Oligonucleotides to treat eye disease

Abstract

The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Usher Syndrome type II and/or USH2A-associated non syndromic retina degeneration, especially by skipping a pseudo exon (PE40) between exon 40 and 41 in the human USH2A gene.

1 . An antisense oligonucleotide (AON) that is capable to inducing skipping of pseudo exon 40 (PE40) from human USH2A pre-mRNA, wherein said AON comprises a sequence that is complementary to at least 18, 19, 20, 21, 22, 23, or 24 consecutive nucleotides of SEQ ID NO:45, 46 or 47. 
     
     
         2 . An antisense oligonucleotide (AON) that is capable to inducing skipping of pseudo exon 40 (PE40) from human USH2A pre-mRNA, wherein said AON comprises a sequence selected from any of the following groups of sequences:
 (i) SEQ ID NO:6, 4, 8, 23, 30, 31, 32, 37;   (ii) SEQ ID NO:3, 5, 7, 19, 24, 25, 26, 34, 35, 36; and   (iii) SEQ ID NO:21, 27, 28, 29.   
     
     
         3 . An AON according to  claim 1 , wherein the appearance of PE40 in USH2A mRNA is due to the c.7595-2144A>G mutation in the USH2A gene. 
     
     
         4 . An AON according to  claim 1 , wherein said AON is an oligoribonucleotide (RNA oligonucleotide) comprising at least one 2′-O alkyl modification. 
     
     
         5 . An AON according to  claim 4 , wherein all nucleotides in said AON are 2′-O-methyl modified. 
     
     
         6 . An AON according to  claim 1 , wherein said AON has at least one phosphorothioate linkage. 
     
     
         7 . An AON according to  claim 6 , wherein all sequential nucleotides are interconnected by phosphorothioate linkages. 
     
     
         8 . A viral vector expressing an AON as defined in  claim 1 , when placed under conditions conducive to expression of the AON. 
     
     
         9 . A pharmaceutical composition comprising an AON according to  claim 1 , and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for intravitreal administration. 
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein the pharmaceutical composition is for intravitreal administration and is dosed in an amount ranging from 0.05 mg to 5 mg. 
     
     
         11 .- 13 . (canceled) 
     
     
         14 . A method for skipping PE40 from human USH2A pre-mRNA in a cell, said method comprising administering to said cell an AON according to  claim 1  or  claim 2 , and allowing the AON to induce, cause or stimulate skipping of PE40 from the human USH2A pre-mRNA. 
     
     
         15 . A method for the treatment of an USH2A-related disease, or a condition requiring the skip of PE40 from the USH2A pre-mRNA in an individual suffering therefrom, said method comprising administering to said individual an effective amount of an AON according to  claim 1  or  claim 2 . 
     
     
         16 . The method of  claim 15 , wherein the USH2A-related disease or the condition requiring the skip of PE40 from the USH2A pre-mRNA is Usher Syndrome Type II. 
     
     
         17 . A pharmaceutical composition comprising a viral vector according to  claim 8  and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is for intravitreal administration. 
     
     
         18 . The method of  claim 14 , wherein said administering of said AON is by administering a viral vector encoding said AON. 
     
     
         19 . The method of  claim 15 , wherein said administering of said AON is by administering a viral vector encoding said AON. 
     
     
         20 . The method of  claim 15 , wherein said administering is intravitreal administration. 
     
     
         21 . An AON according to  claim 1 , wherein said AON is an oligoribonulceotide (RNA oligonucleotide) comprising one or more 2′-O methoxyethyl modifications.