Using a tropism-modified adenoviral vector for the intra-articular production of IL-1 receptor antagonist results in a more efficient inhibition of collagen-induced arthritis than does a conventional Ad5 vector

Introducing an Arg-Gly-Asp (RGD) motif in the HI loop of the fiber knob results in the ability of the adenovirus to utilize the αvβ3 and αvβ5 integrins instead of the coxsackie-adenovirus receptor for cell recognition. In this study we compared the transfection efficiency and the effect of intra-articular IL-1Ra gene delivery on collagen-induced arthritis (CIA) using RGD modified and conventional Ad5 vectors.

DBA/1 mice were immunized with collagen type II, and boostered 22 days later. Four days after the booster, 10⁷ pfu of the Ad5Luc, Ad5Luc.RGD, Ad5mIL-1Ra, or Ad5mIL-1Ra.RGD were injected bilaterally into the knee joint cavity. The clinical score (scale 0–2) of the ipsilateral paws was taken during the course of arthritis, and the knees were scored (scale of 0–3) at the end of the experiment.

24-h after the intra-articular injection into normal knee joints the luciferase (Luc) production was around 22 times higher using the Ad5Luc.RGD as compared to a conventional Ad5Luc vector. Intra-articular injection of 10⁷ pfu adenoviral vectors at day 26 of immunization resulted in a significant inhibition of CIA in the Ad5mIL-1Ra.RGD group (clinical score of the knee at day 38 was 0.82 ± 0.24) as compared to the other groups (clinical scores were 1.57 ± 0.24 for the Ad5mIL-1Ra group and 1.86 ± 0.21 for the Ad5Luc.RGD group).

Our data demonstrate that the RGD modification of adenoviruses improved the synovial transfection efficiency; and that the Ad5IL-1Ra.RGD vector was more efficacious in the treatment of arthritis than the conventional vector with the same transgene.

This study was financially supported by the Dutch Arthritis Association (941) and the Dutch Organization for Scientific Research (902-27-218).

Affiliations

1. Department of Rheumatology, UMC St Radboud, 6525 GA, Nijmegen, PO box 9101, The Netherlands

   • AC Bakker
   • , FAJ van de Loo
   • , OJ Arntz
   • , LAB Joosten
   •  & WB van den Berg

2. UAB, Birmingham, AL, 35294-3300, USA

   • I Dmitriev
   • , V Krasnykh
   •  & DT Curiel

Reprints and Permissions