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Arthritis Gene Therapy Approved in Korea

Evans, Christopher H. PhD; Ghivizzani, Steven C. PhD; Robbins, Paul D. PhD

JAAOS - Journal of the American Academy of Orthopaedic Surgeons: January 15, 2018 - Volume 26 - Issue 2 - p e36-e38
doi: 10.5435/JAAOS-D-17-00695
On the Horizon From the ORS

From the Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN (Dr. Evans), the Department of Orthopaedics and Rehabilitation, University of Florida College of Medicine, Gainesville, FL (Dr. Ghivizzani), and the Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL (Dr. Robbins).

Dr. Evans or an immediate family member serves as a paid consultant to or is an employee of Orthogen AG and TissueGene; has stock or stock options held in Aldabra, Cellastra, Orthogen AG, and TissueGene; and has received nonincome support (such as equipment or services), commercially derived honoraria, or other non–research-related funding (such as paid travel) from Medtronic Sofamor Danek. Dr. Robbins or an immediate family member has stock or stock options held in TissueGene. Neither Dr. Ghivizzani nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article.

On July 12, 2017, South Korea approved the world’s first gene therapy for arthritis.1 This product, Invossa (TissueGene), is based on a line of allogeneic human chondrocytes that have been transduced with a retrovirus encoding transforming growth factor-β1.

To avoid possible insertional mutagenesis, the transduced cells are first irradiated at a dose that prevents cell division without limiting transgene expression. The cells are then mixed in a 1:3 ratio with nontransduced, nonirradiated chondrocytes from the same donor before being shipped to the physician for injection into knee joints with moderate osteoarthritis in which standard pharmacologic and physical therapy has been unsuccessful. Invossa was not given disease-modifying osteoarthritis drug (DMOAD) designation.

Invossa has completed phase II trials in the United States.2 Phase III trials are expected to begin in early 2018 under a special protocol assessment agreement with the US FDA. Because genetically modified chondrocytes can be allografted into sites of cartilage damage where they continue to express transgenes,3 this product holds additional potential for cartilage repair. A phase II clinical trial of this application has been completed.4

Only four other gene therapies had previously been authorized by the regulatory authorities of any jurisdiction for any indication: two cancer treatments and two treatments for rare genetic diseases (Table 1). Since then, the FDA has approved the use of chimeric antigen receptor-T lymphocytes (CAR-T cells) for the management of acute lymphoblastic leukemia and large B-cell lymphoma.

Table 1

Table 1

The concept of arthritis gene therapy was first published 25 years ago,5 and the first human clinical trial was published just over a decade ago.6 The latter, also an ex vivo protocol using a retroviral vector, delivered the interleukin-1 receptor antagonist (IL-1Ra) to the metacarpophalangeal joints of patients with rheumatoid arthritis. There has since been a small number of additional clinical trials in arthritis gene therapy2,6-12 (Table 2).

According to, two additional phase I studies are in the pipeline, one for osteoarthritis13 and the other for rheumatoid arthritis.14 Both use adeno-associated virus as the vector to deliver IL-1Ra for osteoarthritis15 and interferon-β for rheumatoid arthritis16 by intra-articular injection.

Table 2

Table 2

Progress in arthritis gene therapy has been slow and fitful.17,18 However, after many reversals, the field of gene therapy as a whole is gaining considerable momentum and attracting the attention of both venture capital and big pharma.19 Thus, there is every expectation that approved genetic medicines will become available for arthritis, musculoskeletal regenerative medicine,20 and various other orthopaedic indications21 in the not too distant future.

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References printed in bold type are those published within the past 5 years.

