Gene Therapy Research Program
The overall goal of the Gene Therapy Research Program is to develop a strategy and technology to provide a flexible and responsive gene delivery system for the local treatment of arthritis. At the research department of Rheumatology several experimental animal models of rheumatoid arthritis are used. In recent years the role of cytokines in the inflammatory process and cartilage destruction was studied and this defined the therapeutic targets for the current research program: interleukin-1, interleukin-6, nitric oxide and interleukin-18.
(Additional funding by NWO, No 902-27-218)
The areas of emphasis include:studies in gene knockout mice to identify new targets;
application of recombinant adenoviral vectors for local delivery of genes;
improving the transfection efficiency using genetically modified adenoviruses.
The goals of this group are:Development of new recombinant anti-cytokine proteins based on the extra-cellulair domains of their ‘accessory’ proteins.
Development of disease regulated gene expression using cytokine-inducible promoter constructs.
Participating researchers, their research project, and financial support.
Alfons S.K. de Hooge
Role of IL-6 in chronic arthritis: good or bad guy?
The Dutch league against Rheumatism 97-2-402
AntiIl-1 treatment of arthritis.
David T. Curiel, M.D. Director, Gene Therapy Program, University of Alabama at Birmingham, AL 35294-3300, USA
Robert S. Munford, M.D. University of Texas Southwestern Medical Center at Dallas, Texas 75235-9062, USA
Carl Richards, Ph.D. Center for Gene Therapeutics, McMaster University at Hamilton, ON L8N 3Z5 Canada.
Van de Loo AAJ, Arntz OJ, Bakker AC, van Lent PLEM, MJM Jacobs, van den Berg WB: Role of Interleukin-1 in antigen-induced exacerbations of murine arthritis. Am J Pathol, 146: 239-249, 1995.
Van de Loo AAJ, Joosten LAB, van Lent PLEM, Arntz OJ, van den Berg WB: Role of Interleukin-1, Tumor Necrosis Factor I and Interleukin-6 in cartilage proteoglycan metabolism and destruction. Effect of in situ cytokine blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum, 38: 164-172, 1995.
Bakker AC, Joosten LAB, Arntz OJ, Helsen MMA, Bendele A, van de Loo FAJ, van den Berg WB: Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human IL-1ra protein in the knee. Arthritis Rheum, 40: 893-900, 1997.
Van de Loo FAJ, Kuiper S, van Enckevort FHJ, Arntz OJ, van den Berg WB: IL-6 reduces cartilage destruction during experimental arthritis: A study in IL-6 deficient mice. AM J Pathol, 151: 177-191, 1997.
Van de Loo FAJ, Arntz OJ, van Enckevort FHJ, van Lent PLEM, van den Berg WB: Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2-deficient mice and in anti-IL-1-treated wild-type mice with unabated joint inflammation. Arthritis Rheum, 41: 634-646, 1998.
Bakker Ac, van de Loo FAJ, Krashnykh V, Curiel DT, Van den Berg WB: An adenovirus vector with fibers containing the RGD motif has an increased transfection efficiency of the murine synovial membrane in vivo. Arthritis Rheum 42: S106, 1999.
University Medical Centre Nijmegen 'St. Radboud'
University of Nijmegen