Anti-sense oligonucleotides targeted against exon 9 of IL-23Rα gene and method of using same to induce exon skipping and to treat inflammatory bowel diseases
The present invention relates to anti-sense oligonucleotides (AONs) used to induce exon 9 skipping in IL-23Rα gene. Exon 9 skipping of the IL23Rα gene ultimately causes specific induction of a novel soluble truncated IL-23Rα (Δ9) protein, characterized by a lack in a transmembrane domain and has a unique eight (8) amino acids (GLKEGSYC) at its C-terminus end as a result of frame-shift. The present invention provides a utility application of the use of AONs to induce production of a Δ9 protein which inhibits IL-23R-mediated cell signaling. More particularly, Δ9 protein blocks STAT3 formation as well as Th17 maturation. There is provided a therapeutic application of AONs in treating a mammal such as a human patient inflicted with Crohn's disease.
1. An anti-sense RNA oligonucleotide 15-30 nucleobases in length targeted against exon 9 of IL-23Rα gene that increases the production of a soluble truncated IL-23Rα protein having an amino acid sequence set forth in SEQ ID NO: 5, wherein said anti-sense RNA oligonucleotide is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15.
2. A pharmaceutical composition comprising the anti-sense RNA oligonucleotide of claim 1 , and a pharmaceutical acceptable excipient.
3. A method of producing a soluble truncated IL-23Rα protein comprising the step of exposing an anti-sense RNA oligonucleotide to a mammalian cell, wherein said anti-sense RNA oligonucleotide is targeted against exon 9 of IL23Rα gene to induce skipping of exon 9 in said cell, and is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15.
4. A method of treating a human subject inflicted with Crohn's disease, comprising the step of administering a therapeutically effective amount of an anti-sense RNA oligonucleotide to said human, said anti-sense RNA oligonucleotide is targeted against exon 9 of IL-23Rα gene, and induces the production of a soluble truncated IL-23Rα protein having an amino acid sequence set forth in SEQ ID NO: 5, and is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15.