Therapeutic potential of anti–interleukin-17A aptamer: Suppression of interleukin-17A signaling and attenuation of autoimmunity in two mouse models
Akira Ishiguro
University of Tokyo, Tokyo, Japan
Drs. Ishiguro and Nakamura have a patent application pending related to anti–interleukin-17A aptamers; the University of Tokyo is designated as the patent owner under Japanese government regulations.
Search for more papers by this authorCorresponding Author
Yoshikazu Nakamura
University of Tokyo, Tokyo, Japan
Drs. Ishiguro and Nakamura have a patent application pending related to anti–interleukin-17A aptamers; the University of Tokyo is designated as the patent owner under Japanese government regulations.
Division of Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanSearch for more papers by this authorAkira Ishiguro
University of Tokyo, Tokyo, Japan
Drs. Ishiguro and Nakamura have a patent application pending related to anti–interleukin-17A aptamers; the University of Tokyo is designated as the patent owner under Japanese government regulations.
Search for more papers by this authorCorresponding Author
Yoshikazu Nakamura
University of Tokyo, Tokyo, Japan
Drs. Ishiguro and Nakamura have a patent application pending related to anti–interleukin-17A aptamers; the University of Tokyo is designated as the patent owner under Japanese government regulations.
Division of Molecular Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanSearch for more papers by this authorAbstract
Objective
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.
Methods
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.
Results
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 (IC50) in the range of 1–2 nM and 70–80 nM 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.
Conclusion
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.
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