Treatment of transcription factor E3 (TFE3) and insulin receptor substrate 2(IRS2) related diseases by inhibition of natural antisense transcript to TFE3

• US 8,895,527 B2
• Filed: 05/21/2010
• Issued: 11/25/2014
• Est. Priority Date: 05/22/2009
• Status: Active Grant

• Current Assignee: CURNA, Inc. (Opko Health, Inc.)
• Original Assignee: CURNA, Inc. (Opko Health, Inc.)
• Inventors: Collard, Joseph, Khorkova Sherman, Olga
• Primary Examiner(s): WHITEMAN, BRIAN A
• Application Number:
  US13/321,863
• Publication Number:
  US 20120095079A1
• Time in Patent Office: 1,649 Days
• Field of Search: 514/44.A
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12Q 1/6825 Nucleic acid detection involving sensors

Abstract

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.

Claims

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.