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 modified or unmodified antisense compound 20 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human STAT3, wherein said antisense compound comprises SEQ ID NO: 342, or a pharmaceutically acceptable salt thereof.
2. The antisense compound of claim 1 which comprises at least one modified internucleoside linkage.
3. The antisense compound of claim 2 wherein the modified internucleoside linkage is a phosphorothioate linkage.
4. The antisense compound of claim 3 which comprises at least one modified sugar moiety.
5. The antisense compound of claim 4 wherein the modified sugar moiety is a 2′-O-methoxyethyl moiety.
6. The antisense compound of claim 5 which comprises at least one modified nucleobase.
7. The antisense compound of claim 6 wherein the modified nucleobase is a 5-methyl cytosine.
8. The antisense compound of claim 1 which is a chimeric oligonucleotide.
9. A pharmaceutical composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
10. A modified or unmodified antisense oligonucleotide consisting of SEQ ID NO: 342, or a pharmaceutically acceptable salt thereof.
11. A method of inhibiting the expression of STAT3 in cancer cells comprising contacting said cells with the antisense compound of claim 1 so that expression of STAT3 is inhibited.
12. A method of inducing apoptosis in cancer cells comprising contacting said cells with the antisense compound of claim 1 , so that apoptosis is induced.
13. The method of claim 12 , wherein said cancer cells are multiple myeloma cells.
14. A method of sensitizing cells to apoptosis comprising contacting said cells with the antisense compound of claim 1 so that apoptosis is induced.
15. The method of claim 14 wherein said apoptosis is Fas-mediated.
16. The antisense compound of claim 1 wherein the internucleoside linkages are phosphorothioate throughout the oligonucleotide, 5 nucleotides on the 5′ end and 5 nucleotides on the 3′ end are 2′-O-methoxyethyl nucleotides, or a pharmaceutically acceptable salt thereof.
17. The antisense compound of claim 16 wherein all cytosine residues are 5-methyl-cytosines.
18. The antisense compound of claim 17 wherein the pharmaceutically acceptable salt is a sodium salt.
19. The antisense oligonucleotide of claim 10 wherein the internucleoside linkages are phosphorothioate throughout the oligonucleotide, nucleotides 1–5 and 16–20 are 2′-O-methoxyethyl nucleotides, and all cytosines are 5-methyl-cytosines, or a pharmaceutically acceptable salt thereof.
20. The antisense oligonucleotide of claim 19 wherein the pharmaceutically acceptable salt is a sodium salt.
21. A pharmaceutical composition comprising the antisense oligonucleotide of claim 20 in combination with a pharmaceutically acceptable carrier, excipient, or diluent.