Treatment of sialidase 4 (neu4) related diseases by inhibition of natural antisense transcript to neu4

Abstract

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Sialidase 4 (NEU4), in particular, by targeting natural antisense polynucleotides of Sialidase 4 (NEU4). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of NEU4.

What is claimed is: 
     
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         18 . A synthetic, modified oligonucleotide of 10 to 30 nucleotides in length comprising at least one modification wherein the at least one modification is selected from: at least one modified sugar moiety; at least one modified internucleotide linkage; at least one modified nucleotide, and combinations thereof; wherein said oligonucleotide is an antisense compound which hybridizes to a natural antisense polynucleotide of the Sialidase 4 (NEU4) gene and upregulates the function and/or expression of a Sialidase 4 (NEU4) gene in vivo or in vitro as compared to a normal control. 
     
     
         19 . The oligonucleotide according to  claim 18  wherein said oligonucleotide targets the natural antisense polynucleotides selected from the group consisting of SEQ ID NOS: 2-7 of the NEU4 gene. 
     
     
         20 . The oligonucleotide of  claim 19 , wherein the at least one modification comprises an internucleotide linkage selected from the group consisting of: phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof. 
     
     
         21 . The oligonucleotide of  claim 19 , wherein said oligonucleotide comprises at least one phosphorothioate internucleotide linkage. 
     
     
         22 . The oligonucleotide of  claim 19 , wherein said oligonucleotide comprises a backbone of phosphorothioate internucleotide linkages. 
     
     
         23 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises at least one modified nucleotide, said modified nucleotide selected from: a peptide nucleic acid, a locked nucleic acid (LNA), analogue, derivative, and a combination thereof. 
     
     
         24 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified nucleotides selected from: phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and a combination thereof. 
     
     
         25 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified nucleotides selected from: peptide nucleic acids, locked nucleic acids (LNA), analogues, derivatives, and a combination thereof. 
     
     
         26 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises at least one modified sugar moiety selected from: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and a combination thereof. 
     
     
         27 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified sugar moieties selected from: a 2′-O-methoxyethyl modified sugar moiety, a 2′-methoxy modified sugar moiety, a 2′-O-alkyl modified sugar moiety, a bicyclic sugar moiety, and a combination thereof. 
     
     
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         29 . The oligonucleotide of  claim 19 , wherein the oligonucleotide has at least about 80% sequence identity to a complementary sequence of at least about ten consecutive nucleic acids of the antisense and/or sense coding and/or noncoding nucleic acid sequence of the Sialidase 4 (NEU4) polynucleotide. 
     
     
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         31 . The oligonucleotide of  claim 19 , wherein the oligonucleotide comprises the sequences set forth as SEQ ID NOS: 8 to 11. 
     
     
         32 . A pharmaceutical composition comprising one or more oligonucleotides specific for a Sialidase 4 (NEU4) natural antisense polynucleotides according to  claim 18  and a pharmaceutically acceptable excipient. 
     
     
         33 . The composition of  claim 32 , wherein the oligonucleotides have at least about 40% sequence identity as compared to any one of the nucleotide sequences set forth as SEQ ID NOS: 8 to 11. 
     
     
         34 . The composition of  claim 32 , wherein the oligonucleotides comprise nucleotide sequences set forth as SEQ ID NOS: 8 to 11. 
     
     
         35 . The composition of  claim 34 , wherein the oligonucleotides set forth as SEQ ID NOS: 8 to 11 comprise one or more modifications or substitutions. 
     
     
         36 . The composition of  claim 35 , wherein the one or more modifications are selected from: phosphorothioate, methylphosphonate, peptide nucleic acid, locked nucleic acid (LNA) molecules, and combinations thereof. 
     
     
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         39 . A method of inducing apoptosis in a biological system comprising administration of an oligonucleotide of 5 to 30 nucleotides in length and which is at least 50% identical to 5 to 30 consecutive nucleotides within a reverse complement of a natural antisense transcript to a NEU4 polynucleotide to said system. 
     
     
         40 . The method according to  claim 39  wherein the natural antisense transcript has SEQ ID NOS: 2 to 7. 
     
     
         41 . The method according to  claim 39  wherein the biological system is a patient cell or tissue. 
     
     
         42 . A method of inducing apoptosis in a biological system comprising administration of an oligonucleotide of about 5 to 30 nucleotides in length to said system wherein said oligonucleotide upregulates a target gene by targeting to a natural antisense transcript of the gene and wherein said oligonucleotide is at least 50% identical to a reverse complement of the natural antisense transcript of the upregulated gene. 
     
     
         43 . A method of identifying and selecting at least one oligonucleotide selective for a natural antisense transcript of a NEU4 gene as a selected target polynucleotide for in vivo administration comprising: identifying at least one oligonucleotide comprising at least five consecutive nucleotides which are at least partially complementary to a polynucleotide that is antisense to the selected target polynucleotide; measuring the thermal melting point of a hybrid of an antisense oligonucleotide and the target polynucleotide or the polynucleotide that is antisense to the selected target polynucleotide under stringent hybridization conditions; and selecting at least one oligonucleotide for in vivo administration based on the information obtained.