On the Horizon From the ORS
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.
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 ClinicalTrials.gov, 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.
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.
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
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
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
. 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
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