Treatment of uncoupling protein 2 (UCP2) related diseases by inhibition of natural antisense transcript to UCP2
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Uncoupling Protein 2 (UCP2), in particular, by targeting natural antisense polynucleotides of Uncoupling Protein 2 (UCP2). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of UCP2.
1. A synthetic, oligonucleotide of 14 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 is 100% complementary to a 14-30 nucleotide region of a natural antisense polynucleotide of a Uncoupling Protein 2 (UCP2) polynucleotide having SEQ ID NO: 2 or 3 and specifically hybridizes to at least one nucleotide of a target region of a natural antisense polynucleotide of said Uncoupling Protein 2 (UCP2) polynucleotide selected from nucleotides 1 to 174 of SEQ ID NO: 2 or nucleotides 1 to 267; 375-575 and 685-802 of SEQ ID NO:3 and upregulates the function and/or expression of the Uncoupling Protein 2 (UCP2) gene in vivo or in vitro as compared to a normal control.
2. The oligonucleotide of claim 1 , 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.
3. The oligonucleotide of claim 1 , wherein said oligonucleotide comprises at least one phosphorothioate internucleotide linkage.
4. The oligonucleotide of claim 1 , wherein said oligonucleotide comprises a backbone of phosphorothioate internucleotide linkages.
5. The oligonucleotide of claim 1 , wherein the oligonucleotide comprises at least one modified nucleotide, said modified nucleotide selected from: a peptide nucleic acid, a locked nucleic acid (LNA), and a combination thereof.
6. The oligonucleotide of claim 1 , 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.
7. The oligonucleotide of claim 1 , wherein the oligonucleotide comprises a plurality of modifications, wherein said modifications comprise modified nucleotides selected from: peptide nucleic acids, locked nucleic acids (LNA), and a combination thereof.
8. The oligonucleotide of claim 1 , 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.
9. The oligonucleotide of claim 1 , 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.
10. The oligonucleotide of claim 1 , wherein the oligonucleotide comprises the sequences set forth as SEQ ID NOS: 4, 5, 11 and 13.
11. A composition comprising one or more oligonucleotides according to claim 1 and a pharmaceutically acceptable excipient.
12. A composition comprising an oligonucleotide and a pharmaceutically acceptable excipient, wherein the oligonucleotide has at least about 95% sequence identity as compared to any one of the nucleotide sequences set forth as SEQ ID NOS: 4, 5, 11 and 13.
13. The composition of claim 11 , wherein the oligonucleotides comprise nucleotide sequences set forth as SEQ ID NOS: 4, 5, 11 and 13.
14. The composition of claim 13 , wherein the oligonucleotides set forth as SEQ ID NOS: 4, 5, 11 and 13 comprise one or more modifications or substitutions.
15. The composition of claim 14 , wherein the one or more modifications are selected from: phosphorothioate, methylphosphonate, peptide nucleic acid, locked nucleic acid (LNA) molecules, and combinations thereof.