Modified tgf-beta2 oligonucleotides

Abstract

The invention refers to an oligonucleotide consisting of 10 to 18 nucleotides of selected regions of the TGF-beta2 nucleic acid sequence, which comprises modified nucleotides such as LNA, ENA, polyalkylene oxide-, 2′-fluoro, 2′-O-methoxy and/or 2′-O-methyl modified nucleotides. The invention further relates to pharmaceutical compositions comprising such oligonucleotide, wherein the composition or the oligonucleotide is used in the prevention and/or treatment of a malignant and/or benign tumor, an immunologic disease, fibrosis, or an ophthalmic disease such as dry eye, glaucoma or posterior capsular opacification (PCO).

What is claimed is: 
     
         1 . An antisense oligonucleotide comprising:
 10 to 18 nucleotides hybridizing with the TGF-beta2 nucleic acid sequence of SEQ ID NO. 1, wherein one or more nucleotide(s) of the oligonucleotide is/are modified, wherein the modified nucleotide is at least one of an LNA, an ENA, polyalkylene oxide-, 2′-fluoro-, 2′-O-methoxy-, or a 2′O-methyl-modified nucleotide.   
     
     
         2 . The antisense oligonucleotide of  claim 1 , wherein the modified nucleotide is located at the 5′- and/or 3′-end of the oligonucleotide. 
     
     
         3 . The antisense oligonucleotide of  claim 1 , wherein the oligonucleotide comprises a sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 11, SEQ ID NO. 12, SEQ ID NO. 13, SEQ ID NO. 14, SEQ ID NO. 15, SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19 and SEQ ID NO. 20. 
     
     
         4 . The antisense oligonucleotide of  claim 1 , wherein the oligonucleotide is selected from the group consisting of AGTATTTGGTCTCC (ASPH190), AAGTATTTGGTCTC (ASPH191), AAGTATTTGGTCTCC (ASPH192), CAAAGTATTTGGTCT (ASPH193), AGTATTTGGTCTCC (ASPH194), AGTATTTGGTCTCC (ASPH195), AGTATTTGGTCTCC (ASPH196), AGTATTTGGTCTCC (ASPH197), AAGTATTTGGTCTC (ASPH198), AGTATTTGGTCTCCA (ASPH199), AGTATTTGGTCTCCA (ASPH200), AGTATTTGGTCTCCA (ASPH201), AGTATTTGGTCTCCA (ASPH202), AGTATTTGGTCTCCA (ASPH203), AGTATTTGGTCTCCA (ASPH204), AGTATTTGGTCTCCA (ASPH205), AAGTATTTGGTCTCC (ASPH206), AAGTATTTGGTCTCC (ASPH207), AAGTATTTGGTCTCC (ASPH208), AAGTATTTGGTCTCC (ASPH209), AAGTATTTGGTCTCC (ASPH210), AAGTATTTGGTCTCC (ASPH211), CAAAGTATTTGGTCTCC (ASPH212), CAAAGTATTTGGTCTCC (ASPH213), CAAAGTATTTGGTCTCC (ASPH214), CAAAGCTATTTGGTCTCC (ASPH215), CAAAGTATTTGGTCTCC (ASPH216), CAAAGTATTTGGTCTCC (ASPH217), CAAAGTATTTGGTCTCC (ASPH218), CAAAGTATTTGGTCTCC (ASPH219), CAAAGTATTTGGTCTCC (ASPH220), CAAAGTATTTGGTCTCC (ASPH221), CAAAGTATTTGGTCTCC-TEG (ASPH222), CAAAGTATTTGGTCTCC-TEG (ASPH223), CAAAGTATTTGGTCTC (M1-ASPH47), CAAAGTATTTGGTCT (M2-ASPH47), CAAAGTATTTGGTC (M3-ASPH47), AAAGTATTTGGTCTCC (M4-ASPH47), AAAGTATTTGGTCTC (M5-ASPH47), AAAGTATTTGGTCT (M6-ASPH47), AAAGTATTTGGTC (M7-ASPH47), AAGTATTTGGTCTCC (M8-ASPH47), AAGTATTTGGTCTC (M9-ASPH47), AAGTATTTGGTCT (M10-ASPH47), AAGTATTTGGTC (M11-ASPH47), AGTATTTGGTCTCC (M12-ASPH47), AGTATTTGGTCTC (M13-ASPH47), AGTATTTGGTCT (M14-ASPH47), AGTATTTGGTC (M15-ASPH47), and CAAAGTATTTGGTCTCC (ASPH47). 
     
