Arthritis Gene Therapy Approved in Korea
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.