Application of regulatable vectors in gene therapy of experimental arthritis
© The Author(s) 2004
Received: 16 January 2004
Published: 24 February 2004
Gene therapy studies in experimental models of arthritis have demonstrated effective treatment with a variety of immunosuppresive and proapoptotic genes using in vivo and ex vivo strategies. Regardless of which approaches are developed for clinical application of gene therapy, we believe that it is imperative that expression of a therapeutic gene is regulated so that levels of expression are controlled and can be downregulated in the event of adverse effects.
We previously constructed an autoregulatory self-contained plasmid vector pGTRTL in which gene expression is induced with doxy-cycline (Dox). Expression kinetics of luciferase from this vector have been characterized in vitro. In this investigation we examined the dynamics of luciferase expression from pGTRTL delivered in vivo to DBA/1 mice. Therapeutic effect of a small dimeric TNFR2 molecule (dTNFR) expressed constitutively from the vector pcdTNFR and regulated from the vector pGTRTT was compared in DBA/1 mice with established collagen-induced arthritis (CIA).
Plasmid DNA was administered to naïve or arthritic mice by intramuscular injection combined with electroporation. Gene expression from regulated vectors was induced with Dox administered in drinking water. The degree of arthritis was scored every 2–3 days, and at the end of the experiment serum immunoglobulin levels and cytokine release from lymph node cells was measured.
Improved pharmacologically regulated vectors could be developed for clinical application. There is also scope to utilize disease-responsive vectors that contain DNA binding motifs that respond to transcription factors upregulated in arthritic joints.
Funded by the Arthritis Research Campaign UK.