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Antisense oligonucleotide mediated exon skipping as a potential strategy for the treatment of a variety of inflammatory diseases such as rheumatoid arthritis
  1. Seda Yilmaz-Elis1,
  2. Annemieke Aartsma-Rus1,
  3. Anne Vroon2,
  4. Judith van Deutekom2,
  5. Sjef de Kimpe2,
  6. Peter A C 't Hoen1,
  7. Gert-Jan van Ommen1,
  8. J Sjef Verbeek1
  1. 1Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Prosensa Therapeutics BV, Leiden, The Netherlands
  1. Correspondence to Sjef Verbeek, Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands; j.s.verbeek{at}

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Arthritis is an autoantibody-driven disease. Anti-CD20 treatment, removing B cells, treats the disease but introduces a new problem. This treatment removes B cells irrespective of their specificity, and thus attenuates the humoral response which might result in impaired immunity. Since it is impossible to specifically target the autoantigen-specific B cells, therapeutic strategies are generally directed to downstream targets such as the effector cytokines interleukin 1 (IL-1) and tumour necrosis factor α (TNFα). It has already been shown that blocking these cytokines using specific antibodies (anti-TNF), antagonists (IL-1 receptor (IL-1R) antagonist) or soluble receptors (TNFR) decreases disease severity. To date, interference with the TNF pathway has been shown to be very effective and is used successfully in the clinic. However, the development and production of large amounts of specific antibodies and inhibiting proteins such as antagonists or soluble receptors for clinical use is complex and very expensive. In addition, induction of antibody responses against several of these artificial proteins reduces their efficacy. There is therefore still a need for alternative therapeutics directed more specifically at these effector cytokines and other targets that can be used individually or in combination with other therapeutics. Although the strong therapeutic effect of inhibiting the IL-1 pathway shown in mice has not so far been confirmed in humans, it cannot be excluded that inhibition of the IL-1 signaling pathway will be effective in combination therapy including other targets. Moreover, IL-1 inhibition might be an effective therapy in the many other inflammatory and autoimmune diseases in which this cytokine is known to play an important role.

IL-1 receptor accessory protein (IL-1RAcP) is a subunit of the IL-1R complex required for the stabilisation of the IL-1 and …

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