     
         5 . A pharmaceutical composition comprising the antisense oligonucleotide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         6 . A method for inhibiting and/or treating at least one of a malignant tumor, a benign tumor, an immunologic disease, a fibrosis, or an ophthalmic disease, comprising:
 administering either an antisense oligonucleotide or a pharmaceutical composition;   said antisense oligonucleotide comprising:
 10 to 18 nucleotides hybridizing with the TGF-beta2 nucleic acid sequence of SEQ ID NO. 1, wherein one or more nucleotide(s) of the oligonucleotide is/arc modified, wherein the modified nucleotide is at least one of an LNA, an ENA, polyalkylene oxide-, 2′-fluoro-, 2′-O-methoxy-, or a 2′O-methyl-modified nucleotide 
   said pharmaceutical composition comprising:   an antisense oligonucleotide comprising:
 10 to 18 nucleotides hybridizing with the TGF-beta2 nucleic acid sequence of SEQ ID NO. 1, wherein one or more nucleotide(s) of the oligonucleotide is/are modified, wherein the modified nucleotide is at least one or an LNA, an ENA, polyalkylene oxide-, 2′-fluoro-, 2′-O-methoxy-, or a 2′O-methyl-modified nucleotide; and 
   a pharmaceutically acceptable carrier.   
     
     
         7 . The antisense oligonucleotide of  claim 3 , wherein the oligonucleotide is selected from the group consisting of AGTATTTGGTCTCC (ASPH190), AAGTATTTGGTCTC (ASPH191), AAGTATTTGGTCTCC (ASPH192), CAAAGTATTTGGTCT (ASPH193), AGTATTTGGTCTCC (ASPH194), AGTATTTGGTCTCC (ASPH195), AGTATTTGGTCTCC (ASPH196), AGTATTTGGTCTCC (ASPH197), AAGTATTTGGTCTC (ASPH198), AGTATTTGGTCTCCA (ASPH199), AGTATTTGGTCTCCA (ASPH200), AGTATTTGGTCTCCA (ASPH201), AGTATTTGGTCTCCA (ASPH202), AGTATTTGGTCTCCA (ASPH203), AGTATTTGGTCTCCA (ASPH204), AGTATTTGGTCTCCA (ASPH205), AAGTATTTGGTCTCC (ASPH206), AAGTATTTGGTCTCC (ASPH207), AAGTATTTGGTCTCC (ASPH208), AAGTATTTGGTCTCC (ASPH209), AAGTATTTGGTCTCC (ASPH210), AAGTATTTGGTCTCC (ASPH211), CAAAGTATTTGGTCTCC (ASPH212), CAAAGTATTTGGTCTCC (ASPH213), CAAAGTATTTGGTCTCC (ASPH214), CAAAGCTATTTGGTCTCC (ASPH215), CAAAGTATTTGGTCTCC (ASPH216), CAAAGTATTTGGTCTCC (ASPH217), CAAAGTATTTGGTCTCC (ASPH218), CAAAGTATTTGGTCTCC (ASPH219), CAAAGTATTTGGTCTCC (ASPH220), CAAAGTATTTGGTCTCC (ASPH221), CAAAGTATTTGGTCTCC-TEG (ASPH222), CAAAGTATTTGGTCTCC-TEG (ASPH223), CAAAGTATTTGGTCTC (M1-ASPH47), CAAAGTATTTGGTCT (M2-ASPH47), CAAAGTATTTGGTC (M3-ASPH47), AAAGTATTTGGTCTCC (M4-ASPH47), AAAGTATTTGGTCTC (M5-ASPH47), AAAGTATTTGGTCT (M6-ASPH47), AAAGTATTTGGTC (M7-ASPH47), AAGTATTTGGTCTCC (M8-ASPH47), AAGTATTTGGTCTC (M9-ASPH47), AAGTATTTGGTCT (M10-ASPH47), AAGTATTTGGTC (M11-ASPH47), AGTATTTGGTCTCC (M12-ASPH47), AGTATTTGGTCTC (M13-ASPH47), AGTATTTGGTCT (M14-ASPH47), AGTATTTGGTC (M15-ASPH47), and CAAAGTATTTGGTCTCC (ASPH47).