Modification of MYD88 splicing using modified oligonucleotides
View Patent ↗Antisense compounds, compositions and methods are provided for modulating the expression of MyD88. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding MyD88. Methods of using these compounds for modulation of MyD88 expression and for treatment of diseases associated with expression of MyD88 are provided.
1. A method of modulating splicing of MyD88 pre-mRNA in a cell comprising: contacting the cell with compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence at least 80% complementary to SEQ ID NO: 146 as measured over the entirety of the modified oligonucleotide, and wherein each nucleoside of the modified oligonucleotide comprises a sugar modification; and thereby modulating splicing of MyD88 pre-mRNA in the cell wherein the compound is single-stranded and not hybridized to a second strand in a duplex.
2. The method of claim 1 wherein the modified oligonucleotide is complementary to a splice donor site.
3. The method of claim 1 wherein the modified oligonucleotide is complementary to a splice acceptor site.
4. The method of claim 1 wherein the modified oligonucleotide is complementary to an exon II splice donor site.
5. The method of claim 1 wherein the modified oligonucleotide is complementary to an exon II splice acceptor site.
6. The method of claim 1 wherein the modulating splicing of MyD88 pre-mRNA is an increase in the ratio of MyD88 lacking exon II relative to the amount of MyD88 including exon II.
7. The method of claim 1 , wherein, each nucleoside of the modified oligonucleotide comprises the same sugar modification.
8. The method of claim 7 wherein the sugar modification is selected from the group consisting of 2′-O-methoxyethyl, 2′-fluoro, locked nucleic acid, ethylene bridged nucleic acid, and morpholino.
9. The compound of claim 8 wherein the sugar modification is 2′-O-methoxyethyl.
10. The compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.
11. The compound of claim 1 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.
12. The method of claim 1 , wherein the cell is in an animal.
13. The method of claim 12 , wherein the animal is a human.
14. The method of claim 1 , wherein the modulating splicing of MyD88 pre-mRNA in the cell results in modulating IL-1β signaling in the cell.
15. The method of claim 1 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, wherein each nucleoside of the modified oligonucleotide comprises a 2′-O-methoxyethyl modification, wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.
16. A method of modulating an inflammatory response in an animal comprising: administering to the animal a compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence at least 80% complementary to SEQ ID NO: 146 as measured over the entirety of the modified oligonucleotide, wherein each nucleoside of the modified oligonucleotide comprises a sugar modification, and wherein splicing of MyD88 pre-mRNA is modulated; and thereby modulating the inflammatory response in an animal wherein the compound is single-stranded and not hybridized to a second strand in a duplex.
17. The method of claim 16 wherein the results an increase in the ratio of MyD88 lacking exon II relative to the amount of MyD88 including exon II in a cell in the animal.
18. The method of claim 16 , wherein the modulating an inflammatory response is a reduction in the immune response.
19. The method of claim 16 , wherein the animal has an inflammatory disease.
20. The method of claim 16 , wherein the animal is a human.