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Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins¹

Myew-Ling Toh^*, Saw-See Hong, Fons van de Loo, Laure Franqueville, Leif Lindholm, Wim van den Berg, Pierre Boulanger^2, and Pierre Miossec^2,*

^* Department of Immunology and Rheumatology, Mixed Unit Civil Hospital of Lyon-BioMérieux, Edouard Herriot Hospital, Lyon, France; Laboratoire de Virologie et Pathogenèse Virale, Centre National de la Recherche Scientifique-University of California Biomechanics Laboratory, Faculté de Médecine RTH Laennec, Lyon, France; Department of Medical Microbiology and Immunology, University of Göteborg, and Got-A-Gene, Göteborg, Sweden; and University Medical Center Nijmegen, Nijmegen Center for Molecular Life Sciences, Rheumatology and Advanced Therapeutics, Nijmegen, The Netherlands

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) do not express the coxsackie-adenovirus (Ad) receptor and are poorly permissive to Ad serotype 5 (Ad5). Genetically modified, coxsackie-Ad receptor-independent Ad5 vectors were studied for gene delivery in human RA FLS and synovium explants and murine collagen-induced arthritis. Short-fiber Ad5 vectors with seven fiber shaft repeats Ad5GFP-R7-knob, Ad5GFP-R7-arginine-glycine-aspartic acid (RGD) (RGD-liganded), and Ad5GFPknob (knob-deleted) were compared with Ad5GFP-FiWT, a conventional wild-type (WT) Ad5 vector. Gene transfer by Ad5GFP-R7-knob and Ad5GFP-R7-RGD was 40- to 50-fold and 25-fold higher, respectively, than Ad5GFP-FiWT in FLS. Ad5GFPknob was more efficacious than its knob-bearing version Ad5GFP-R7-knob in FLS transduction. Virus attachment and entry required RGD- and LDV-binding integrins including _v, _v3, a_v5, and ₁. Ad5GFP-R7-knob infection of FLS was partially neutralized by synovial fluid (SF), but remained 30- to 40-fold higher than Ad5GFP-FiWT in the presence of SF. Ad5GFPknob was partially neutralized by SF at low virus input, but escaped viral neutralization by SF at higher virus input. Gene transfer to human synovium ex vivo explants and murine collagen-induced arthritis in vivo was also more efficient with short fiber-modified vectors (with and without the knob domain) than Ad5GFPFiWT. Gene transfer by short fiber-modified vectors was enhanced by inflammatory cytokines in vitro and in the presence of inflammation in murine synovium in vivo. Our data indicated that the highly efficient gene delivery RA was mediated by RGD- and non-RGD-binding integrins and enhanced by inflammation. Short fiber modifications with knob ablation may be a strategy to enhance gene delivery, reducing vector dose and vector-induced inflammation and toxicity.

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				O. Granio, M. Porcherot, S. Corjon, K. Kitidee, P. Henning, A. Eljaafari, A. Cimarelli, L. Lindholm, P. Miossec, P. Boulanger, et al. Improved Adenovirus Type 5 Vector-Mediated Transduction of Resistant Cells by Piggybacking on Coxsackie B-Adenovirus Receptor-Pseudotyped Baculovirus J. Virol., June 15, 2009; 83(12): 6048 - 6066. [Abstract] [Full Text] [PDF]