Modulation of nuclear-retained RNA
Provided herein are methods, compounds, and compositions for reducing expression of a nrRNA in an animal. Also provided herein are methods, compounds, and compositions for treating, ameliorating, delaying or reducing a symptom of a disease or disorder associated with a nuclear-retained RNA in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate a disease or condition associated with a nuclear-retained RNA, or a symptom thereof.
1. A method comprising administering to an animal an antisense oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, and wherein the nucleobase sequence of the antisense oligonucleotide is at least 80% complementary to an alpha1 actin RNA as measured over the entirety of the antisense oligonucleotide.
2. The method of claim 1 , wherein the antisense oligonucleotide is chimeric.
3. The method of claim 1 , wherein the antisense oligonucleotide is a gapmer.
4. The method of claim 1 , wherein the nucleobase sequence of the antisense oligonucleotide is at least 95% complementary to alpha1 actin RNA as measured over the entirety of said antisense oligonucleotide.
5. The method of claim 1 , wherein the nucleobase sequence of the antisense oligonucleotide is 100% complementary to alpha1 actin RNA as measured over the entirety of said antisense oligonucleotide.
6. The method of claim 1 , wherein at least one internucleoside linkage of said antisense oligonucleotide is a modified internucleoside linkage.
7. The method of claim 6 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
8. The method of claim 1 , wherein at least one nucleoside of said antisense oligonucleotide comprises a modified sugar.
9. The method of claim 8 , wherein at least one modified sugar is a bicyclic sugar.
10. The method of claim 8 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
11. The method of claim 1 , wherein at least one nucleoside of said antisense oligonucleotide comprises a modified nucleobase.
12. The method of claim 11 , wherein the modified nucleobase is a 5-methylcytosine.
13. The method of claim 1 , wherein the antisense oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
14. The method of claim 13 , wherein at least one internucleoside linkage of said antisense oligonucleotide is a modified internucleoside linkage.
15. The method of claim 14 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
16. The method of claim 13 , wherein at least one nucleoside of said antisense oligonucleotide comprises a modified sugar.
17. The method of claim 16 , wherein at least one modified sugar is a bicyclic sugar.
18. The method of claim 16 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
19. The method of claim 13 , wherein the antisense oligonucleotide consists of 20 linked nucleosides.
20. The method of claim 19 , wherein the antisense oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting of five linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, wherein each internucleoside linkage of said antisense oligonucleotide is a phosphorothioate linkage, and wherein each cytosine in said antisense oligonucleotide is a 5′-methylcytosine.