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

• US 9,677,074 B2
• Filed: 05/04/2015
• Issued: 06/13/2017
• Est. Priority Date: 12/31/2009
• Status: Expired due to Fees

• Current Assignee: CURNA, Inc. (Opko Health, Inc.)
• Original Assignee: CURNA, Inc. (Opko Health, Inc.)
• Inventors: Collard, Joseph, Khorkova Sherman, Olga
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US14/702,999
• Publication Number:
  US 20150232850A1
• Time in Patent Office: 771 Days
• Field of Search: None
• CPC Class Codes: A61K 31/711 Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/11 Antisense
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/312 : Phosphonates
• CPC Class Codes: C12N 2310/313 : Phosphorodithioates
• CPC Class Codes: C12N 2310/314 : Phosphoramidates
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12N 2310/316 : Phosphonothioates
• CPC Class Codes: C12N 2310/3181 : Peptide nucleic acid, PNA
• CPC Class Codes: C12N 2310/32 : of the sugar
• CPC Class Codes: C12N 2310/321 : 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 : 2'-R Modification
• CPC Class Codes: C12N 2310/3231 : having an additional ring, e.g. LNA, ENA

Abstract

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Insulin Receptor Substrate 2 (IRS2) polynucleotides, in particular, by targeting natural antisense polynucleotides of Insulin Receptor Substrate 2 (IRS2) polynucleotides and Transcription factor E3 (TFE3). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of IRS2.

Claims

1. A method of upregulating a function of and/or the expression of a Insulin Receptor Substrate 2 (IRS2) polynucleotide in mammalian cells or tissues in vivo or in vitro comprising:

contacting said cells or tissues with at least one antisense oligonucleotide of 10 to 30 nucleotides in length that targets, is 100% complementary to and specifically hybridizes to a complementary region of a natural antisense polynucleotide of the Insulin Receptor Substrate 2 (IRS2) polynucleotide consisting essentially of SEQ ID NO;

3;

thereby upregulating a function of and/or the expression of the Insulin Receptor Substrate 2 (IRS2) polynucleotide in mammalian cells or tissues in vivo or in vitro.

2. The method of claim 1, wherein a function of and/or the expression of the 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-coding nucleic acid sequences of a Insulin Receptor Substrate 2 (IRS2) 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 Insulin Receptor Substrate 2 (IRS2) 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 internucleoside linkage, at leas 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, alkylphosphonothioate, 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 5, wherein the at least one oligonucleotide comprises at least one oligonucleotide sequences set forth as SEQ ID NOS:

6, 8 and 9.

10. A method of upregulating a function of and/or the expression of a 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 specifically hybridizing to and at least 90% complementary to a natural antisense polynucleotide of a Insulin Receptor Substrate 2 (IRS2) polynucleotide consisting essentially of SEQ ID NO;

3, wherein said at least one siRNA oligonucleotide upregulates a function of and/or the expression of or Insulin Receptor Substrate 2 (IRS2) in mammalian cells or tissues in vivo or in vitro.

11. A method of treating a disease associated with at least one Insulin Receptor Substrate 2 (IRS2) polynucleotide and/or at least one encoded product thereof, comprising:

administering to a patient a therapeutically effective dose of at least one modified antisense oligonucleotide of 10 to 30 nucleotides in length that specifically hybridizes and is at least 90% complementary to a complementary sequence of a natural antisense sequence of said at least one Insulin Receptor Substrate 2 (IRS2) polynucleotide consisting essentially of SEQ ID NO;

3 and upregulates expression of said at least one Insulin Receptor Substrate 2 (IRS2) polynucleotide;

thereby treating the disease associated with the at least one Insulin Receptor Substrate 2 (IRS2) polynucleotide and/or at least one encoded product thereof wherein the disease is selected from the group consisting of diabetes and Alzheimer'"'"'s disease.

12. The method of claim 11, wherein the oligonucleotides have nucleotide sequences selected from the group consisting of SEQ ID NOs:

6, 8 and 9.