Treatment of transcription factor E3 (TFE3) and insulin receptor substrate 2(IRS2) related diseases by inhibition of natural antisense transcript to TFE3
View Patent ↗The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) polynucleotides, in particular, by targeting natural antisense polynucleotides of Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of TFE3 and/or IRS2.
1. A method of upregulating a function of and/or the expression of an Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) polynucleotide in cells or tissues in vivo or in vitro comprising:
contacting, said cells or tissues with at least one antisense oligonucleotide of 15-30 nucleotides in length that specifically targets a region of a natural antisense polynucleotide of the Transcription factor E3 (TFE3) polynucleotide comprising SEQ ID NO: 3; thereby upregulating a function of and/or the expression of the Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) polynucleotide in cells or tissues in vivo or in vitro.
2. The method of claim 1 , wherein a function of and/or the expression of the Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) is increased in vivo or in vitro with respect to a control.
3. The method of claim 1 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide antisense to coding and/or non-ending nucleic acid sequences of a Transcription factor E3 (TFE3) polynucleotide.
4. The method of claim 1 , wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide having overlapping: and/or non-overlapping sequences with a Transcription factor E3 (TFE3) polynucleotide.
5. The method 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 intemucleoside 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′-metboxy 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 front: a phosphorothioate, alkylphosphonate, phosphorodithioate, alkylphosphonothioate, phosphoramidate, earbamate, 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 at least one oligonucleotide sequences set forth as SEQ ID NOS: 4 to 6.
10. A method of upregulating a function of and/or the expression of an Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) gene in mammalian cells or tissues in vivo or in vitro comprising:
contacting said cells or tissues with at least one short interfering RNA (siRNA) oligonucleotide 19 to 30 nucleotides in length, said at least one siRNA oligonucleotide being specific for a natural antisense polynucleotide of an Transcription factor E3 (TFE3) polynucleotide selected from SEQ ID NO: 3, wherein said at least one siRNA oligonucleotide has at least 80% sequence complementarity to about 19 consecutive nucleic acids of said natural antisense polynucleotide of the Transcription factor E3 (TFE3) polynucleotide; and, upregulating a function of and/or the expression of Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) in mammalian cells or tissues in vivo or in vitro.
11. The method of claim 10 , wherein said oligonueleotide has at least 90% sequence complementarity to the natural antisense polynucleotide of the Transcription factor E3 (TFE3) polynucleotide.
12. A method of upregulating a function of and/or the expression of Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) in mammalian cells or tissues in vitro comprising:
contacting said cells or tissues with at least one antisense oligonucleotide of about 15 to 30 nucleotides in length specific for a natural antisense strand of an Transetiption factor E3 (TFE3) polynucleotide selected from SEQ ID NO: 3 wherein said at least one antisense oligonucleotide has at least 80% sequence complementarity to said natural antisense strand thereby upregulating the function and/or expression of the Transcription factor E3 (TFE3) and/or Insulin Receptor Substrate 2 (IRS2) in mammalian cells or tissues in vitro.