Antisense oligonucleotide modulation of STAT3 expression
View Patent ↗Compounds, compositions and methods are provided for inhibiting the expression of human STAT3. The compositions comprise antisense oligonucleotides targeted to nucleic acids encoding STAT3. Methods of using these oligonucleotides for inhibition of STAT3 expression and for promotion of apoptosis are provided. Methods for treatment of diseases, particularly inflammatory diseases and cancers, associated with overexpression or constitutive activation of STAT3 or insufficient apoptosis are also provided.
1. A method of inhibiting the expression of STAT3 in a cancer cell comprising contacting said cancer cell with a compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides wherein the modified oligonucleotide is at least 90% complementary to nucleobases 2941 to 3066 of SEQ ID NO:154 over its entire length, thereby inhibiting expression of STAT3.
2. The method of claim 1 , wherein the modified oligonucleotide is single-stranded.
3. The method of claim 1 , wherein the modified oligonucleotide is 100% complementary to nucleobases 2941 to 3066 of SEQ ID NO:154 as measured over the entirety of the oligonucleotide.
4. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.
5. The method of claim 4 , wherein the modified sugar is selected from the group consisting of a 2′-O-(2 methoxyethyl), and a bicyclic 2′-C, 4′-C-oxymethylene linkage 4′-(CH 2 ) n —O-2′, wherein n is 1 or 2.
6. The method of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxyribonucleosides;
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.
7. The method of claim 6 , wherein the modified oligonucleotide comprises:
a gap segment consisting often linked deoxyribonucleosides;
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; and wherein each internucleoside linkage of said antisense oligonucleotide is a phosphorothioate linkage; and wherein each cytosine in said antisense oligonucleotide is a 5-methylcytosine.
8. The method of claim 1 , wherein the modified oligonucleotide comprises a modified internucleoside linkage.
9. The method of claim 8 , wherein the modified internucleoside linkage is a phosphorothioate linkage.
10. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
11. The method of claim 10 , wherein the modified nucleobase is a 5-methylcytosine.