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 compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence at least 80% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 set forth in nucleotides 1338 to 1378 of SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide, and wherein each nucleoside of the modified oligonucleotide comprises a sugar modification.
2. The compound of claim 1 wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.
3. The compound of claim 1 wherein the modified oligonucleotide consists of 15 to 30 linked nucleosides.
4. The compound of claim 1 , wherein, each nucleoside of the modified oligonucleotide comprises the same sugar modification.
5. The compound of claim 4 wherein the sugar modification is selected from the group consisting of 2′-O-methoxyethyl, 2′-fluoro, locked nucleic acid and ethylene bridged nucleic acid.
6. The compound of claim 5 wherein the sugar modification is 2′-O-methoxyethyl.
7. The compound of claim 6 , wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage.
8. The compound of claim 7 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
9. The compound of claim 1 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
10. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence at least 80% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 as set forth in SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide, wherein each nucleoside of the modified oligonucleotide comprises a sugar modification, and wherein the nucleobase sequence of the modified oligonucleotide has 100% identity to SEQ ID NO: 135 over the length of the modified oligonucleotide.
11. The compound of claim 10 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
12. A compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and having a nucleobase sequence at least 80% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 as set forth in SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide, wherein each nucleoside of the modified oligonucleotide comprises a sugar modification, and wherein the nucleobase sequence of the modified oligonucleotide has at least 80% identity to SEQ ID NO: 135 over the length of the modified oligonucleotide.
13. The compound of claim 12 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
14. The compound of claim 12 , wherein the nucleobase sequence of the modified oligonucleotide has at least 90% identity to SEQ ID NO: 135 over the length of the modified oligonucleotide.
15. The compound of claim 12 , wherein the nucleobase sequence of the modified oligonucleotide has at least 95% identity to SEQ ID NO: 135 over the length of the modified oligonucleotide.
16. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence at least 90% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 set forth in nucleotides 1338 to 1378 of SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide, wherein said nucleobase sequence comprises at least 8 consecutive nucleobases from the nucleobase sequence of SEQ ID NO:135, and wherein each nucleoside of the modified oligonucleotide comprises a sugar modification.
17. The compound of claim 16 , wherein said nucleobase sequence is at least 95% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 set forth in nucleotides 1338 to 1378 of SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide.
18. The compound of claim 16 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
19. The compound of claim 16 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides.
20. The compound of claim 16 wherein the modified oligonucleotide consists of 15 to 30 linked nucleosides.
21. The compound of claim 16 , wherein each nucleoside of the modified oligonucleotide comprises the same sugar modification.
22. The compound of claim 21 , wherein the sugar modification is selected from the group consisting of 2′-O-methoxyethyl, 2′-fluoro, locked nucleic acid and ethylene bridged nucleic acid.
23. The compound of claim 22 , wherein the sugar modification is 2′-O-methoxyethyl.
24. The compound of claim 23 , wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage.
25. The compound of claim 24 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.
26. A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence that is 100% complementary to the exon II donor site of a nucleic acid molecule encoding human MyD88 as set forth in nucleotides 1338 to 1378 of SEQ ID NO: 146 as measured over the entirety of said modified oligonucleotide, wherein said nucleobase sequence comprises at least 8 consecutive nucleobases from the nucleobase sequence of SEQ ID NO: 135, and wherein each nucleoside of the modified oligonucleotide comprises a sugar modification.
27. The compound of claim 26 , wherein said compound is single-stranded and not hybridized to a second strand in a duplex.