in bone and retain the ability to form cartilage and bone after extended passaging , 1999, Gene Therapy.

[61]  E. Tindall,et al.  Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. , 1997, The New England journal of medicine.

[62]  S. Woo,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 , 1999, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[63]  Steven C. Ghivizzani,et al.  Viral vectors for gene therapy. , 1998, Pharmacology & therapeutics.

[64]  P. Robbins,et al.  Possible orthopaedic applications of gene therapy. , 1995, The Journal of bone and joint surgery. American volume.

[65]  James D. Kang,et al.  Adenovirus‐Mediated Gene Transfer to Nucleus Pulposus Cells: Implications for the Treatment of Intervertebral Disc Degeneration , 1998, Spine.

[66]  J. Mier,et al.  Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. , 1992, Cytokine.

[67]  C. Gabay,et al.  Interleukin-1 receptor antagonist: role in biology. , 1998, Annual review of immunology.

[68]  Y. Kaneda,et al.  In vivo direct gene transfer into articular cartilage by intraarticular injection mediated by HVJ (Sendai virus) and liposomes. , 1997, Arthritis and rheumatism.

[69]  P. Robbins,et al.  Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1. , 2000, Arthritis and rheumatism.

[70]  S. Goldstein,et al.  Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.