In the exon skipping approach, antisense oligonucleotides (AONs), which are short singlestranded oligoribonucleotides typically around 20 bp in length, block the access of the spliceosome and other splicing factors by specific binding to sequences with a role in exon inclusion in the premRNA which results in exclusion of that exon from the mature mRNA. AON-mediated exon skipping can be applied to induce a shift in the ratio between alternative splice products, to restore correct splicing of an aberrantly spliced transcript, or to produce a novel splice variant that normally is not expressed. In Duchenne muscular dystrophy (DMD), restoring the open reading frame by skipping the exon with the non-sense mutation allows the generation of internally deleted but functional dystrophin proteins, converting severe DMD into a milder Becker muscular dystrophy phenotype. In fact, exon skipping is currently one of the most promising therapeutic tools for DMD and a successful first clinical trial has recently been completed. 2

The exon skipping strategy can be applied to induce the expression of soluble receptors and to decrease the expression of membrane-bound receptors by using specific AONs targeting the exon which encodes the transmembrane region, resulting in its deletion from the mature transcript. It has already been shown that, in this way, membrane-bound receptors of the cytokines TNFα and IL-5 can be successfully converted into soluble forms. 3 4 Moreover, in the experimental mouse model of collagen-induced arthritis, an AON specifically inducing the skipping of the transmembrane encoding exon 7 of TNFR2 increased the production of Δ7TNFR2 protein from liver that has a TNFα inhibiting activity. The prolonged administration confirmed that AON treatment suppressed the severity of arthritis. 3