Use of single-stranded antisense oligonucleotide in prevention or treatment of genetic diseases involving a trinucleotide repeat expansion

Abstract

The invention relates to antisense oligonucleotides (AONs) comprising repetitive trinucleotide units for use in the treatment or prevention of genetic eye diseases, preferably eye dystrophy disorders caused by RNA toxicity such as Fuch's Endothelial Corneal Dystrophy (FECD). The oligonucleotides of the present invention are used to target trinucleotide repeat (TNR) sequence expansions present in intron sequences, to prevent the disease-related sequestration of cellular proteins that interact with such TNR expansions.

1 . A single-stranded antisense oligonucleotide for use in the prevention and/or treatment of a genetic disease, wherein said oligonucleotide is at least partially complementary to a target RNA molecule, and wherein said oligonucleotide is capable of binding a trinucleotide repeat (TNR) expansion present in an intron sequence within said target RNA molecule. 
     
     
         2 . An oligonucleotide for use according to  claim 1 , wherein said TNR expansion comprises the sequence 5′-(CUG)n-3′, wherein n is an integer of 40 or greater. 
     
     
         3 . An oligonucleotide for use according to  claim 2 , wherein n is an integer of 50 or greater. 
     
     
         4 . An oligonucleotide for use according to any one of  claims 1  to  3 , wherein all nucleotides of the oligonucleotide are 2′-O methyl phosphorothioate ribonucleotides. 
     
     
         5 . An oligonucleotide for use according to any one of  claims 1  to  4 , said oligonucleotide comprising the sequence 5′-(CAG)m-3′, 5′-(CAI)m-3′, 5′-(CGG)m-3′, 5′-(CGI)m-3′, 5′-(CIG)m-3′, 5′-(CII)m-3′, 5′-(UAG)m-3′, 5′-(UAI)m-3′, 5′-(UGG)m-3′, 5′-(UGI)m-3′, 5′-(UI)m-3′ and/or 5′-(UII)m-3′, wherein m is an integer ranging from 2 to 66. 
     
     
         6 . An oligonucleotide for use according to  claim 5 , wherein m is an integer of 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17. 
     
     
         7 . An oligonucleotide for use according to any one of  claims 1  to  6 , wherein the oligonucleotide has a length of 9 or more nucleotides. 
     
     
         8 . An oligonucleotide for use according to any one of  claims 1  to  7 , wherein said TNR expansion is present in a transcript of the TCF4 gene. 
     
     
         9 . An oligonucleotide for use according to any one of  claims 1  to  8 , wherein said genetic disease is an eye dystrophy caused by RNA toxicity. 
     
     
         10 . An oligonucleotide for use according to  claim 9 , wherein said eye dystrophy is Fuchs Endothelial Corneal Dystrophy (FECD). 
     
     
         11 . An oligonucleotide for use according to any one of  claims 1  to  10 , wherein said oligonucleotide is selected from the group consisting of the antisense oligonucleotides (AONs) with SEQ ID NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 101, 102 and 103. 
     
     
         12 . An oligonucleotide for use according to any one of  claims 1  to  11 , wherein said use is in a human subject suffering from said genetic disease, or at risk of suffering from said genetic disease. 
     
     
         13 . An oligonucleotide as defined in any one of  claims 1  to  12 . 
     
     
         14 . A pharmaceutical composition comprising an oligonucleotide according to  claim 13 , and a pharmaceutically acceptable excipient. 
     
     
         15 . A composition according to  claim 14 , further comprising an oligonucleotide delivery enhancing agent. 
     
     
         16 . A pharmaceutical composition comprising a viral or a non-viral gene delivery vehicle coding for a nucleic acid sequence that comprises or consists of an oligonucleotide according to  claim 13 . 
     
     
         17 . A method of treating or preventing FECD in a human subject, said method comprising administering an oligonucleotide according to  claim 13 , or a composition according to any one of  claims 14  to  16 , to the corneal stroma of said human subject by intrastromal injection, or to the anterior chamber fluid of said human subject by intracameral injection, or to the posterior chamber of said human subject by intravitreal injection.