Antisense oligonucleotide modulation of stat3 expression

Abstract

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 - 18 . (canceled)  
     
     
         19 . A modified antisense oligonucleotide, comprising the nucleotide sequence shown in SEQ ID NO:184 or SEQ ID NO:240, having at least one chemically modified internucleoside linkage, sugar moiety, or nucleobase, or a pharmaceutically acceptable salt thereof.  
     
     
         20 . The modified antisense oligonucleotide or pharmaceutically acceptable salt thereof of  claim 19 , having at least one phosphorothioate internucleoside linkage.  
     
     
         21 . The modified antisense oligonucleotide or pharmaceutically acceptable salt thereof of  claim 19 , having at least one 2′-O-(2-methoxyethyl) sugar moiety.  
     
     
         22 . The modified antisense oligonucleotide or pharmaceutically acceptable salt thereof of  claim 19 , having at least one 5-methylcytosine residue.  
     
     
         23 . The modified antisense oligonucleotide or pharmaceutically acceptable salt thereof of  claim 19 , wherein every internucleoside linkage is a phosphorothioate linkage, nucleotides 1-5 and 16-20 reading from the 5′ end to the 3′ end of SEQ ID NO:184 and SEQ ID NO:240 each comprise a 2′-O-(2-methoxyethyl) sugar moiety, nucleotides 6-15 are 2′-deoxynucleotides, and every cytosine residue is a 5-methylcytosine.  
     
     
         24 . The modified antisense oligonucleotide or pharmaceutically acceptable salt thereof of  claim 23 , which is in the form of a sodium salt.  
     
     
         25 . (canceled)  
     
     
         26 . (canceled)  
     
     
         27 . A modified antisense oligonucleotide, consisting of the nucleotide sequence shown in SEQ ID NO:184 or SEQ ID NO:240, having at least one chemically modified internucleoside linkage, sugar moiety, or nucleobase, G which modified antisense oligonucleotide is in the form of a sodium salt.  
     
     
         28 . (canceled)  
     
     
         29 . A The modified antisense oligonucleotide of  claim 27 , wherein every internucleoside linkage is a phosphorothioate linkage, nucleotides 1-5 and 16-20 reading from the 5′ end to the 3′ end each comprise a 2′-O-(2-methoxyethyl) sugar moiety, and nucleotides 6-15 are 2′-deoxynucleotides, which modified antisense oligonucleotide is in the form of a sodium salt.  
     
     
         30 . (canceled)  
     
     
         31 . A The modified antisense oligonucleotide of  claim 27 , wherein every internucleoside linkage is a phosphorothioate linkage, nucleotides 1-5 and 16-20 reading from the 5′ end to the 3′ end each comprise a 2′-O-(2-methoxyethyl) sugar moiety, nucleotides 6-15 are 2′-deoxynucleotides, and at least one cytosine is a 5-methylcytosine, which modified antisense oligonucleotide is in the form of a sodium salt.  
     
     
         32 . (canceled)  
     
     
         33 . A modified antisense oligonucleotide, consisting of the nucleotide sequence shown in SEQ ID NO:184 or SEQ ID NO:240, wherein every internucleoside linkage is a phosphorothioate linkage, nucleotides 1-5 and 16-20 reading from the 5′ end to the 3′ end each comprise a 2′-O-(2-methoxyethyl) sugar moiety, nucleotides 6-15 are 2′-deoxynucleotides, and every cytosine residue is a 5-methylcytosine, which modified antisense oligonucleotide is in the form of a sodium salt.  
     
     
         34 . A pharmaceutical composition, comprising said sodium salt of said modified antisense oligonucleotide of  claim 33 , and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         35 . A method of treating a cancer selected from the group consisting of breast cancer, prostate cancer, myeloma, melanoma, leukemia, lymphoma, and non small cell lung cancer, comprising administering to a patient an effective amount of said sodium salt of said modified antisense oligonucleotide of  claim 33.