OBJECTIVE: To determine if the rheumatoid synovium is a suitable target for hypoxia-regulated gene therapy. METHODS: Sequential sections of wax-embedded synovial membrane samples were obtained from 10 patients with rheumatoid arthritis (RA), 10 with primary osteoarthritis (OA), and from 6 healthy controls. Membrane sections from each patient were immunostained for hypoxia-inducible factor 1alpha (HIF-1alpha) and CD68 (a pan-macrophage marker). RESULTS: HIF-1alpha was expressed abundantly by macrophages in most rheumatoid synovia, predominantly close to the intimal layer but also in the subintimal zone. There was markedly lower expression of HIF-1alpha in OA synovia, and it was absent from all of the healthy synovia. CONCLUSION: These observations indicate that macrophages transduced with a therapeutic gene under the control of a hypoxia-inducible promoter could be administered to RA patients systemically. Migration of these cells to synovial tissue would result in the transgene being switched on in diseased joints but not in healthy tissues.
OBJECTIVE: To determine if the rheumatoid synovium is a suitable target for hypoxia-regulated gene therapy. METHODS: Sequential sections of wax-embedded synovial membrane samples were obtained from 10 patients with rheumatoid arthritis (RA), 10 with primary osteoarthritis (OA), and from 6 healthy controls. Membrane sections from each patient were immunostained for hypoxia-inducible factor 1alpha (HIF-1alpha) and CD68 (a pan-macrophage marker). RESULTS:HIF-1alpha was expressed abundantly by macrophages in most rheumatoid synovia, predominantly close to the intimal layer but also in the subintimal zone. There was markedly lower expression of HIF-1alpha in OA synovia, and it was absent from all of the healthy synovia. CONCLUSION: These observations indicate that macrophages transduced with a therapeutic gene under the control of a hypoxia-inducible promoter could be administered to RApatients systemically. Migration of these cells to synovial tissue would result in the transgene being switched on in diseased joints but not in healthy tissues.
Authors: Thorsten Cramer; Yuji Yamanishi; Björn E Clausen; Irmgard Förster; Rafal Pawlinski; Nigel Mackman; Volker H Haase; Rudolf Jaenisch; Maripat Corr; Victor Nizet; Gary S Firestein; Hans Peter Gerber; Napoleone Ferrara; Randall S Johnson Journal: Cell Date: 2003-03-07 Impact factor: 41.582
Authors: Jörn Karhausen; Glenn T Furuta; John E Tomaszewski; Randall S Johnson; Sean P Colgan; Volker H Haase Journal: J Clin Invest Date: 2004-10 Impact factor: 14.808