This application requests funding to help defray the costs of conducting the first human trial in which a potentially therapeutic agent will be transferred to a joint. The protocol was approved by the Recombinant DNA Advisory Committee (RAC) of the NIH in June, 1994; a pre-IND meeting with the FDA was held in 10/94 and the IND itself is in the process of being filed. The applicants propose to use a replication-defective retrovirus (MFG) carrying a cDNA encoding the human interleukin-1 receptor antagonist protein (IRAP) to transduce autologous human synovial cells grown ex vivo, and then to reinject the cells into metacarpaphalageal joints (MCP) in 6 post-menopausal patients with chronic rheumatoid arthritis rheumatoid arthritis (RA).
The Specific Aims are to: 1) establish synovial cell cultures from biopsies from MCP joints from 6 patients with RA and transduce the cells with a replication-defective retrovirus (MFG) carrying a cDNA encoding the human IRAP; 2) transfer the autologous transduced synoviocytes to MCP joints of patients 1 week before MCP arthroplasty; and 3) after 1 week, at the time of joint replacement surgery, lavages will be performed and periarticular tissues recovered to determine whether the IRAP gene has been successfully transferred to the synovium and expressed intrarticularly, and whether a local biological response to the transgene product has occurred based on evaluation of the expression pattern of cytokines and inflammatory markers, and whether there has been changes in articular cartilage glycosaminoglycan (GAG) synthesis. The IRAP was selected because it is a naturally occurring antagonist of IL-1alpha and IL-1beta, cytokines that play a role in a variety of immune and inflammatory diosorders. IRAP competes for binding to the IL-1 receptor but fails to transduce biological responses. The applicants suggest that the proposed human studies should advance the development of gene treatments for arthritis and other diseases of bones and joints.
| Evans, Christopher H; Huard, Johnny (2015) Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 11:234-42 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2013) Arthritis gene therapy and its tortuous path into the clinic. Transl Res 161:205-16 |
| Evans, C H; Ghivizzani, S C; Robbins, P D (2012) Orthopedic gene therapy--lost in translation? J Cell Physiol 227:416-20 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2011) Getting arthritis gene therapy into the clinic. Nat Rev Rheumatol 7:244-9 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2009) Gene therapy of the rheumatic diseases: 1998 to 2008. Arthritis Res Ther 11:209 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2009) Orthopedic gene therapy in 2008. Mol Ther 17:231-44 |
| Wehling, Peter; Reinecke, Julio; Baltzer, Axel W A et al. (2009) Clinical responses to gene therapy in joints of two subjects with rheumatoid arthritis. Hum Gene Ther 20:97-101 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2008) Arthritis gene therapy's first death. Arthritis Res Ther 10:110 |
| Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2006) Gene therapy for arthritis: what next? Arthritis Rheum 54:1714-29 |
| Evans, Christopher H; Robbins, Paul D; Ghivizzani, Steven C et al. (2005) Gene transfer to human joints: progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 102:8698-703 |
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