Treatment of sirtuin (SIRT) related diseases by inhibition of natural antisense transcript to a sirtuin (SIRT)
The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of a Sirtuin (SIRT), in particular, by targeting natural antisense polynucleotides of a Sirtuin (SIRT). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of Sirtuins (SIRT)s.
1. A method of upregulating function of and/or the expression of a Sirtuin (SIRT) gene/ polynucleotide selected from the group consisting of SIRT 3, 4, 5 and 7 in patient cells or tissues in vivo or in vitro comprising: contacting said cells or tissues with at least one antisense oligonucleotide of 10-30 nucleotides in length that specifically targets a complementary region of a natural antisense oligonucleotide of the Sirtuin (SIRT) polynucleotide wherein said natural antisense oligonucleotide is selected from the group consisting of polynucleotides 1 to 726 of SEQ ID NO: 17, 1 to 320 of SEQ ID NO: 18, 1 to 616 of SEQ ID NO: 19, 1 to 492 of SEQ ID NO: 20, 1 to 705 of SEQ ID NO: 23 or 1 to 2714 of SEQ ID NO: 141 or 1 to 1757 of SEQ ID NO: 142 or 1 to 3647 of SEQ ID NO: 143; and wherein said oligonucleotide is specifically hybridizable thereto thereby upregulating a function of and/or the expression of the Sirtuin (SIRT) polynucleotide in patient cells or tissues in vivo or in vitro.
2. The method of claim 1 , wherein the at least one antisense oligonucleotide targets a natural antisense sequence of a Sirtuin (SIRT) polynucleotide selected from SEQ ID NO: 23.
3. The method of claim 1 wherein the at least one antisense oligonucleotide targets a natural antisense oligonucleotide antisense to coding regions of the Sirtuin (SIRT) polynucleotide.
4. The method of claim 1 , wherein said cells or tissues are targeted with an antisense oligonucleotide that targets a natural antisense oligonucleotide having overlapping sequences with a Sirtuin (SIRT) RNA polynucleotide transcribed from the SIRT gene.
5. The method of any of claim 1 , wherein the at least one antisense oligonucleotide comprises one or more modifications selected from: at least one modified sugar moiety, at least one modified internucleoside linkage, at least one modified nucleotide, and combinations thereof.
6. The method of claim 5 , wherein the one or more modifications comprise 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 combinations thereof.
7. The method of claim 5 , wherein the one or more modifications comprise at least one modified internucleoside linkage selected from: a phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioates, phosphoramidate, carbamate, carbonate, phosphate triester, acetamidate, carboxymethyl ester, and combinations thereof.
8. The method of claim 5 , wherein the one or more modifications comprise at least one modified nucleotide selected from: a peptide nucleic acid (PNA), a locked nucleic acid (LNA), an arabino-nucleic acid (FANA), an analogue, a derivative, and combinations thereof.
9. The method of claim 1 , wherein the at least one oligonucleotide comprises a sequence as set forth in any of SEQ ID NOS: 94-111.122 to 127 and 144-145.
10. A method of upregulating a function of and/or the expression of a Sirtuin (SIRT) polynucleotide selected from the group consisting of SIRT 2, 4, 5 and 7 in a discordant manner in mammalian cells or tissues in vivo or in vitro comprising: contacting said cells or tissues with at least one single stranded oligonucleotide of 10 to 30 nucleotides in length or a short interfering RNA (siRNA) oligonucleotide 19 to 30 nucleotides in length, said at least one single stranded oligonucleotide or siRNA oligonucleotide being specific for a natural antisense polynucleotide of the Sirtuin (SIRT) polynucleotide, wherein said at least one single stranded or siRNA oligonucleotide has at least 80% sequence complementarity to at least about 10-19 nucleotides respectively of the natural antisense polynucleotide of the Sirtuin (SIRT) polynucleotide; and, upregulating a function of and/or the expression of the Sirtuin (SIRT) in mammalian cells or tissues in vivo or in vitro.
11. The method of claim 10 , wherein said oligonucleotide has at least 90% sequence complementarity.
12. A method of upregulating a function of and/or the expression of a Sirtuin (SIRT) polynucleotide selected from the group consisting of SIRT 2, 4, 5 and 7 in mammalian cells or tissues in vivo or in vitro comprising: contacting said cells or tissues with at least one antisense oligonucleotide of about 15 to 30 nucleotides in length specific for noncoding and/or coding sequences of a natural antisense strand of the Sirtuin (SIRT) polynucleotide and wherein said oligonucleotide is specifically hybridizable thereto wherein said at least one antisense oligonucleotide has at least 90% sequence identity to at least one 15-30 nucleic acid sequence set forth within SEQ ID NOS: 3, 5, 6, 8 and 134-136 and 0.139 or an RNA transcribed from the SIRT 2, 4, 5 or 7 polynucleotide; and, upregulating the function and/or expression of the Sirtuin (SIRT) in mammalian cells or tissues in vivo or in vitro.