Antisense compounds targeting genes associated with fibronectin
Provided are compounds comprising oligonucleotides complementary to a fibronectin transcript. Certain such compounds are useful for hybridizing to a fibronectin transcript, including but not limited to a fibronectin transcript in a cell. Such hybridization results in modulation of splicing of the fibronectin transcript. Such compounds are used to treat one or more symptoms associated with fibrosis. Such compounds are used to treat one or more symptoms associated with renal fibrosis.
1. A method of modulating splicing of a fibronectin transcript in a cell, comprising contacting a cell with a compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a complementary region comprising at least 12 contiguous nucleobases complementary to a target region of equal length of a fibronectin transcript, wherein the target region is within nucleobase 55469 and nucleobase 55790 of SEQ ID NO.: 1.
2. The method of claim 1 , wherein the modulation of the fibronectin transcript in a cell decreases the amount of EDA+ fibronectin mRNA in a cell.
3. The method of claim 1 , wherein the complementary region of the modified oligonucleotide comprises at least 15 contiguous nucleobases.
4. The method of claim 1 , wherein the complementary region of the modified oligonucleotide comprises at least 18 contiguous nucleobases.
5. The method of claim 1 , wherein the complementary region of the modified oligonucleotide comprises at least 20 contiguous nucleobases.
6. The method of claim 1 , wherein the complementary region of the modified oligonucleotide is 100% complementary to the target region.
7. The method of claim 3 , wherein the complementary region of the modified oligonucleotide is 100% complementary to the target region.
8. The method of claim 4 , wherein the nucleobase sequence of the oligonucleotide is at least 90% complementary to an equal-length region of the fibronectin transcript, as measured over the entire length of the oligonucleotide.
9. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
10. The method of claim 9 , wherein the modified sugar moiety is a 2′-substituted sugar moiety, wherein the 2′-substituent is selected from among: 2′-OMe, 2′-F, and 2′-MOE.
11. The method of claim 9 , wherein the modified sugar moiety is a bicyclic sugar moiety.
12. The method of claim 11 , wherein the bicyclic sugar moiety is LNA or cEt.
13. The method of claim 9 , wherein the modified sugar moiety is a sugar surrogate, wherein the sugar surrogate is a morpholino or a modified morpholino.
14. The method of claim 9 , wherein the modified oligonucleotide comprises at least two modified nucleosides comprising modified sugar moieties that are different from one another.
15. The method of claim 9 , wherein the modified oligonucleotide comprises at least two modified nucleosides that have the same 2′-substituted sugar moiety.
16. The method of claim 15 , wherein the 2′-substituent of the 2′-substituted sugar moiety is 2′-MOE.
17. The method of claims 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
18. The method of claim 17 , comprising at least one phosphorothioate internucleoside linkage.
19. The method of claim 1 , wherein the cell is in a human.
20. The method of claim 19 , wherein fibrosis in the human is reduced.