Modified tgf-beta oligonucleotide for use in a method of preventing and/or treating an ophthalmic disease

Abstract

The invention refers to an oligonucleotide consisting of 10 to 20 nucleotides of selected regions of the TGF-beta1, TGF-beta2 or TGF-beta3 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 a method for the prevention and/or treatment of glaucoma, posterior capsular opacification, dry eye, Marfan or Loeys-Dietz syndrome, riboblastoma, choroidcarcinoma, macular degeneration, such as age-related macular degeneration, diabetic macular endma, or cataract.

1 . A method of inhibiting and/or treating an ophthalmic disease associated with TGF-beta2, TGF-beta1 or TGF-beta3 expression comprising:
 administering to a subject an antisense oligonucleotide consisting of 12 to 18 nucleotides of the TGF-beta2 nucleic acid sequence of SEQ ID NO.2, of the TGF-beta1 nucleic acid sequence of SEQ ID NO. 1, or of the TGF-beta3 nucleic acid sequence of SEQ ID NO.3, wherein one or more nucleotides(s) of the oligonucleotide is/are modified, wherein the modified nucleotide is a LNA, and/or an ENA, polyalkylene oxide-, 2′-fluoro-, 2′-O-methoxy-, and/or 2′-O-methyl-modified nucleotide.   
     
     
         2 . The method of  claim 1 , wherein the modified nucleotide is located at the 5′- and/or 3′-end of the antisense oligonucleotide. 
     
     
         3 . The method of  claim 1 , wherein the ophthalmic disease is selected from the group consisting of glaucoma, posterior capsular opacification, dry eye, Marfan or Loeys-Dietz syndrome, macular degeneration, retinoblastoma and choroid carcinoma. 
     
     
         4 . The method of  claim 1 , wherein the ophthalmic disease is macular degeneration and wherein the macular degeneration is an age-related macular degeneration, diabetic macular edema, or cataract. 
     
     
         5 . The method of  claim 1 , wherein said method is directed to treating an ophthalmic disease, and wherein said administering is to a subject in need thereof. 
     
     
         6 . A method of inhibiting and/or treating an ophthalmic disease associated with TGF-beta2, TGF-beta1 or TGF-beta3 expression comprising:
 administering to a subject an antisense oligonucleotide consisting of 12 to 18 nucleotides of the TGF-beta2 nucleic acid sequence of SEQ ID NO.2, of the TGF-beta1 nucleic acid sequence of SEQ ID NO.1, or of the TGF-beta3 nucleic acid sequence of SEQ ID NO.3, wherein one or more nucleotides(s) of the oligonucleotide is/are modified, wherein the modified nucleotide is a LNA, and/or an ENA, polyalkylene oxide-, 2′-fluoro-, 2′-O-methoxy-, and/or 2′-O-methyl-modified nucleotide, wherein said oligonucleotide is selected from the group consisting of TACTATTATGGCATCCC (SEQ ID No. 64), CTAGTACCGCCTT (SEQ ID No. 106), TCTGATCACCACCACTGG (SEQ ID No. 43), GACCGTGACCAGAT (SEQ ID No. 9), TCTGAACTAGTACCGCC (SEQ ID No. 60), CAGATGCCAGTFTTTTAAC (SEQ ID No. 48), AGCGTAATTGGTCATCA (SEQ ID No. 66), GGTTAGAGAGGTTCTA (SEQ ID No. 128), CGTCGCTCCTCTCG (SEQ ID No. 92), CGTCGCTCCTCTCG (SEQ ID No. 61), CAAAGTATTTGGTCTCC (SEQ ID No. 49), ACCACTAGAGCACC (SEQ ID No. 98), ATGGTTAAGGTTC (SEQ ID No. 129), TCTGTAGGAGGGC (SEQ ID No. 47), AGTATTGGTCTCCA (SEQ ID No. 403).   
     
     
         7 . The method of  claim 6 , wherein said method is directed to treating an ophthalmic disease, and wherein said administering is to a subject in need thereof. 
     
     
         8 . The method of  claim 7 , wherein the ophthalmic disease is selected from the group consisting of glaucoma, posterior capsular opacification, dry eye, Marfan or Loeys-Dietz syndrome, macular degeneration, retinoblastoma and choroid carcinoma. 
     
     
         9 . The method of  claim 7 , wherein the ophthalmic disease is macular degeneration and wherein the macular degeneration is an age-related macular degeneration, diabetic macular edema, or cataract. 
     
     
         10 . A method of inhibiting and/or treating an ophthalmic disease associated with TGF-beta2, TGF-beta1 or TGF-beta3 expression comprising: administering to a subject an antisense oligonucleotide, said oligonucleotide comprising TACTATTATGGCATCCC (SEQ ID No. 64), CTAGTACCGCCTT (SEQ ID No. 106), TCTGATCACCACTGG (SEQ ID No. 43), GACCGTGACCAGAT (SEQ ID No. 9), TCTGAACTAGTACCGCC (SEQ ID No. 60), CAGATGCCAGTTTTAAC (SEQ ID No. 48), AGCGTAATTGGTCATCA (SEQ ID No. 66), GGTTAGAGGTTCTA (SEQ ID No. 128), CGTCGCTCCTCTCG (SEQ ID No. 92), CGTCGCTCCTCTCG (SEQ ID No. 61), CAAAGTATTTGGTCTCC (SEQ ID No. 49), ACCACTAGAGCACC (SEQ ID No. 98), ATGGTTAGAGGTTC (SEQ ID No. 129), TCTGTAGGAGGGC (SEQ ID No. 47), AGTATTTGGTCTCCA (SEQ ID No. 403). 
     
     
         11 . The method of  claim 10 , wherein said method is directed to treating an ophthalmic disease, and wherein said administering is to a subject in need thereof. 
     
     
         12 . The method of  claim 11 , wherein the ophthalmic disease is selected from the group consisting of glaucoma, posterior capsular opacification, dry eye, Marfan or Loeys-Dietz syndrome, macular degeneration, retinoblastoma and choroid carcinoma. 
     
     
         13 . The method of  claim 11 , wherein the ophthalmic disease is macular degeneration and wherein the macular degeneration is an age-related macular degeneration, diabetic macular edema, or cataract.