Compounds and methods for modulating target nuclear and sub-nuclear nucleic acid molecules in cells and animals
The present invention provides compounds and methods for modulating target nucleic acids found in organelles or sub-organelles of cells. The invention includes, but is not limited to compounds and methods that modulate target nucleic acids in a sub-nuclear organelle, such as the nucleolus and/or a cajal body. In certain embodiments, the cell is in an animal.
1. A method of reducing the amount or activity of a target sub-nuclear RNA in a cell in an animal comprising administering to the animal a pharmaceutical composition comprising an antisense compound comprising a modified oligonucleotide complementary to the target sub-nuclear RNA; and thereby reducing the amount or activity of the target sub-nuclear RNA in the cell in the animal;
wherein the modified oligonucleotide comprises:
a 5′-region consisting of 1 to 7 modified nucleosides;
a 3′-region consisting of 1 to 7 modified nucleosides; and
a central region consisting of 5 to 28 deoxyribonucleosides; and
wherein the animal is a mammal; and
wherein the target sub-nuclear RNA is found in a paraspeckle, is found in a nuclear speckle, is found in a Cajal Body (scaRNA), or is a long non-coding RNA.
2. The method of claim 1 , wherein at least one modified nucleoside comprises a modified sugar moiety selected from among: 2′-MOE, 2′-OMe, 2′-F, LNA, ENA, cEt, and a tetrahydropyran.
3. The method of claim 1 , wherein at least one modified nucleoside comprises a modified sugar moiety selected from among: 2′-MOE, 2′-OMe, 2′-F, and a BNA.
4. The method of claim 3 , wherein the BNA is selected from LNA, ENA, and cEt.
5. The method of claim 1 , wherein the modified oligonucleotide comprises one or more modified internucleoside linkages.
6. The method of claim 1 , wherein the antisense compound comprises a conjugate group.
7. The method of claim 1 , wherein the reduced activity of the target sub-nuclear RNA results in a change in the methylation, pseudouridylation, polyadenylation, or splicing of at least one object RNA, wherein the object RNA is a RNA molecule, other than the target sub-nuclear RNA, that is affected directly or indirectly by the antisense compound.
8. The method of claim 7 , wherein the reduced activity of the target sub-nuclear RNA results in a change in the methylation of at least one object RNA.
9. The method of claim 7 , wherein the reduced activity of the target sub-nuclear RNA results in a change in the polyadenylation of at least one object RNA.
10. The method of claim 7 , wherein at least one object RNA encodes a histone.
11. The method of claim 1 , wherein the cell is a cancer cell.
12. The method of claim 11 , wherein the animal has cancer.
13. The method of claim 1 , wherein the animal is a human.
14. The method of claim 1 , wherein the pharmaceutical composition is administered systemically.
15. The method of claim 1 , wherein the pharmaceutical composition is administered by subcutaneous injection.