Anticytokine gene therapy of autoimmune diseases

Abstract

Viral and nonviral gene therapy vectors have been successfully employed to deliver inflammatory cytokine inhibitors (anticytokines), or anti-inflammatory cytokines, such as transforming growth factor β-1 (TGF-β1), which protect against experimental autoimmune diseases. These vectors carry the relevant genes into a variety of tissues, for either localised or systemic release of the encoded protein. Administration of cDNA encoding soluble IFN-γ receptor (IFN-γR)/IgG-Fc fusion proteins, soluble TNF-α receptors, or IL-1 receptor antagonist (IL-1ra), protects against either lupus, various forms of arthritis, autoimmune diabetes, or other autoimmune diseases. These inhibitors, unlike many cytokines, have little or no toxic potential. Similarly, TGF-β1 gene therapy protects against numerous forms of autoimmunity, though its administration entails more risk than anticytokine therapy. We have relied on the injection of naked plasmid DNA into skeletal muscle, with or without enhancement of gene transfer by in vivo electroporation. Expression plasmids offer interesting advantages over viral vectors, since they are simple to produce, non-immunogenic and nonpathogenic. They can be repeatedly administered and after each treatment the encoded proteins are produced for relatively long periods, ranging from weeks to months. Moreover, soluble receptors which block cytokine action, encoded by gene therapy vectors, can be constructed from non-immunogenic self elements that are unlikely to be neutralised by the host immune response (unlike monoclonal antibodies [mAbs]), allowing long-term gene therapy of chronic inflammatory disorders.