Antisense compounds targeting genes associated with fibronectin
The present invention provides 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. In certain embodiments, such hybridization results in modulation of splicing of the fibronectin transcript. In certain embodiments, such compounds are used to treat one or more symptoms associated with fibrosis. In certain embodiments, such compounds are used to treat one or more symptoms associated with renal fibrosis.
1. A compound comprising a modified oligonucleotide consisting of 8 to 30 linked nucleosides and having a nucleobase sequence comprising a complementary region comprising at least 8 contiguous nucleobases complementary to a target region of equal length of a fibronectin transcript, wherein the target region is within nucleobase 55441 and nucleobase 55790 of SEQ ID NO.: 1, and wherein the modified oligonucleotide comprises a region having a sugar motif described by Formula I as follows:
[(A)-(B) 2 ] n
wherein:
each A is independently a bicyclic nucleoside;
each B is independently a 2′-substituted nucleoside or a 2′-deoxynucleoside; and
n is an integer from 3-6.
2. The compound of claim 1 , wherein the antisense oligonucleotide comprises a region having a sugar motif described by Formula II as follows:
(A) 2 -[(B) 2 -(A)] n -(A)
wherein:
each A is independently a bicyclic nucleoside;
each B is independently a 2′-substituted nucleoside or a 2′-deoxynucleoside; and
n is an integer from 3-6.
3. The compound of claim 1 , wherein the antisense oligonucleotide comprises a region having a sugar motif described by Formula III as follows:
(A) 2 -[(B) 2 -(A)] n
wherein:
each A is independently a bicyclic nucleoside;
each B is independently a 2′-substituted nucleoside or a 2′-deoxynucleoside; and
n is an integer from 3-6.
4. The compound of claim 1 , wherein each A comprises a bicyclic nucleoside selected from among LNA and cEt.
5. The compound of claim 4 , wherein each A comprises a cEt modification.
6. The compound of claim 1 , wherein each B comprises a 2′-substituted nucleoside having a 2′-modification selected from among 2′-OMe, 2′-F, and 2′-MOE.
7. The compound of claim 6 , wherein the 2′-modification is a 2′-MOE modification.
8. The compound of claim 1 , wherein each B comprises a 2′-deoxynucleoside.
9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.