Therapeutic potential of anti–interleukin‐17A aptamer: Suppression of interleukin‐17A signaling and attenuation of autoimmunity in two mouse models

<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>The proinflammatory cytokine interleukin‐17A (IL‐17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high‐affinity RNA molecule, called an aptamer, against human IL‐17A on IL‐17A–induced signal transduction in vitro and its anti‐autoimmune efficacy in vivo in 2 mouse models of inflammation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>By screening a large library of nuclease‐resistant RNA oligonucleotides, we selected an RNA aptamer, Apt21‐2, that binds human and mouse IL‐17 and blocks the interaction between IL‐17A and its receptor. The inhibition of IL‐17A–mediated phosphorylation and marker protein production was analyzed in human and mouse cells. Mice with glucose‐6‐phosphate isomerase (GPI)–induced rheumatoid arthritis and myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis were used to assess efficacy.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Apt21‐2 prevented efficient phosphorylation of the IL‐17A signaling factors IκB and JNK and inhibited the production of IL‐6 in human and mouse cells. A PEGylated form of Apt21‐2 (PEG21‐2idT) exhibited a 50% inhibition concentration (IC<jats:sub>50</jats:sub>) in the range of 1–2 n<jats:italic>M</jats:italic> and 70–80 n<jats:italic>M</jats:italic> in human and mouse cells, respectively. When administered immediately after immunization with GPI or MOG, PEG21‐2idT inhibited in a dose‐dependent manner the development of arthritic or neurologic symptoms. Significantly, PEG21‐2idT slowed the progression of arthritis when administered after the onset of GPI‐induced arthritis.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings indicate that the chemically processed anti–IL‐17A aptamer PEG21‐2idT inhibits the actions of IL‐17A as well as the development of autoimmunity in 2 mouse models of inflammation. These results offer for the first time an aptamer‐based therapeutic approach to the treatment of Th17 cell–mediated autoimmune disorders.</jats:p></jats:sec>