Antisense-mediated exon skipping to generate soluble receptors

Soluble receptors modify the biological response to ligand by competing with their membrane-bound counterparts for the ligand. They act as competitive inhibitors of the signaling by binding to ligands without inducing cellular signal transduction pathways and thus neutralizing the bioactivity of the ligand. Shifting of transmembrane receptors to their soluble isoforms can be manipulated by using antisense oligonucleotide (AON) mediated exon skipping by targeting the exons which encode the transmembrane region and deleting them from the mature transcript. It has been shown that membrane bound receptors of cytokines TNF-α and IL-5 can be successfully converted into soluble forms by AON mediated exon skipping. This approach can be applied for the treatment of other inflammatory diseases or conditions where cytokines play important role by favoring the expression of soluble cytokine receptors inhibiting proinflammatory pathways. With this strategy, decrease in mRNA and protein levels of membrane-bound receptors upon AON treatment can be tested in vitro and in vivo by using the techniques mentioned in this chapter. The efficacy of AONs in producing therapeutic isoforms of the receptors should be tested further in vivo on disease models.