Gene Therapy Group
Groupmembers
Margriet Vervoordeldonk, PhD – Team Leader
Frits Fallaux, PhD – Senior Scientist
Janik Adriaansen, PhD student
Karin de Cortie, (bio-)technician
Rodger Kuhlman, technician
Rianne Tooten, (bio-)technician
Karin Verwegen, (technician)
For more information contact: m.j.vervoordeldonk@amc.uva.nl
Research
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint swelling and progressive destruction of cartilage and bone. Biologicals targeting cytokines and their receptors have been proven useful as specific therapies for RA. Anti-tumor necrosis factor (TNF)-alpha therapies (both anti-TNF antibodies and soluble TNF receptors) have shown clinical efficacy in 60-70% of the RA patients. The majority of these ACR 20% responders, however, will still have some actively inflamed joints and this may reflect reduced bioavailability in some affected joints. Gene therapy can provide stable, regulated production of beneficial molecule(s) at the site of inflammation.
Among the large variety of viruses currently developed as vector for human gene transfer, promising candidates are represented by the smallest of all viruses, the adeno-associated viruses (AAV). We study intra-articular gene transfer through a recombinant AAV encoding a TNF blocking agent in both adjuvant arthritis (AA) in rats and collagen-induced arthritis (CIA) in mice, two well studied animal models for RA. Excessive and uncontrolled production of the therapeutic gene might lead to spill-over to the circulation that will skew the immune system to cause side effects. To put the transgene under control of disease-inducible transcriptional regulation we will not only reduce the risks of spill-over but allow the drug treatment to meet the variable demand during the intermittent course of arthritis. In addition to the development of a TNF blocking agent our research focuses on the identification of new therapeutic targets and promoters and to test these as well in vitro in fibroblast-like synoviocytes and synovial tissue biopsies, as in vivo in animal models of arthritis. In addition, a part of the research is focussed on the development of optimized vectors for gene therapeutic approaches in RA.
Selected publications
1. Tas SW, Vervoordeldonk MJ, Hajji N, Schuitemaker JH, van der Sluijs KF, May MJ, Ghosh S, Kapsenberg ML, Tak PP, de Jong EC. Non-canonical NF-kB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood. 2007; 110: 1540-9.
2. Adriaansen J, Fallaux FJ, de Cortie CJ, Vervoordeldonk MJ and Tak PP. Local delivery of beta interferon using an adeno-associated virus type 5 effectively inhibits adjuvant arthritis in rats. J Gen Virol. 2007; 88: 1717-21.
3. Adriaansen J, Kuhlman RR, van Holten J, Kaynor C, Vervoordeldonk MJBM and Tak PP. Intraarticular interferon-beta gene therapy ameliorates adjuvant arthritis in rats. Hum Gene Ther. 2006; 17: 985-96.
4. Tas SW, Adriaansen J, Hajji N, Bakker AC, Firestein GS, Vervoordeldonk MJ and Tak PP, Amelioration of arthritis by intra-articular dominant negative IKKß gene therapy using adeno-associated virus type 5. Hum Gene Ther. 2006; 17: 821-32.
5. Tas SW, Stenvers DJ, Hajji N, Firestein GS, Vervoordeldonk MJ and Tak PP. Reduction of pro-inflammatory cytokine expression in the synovium by targeting inhibitor of nuclear factor (NF)-kB kinase ß in vivo. Arthritis Rheum. 2006; 54:3716-9.
6. Adriaansen J, Vervoordeldonk MJ and Tak PP. Gene therapy as therapeutic approach for the treatment of rheumatoid arthritis: innovative vectors and therapeutic genes. Review. Rheumatology (
7. Adriaansen J, Vervoordeldonk MJ, Vanderbyl S, de Jong G and Tak PP. Engraftment of fibroblasts containing artificial chromosomes at the site of inflammation. J Gene Med. 2006; 8: 63-71.
8. Adriaansen J, Tas SW, Klarenbeek PL, Bakker AC, Apparailly F, Firestein GS, Jorgensen C, Vervoordeldonk MJBM and Tak PP. Gene transfer to synovial tissue can be improved using adeno-associated virus type 5: implications for intra-articulair gene therapy. Ann Rheum Dis. 2005; 64: 1677-84.
9. Apparailly F, Khoury M, Vervoordeldonk MJB, Adriaansen J, Gicquel E, Perez N, Riviere C, Louis-Plence P, Noel D, Douar AM, Tak PP and Jorgensen C. Adeno-associated virus pseudotype 5 vector improve gene transfer in arthritic joints. Hum Gene Ther. 2005; 16: 426-34.