Modulation of UBE3A-ATS expression
Certain embodiments are directed to methods and compounds for inhibiting UBE3A-ATS, the endogenous antisense transcript of ubiquitin protein ligase E3A (UBE3A). Such methods and compounds are useful for inducing expression of paternal UBE3A in cells and animals.
1. A method of treating Angelman syndrome in an animal comprising administering to an animal with Angelman syndrome an antisense compound targeted to UBE3A-ATS, wherein the antisense compound comprises an oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the oligonucleotide is at least 85% complementary to a sequence within nucleobases 446213 to 513602 of SEQ ID NO: 2.
2. The method of claim 1 , wherein UBE3A-ATS comprises a nucleic acid sequence at least 85% identical to SEQ ID NO:2.
3. The method of claim 1 , wherein the oligonucleotide is at least 90% complementary over its entire length to an equal length region of a UBE3A-ATS nucleic acid sequence.
4. The method of claim 1 , wherein the oligonucleotide is at least 95% complementary over its entire length to an equal length region of a UBE3A-ATS nucleic acid sequence.
5. The method of claim 1 , wherein the oligonucleotide is 100% complementary over its entire length to an equal length region of a UBE3A-ATS nucleic acid sequence.
6. The method of claim 1 , wherein the oligonucleotide is a single-stranded oligonucleotide.
7. The method of claim 6 , wherein the oligonucleotide is a modified oligonucleotide.
8. The method of claim 7 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
9. The method of claim 8 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
10. The method of claim 7 , wherein at least one nucleoside comprises a modified sugar.
11. The method of claim 10 , wherein the modified sugar is a bicyclic sugar comprising a bridge between the 4′ and the 2′ positions of the sugar.
12. The method of claim 11 , wherein the bridge is selected from 4′-CH(CH 3 )—O-2′, 4′-CH 2 -2′, 4′-(CH 2 ) 2 -2′, 4′-CH 2 —O-2′, 4′-(CH 2 ) 2 —O-2′, 4′-CH 2 —O—N(R 1 )-2′ and 4′-CH2-N(R 1 )—O-2′- wherein each R1 is, independently, H, a protecting group or C1-C12 alkyl.
13. The method of claim 12 , wherein the bridge is 4′-CH(CH 3 )—O-2′.
14. The method of claim 12 , wherein the bridge is selected from 4′-CH 2 —O-2′ and 4′-(CH 2 ) 2 —O-2′.
15. The method of claim 10 , wherein the modified sugar comprises a 2′-O-methoxyethyl group.
16. The method of claim 7 , wherein at least one nucleoside comprises a modified nucleobase.