1. Ji-young S: Korea OKs First Cell Gene Therapy ‘Invossa.’ The Korea Herald. July 12, 2017.
2. Cherian JJ, Parvizi J, Bramlet D, Lee KH, Romness DW, Mont MA: Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage 2015;23(12):2109-2118.26188189
3. Kang R, Marui T, Ghivizzani SC, et al.: Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: A feasibility study. Osteoarthritis Cartilage 1997;5(2):139-143.9135825
4. Kolon Life Science: Efficacy and safety study of TissueGene-C mixed with fibrin-glue for the patients with degenerative arthritis. NLM identifier: NCT01825811. Accessed November 14, 2017.
5. Bandara G, Robbins PD, Georgescu HI, Mueller GM, Glorioso JC, Evans CH: Gene transfer to synoviocytes: Prospects for gene treatment of arthritis. DNA Cell Biol 1992;11(3):227-231.1567555
6. Evans CH, Robbins PD, Ghivizzani SC, et al.: Gene transfer to human joints: Progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 2005;102(24):8698-8703.15939878
7. Wehling P, Reinecke J, Baltzer AW, et al.: Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum Gene Ther 2009;20(2):97-101.18986219
8. Mease PJ, Wei N, Fudman EJ, et al.: Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: Results of a phase 1/2 study. J Rheumatol 2010;37(4):692-703.20032102
9. Mease PJ, Hobbs K, Chalmers A, et al.: Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: A phase 1 dose-escalation safety and tolerability study. Ann Rheum Dis 2009;68(8):1247-1254.18678578
10. Lee MC, Ha CW, Elmallah RK, et al.: A placebo-controlled randomised trial to assess the effect of TGF-ß1-expressing chondrocytes in patients with arthritis of the knee. Bone Joint J 2015;97-B(7):924-932.26130347
11. Ha CW, Cho JJ, Elmallah RK, et al.: A multicenter, single-blind, phase IIa clinical trial to evaluate the efficacy and safety of a cell-mediated gene therapy in degenerative knee arthritis patients. Hum Gene Ther Clin Dev 2015;26(2):125-130.25760423
12. Ha CW, Noh MJ, Choi KB, Lee KH: Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy 2012;14(2):247-256.22242865
13. Mayo Clinic: Safety of intra-articular SC-rAAV2.5IL-Ra in subjects with moderate knee OA (AAVIL-1Ra). NLM identifier: NCT02790723. Accessed November 14, 2017.
14. Arthrogen: ART-I02 in patients with rheumatoid arthritis. NLM identifier: NCT02727764. Accessed November 14, 2017.
15. Wang G, Evans CH, Benson JM, et al.: Safety and biodistribution assessment of sc-rAAV2.5IL-1Ra administered via intra-articular injection in a mono-iodoacetate-induced osteoarthritis rat model. Mol Ther Methods Clin Dev 2016;3:15052.26817025
16. Aalbers CJ, Bevaart L, Loiler S, et al.: Preclinical potency and biodistribution studies of an AAV 5 vector expressing human interferon-β (ART-I02) for local treatment of patients with rheumatoid arthritis. PLoS One 2015;10(6):e0130612.26107769
17. Evans CH, Ghivizzani SC, Robbins PD: Arthritis gene therapy and its tortuous path into the clinic. Transl Res 2013;161(4):205-216.23369825
18. Evans CH, Ghivizzani SC, Robbins PD: Arthritis gene therapy: A brief history and perspective, in Laurence J, Franklin M, eds: Translating Gene Therapy to the Clinic. New York, NY, Academic Press, 2015, pp 85-98.
19. Hanna E, Rémuzat C, Auquier P, Toumi M: Gene therapies development: Slow progress and promising prospect. J Mark Access Health Policy 2017;5(1):1265293.28265348
20. Evans CH, Huard J: Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 2015;11(4):234-242.25776949
21. Evans CH, Ghivizzani SC, Herndon JH, Robbins PD: Gene therapy for the treatment of musculoskeletal diseases. J Am Acad Orthop Surg 2005;13(4):230-242.16112980

translation; novel therapies; gene therapy; arthritis; cartilage; advanced treatments

Copyright 2018 by the American Academy of Orthopaedic Surgeons.