Treatment of methionine sulfoxide reductase a (MSRA) related diseases by inhibition of natural antisense transcript to MSRA

• US 8,980,858 B2
• Filed: 05/25/2011
• Issued: 03/17/2015
• Est. Priority Date: 05/26/2010
• 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): GIBBS, TERRA C
• Application Number:
  US13/699,356
• Publication Number:
  US 20130072546A1
• Time in Patent Office: 1,392 Days
• Field of Search: 514/44, 536/24.5
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/16 Otologicals
• 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: 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 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2330/10 naturally occurring
• CPC Class Codes: C12N 9/0051 acting on a sulfur group of donors (1.8)
• CPC Class Codes: C12Y 108/04011 Peptide-methionine (S)-S-oxide reductase (1.8.4.11)

Abstract

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Methionine Sulfoxide Reductase A (MSRA), in particular, by targeting natural antisense polynucleotides of Methionine Sulfoxide Reductase A (MSRA). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of MSRA.

Claims

1. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 in a mammal comprising;

contacting said mammal with at least one antisense oligonucleotide 12 to 30 nucleotides in length wherein said at least one oligonucleotide has at least 80% sequence identity to a reverse complement of a natural antisense of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide;

thereby upregulating a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

2. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide in a mammal according to claim 1 comprising:

contacting said mammal with at least one antisense oligonucleotide 12 to 30 nucleotides in length wherein said at least one oligonucleotide has at least 90% sequence identity to a reverse complement of a polynucleotide comprising 12 to 30 nucleotides within the natural antisense transcript nucleotides 1 to 3774 of SEQ ID NO;

2;

thereby upregulating a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

14. The method of claim 1, wherein the at least one oligonucleotide comprises at least one oligonucleotide sequences set forth as SEQ ID NOS:

3 to 9.

3. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 in mammalian cells or tissues in vivo or in vitro comprising;

contacting said cells or tissues with at least one antisense oligonucleotide 12 to 30 nucleotides in length wherein said oligonucleotide has at least 90% sequence identity to an RNA transcribed from the Methionine Sulfoxide Reductase A (MSRA) polynucleotide;

thereby upregulating a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide in mammalian cells or tissues in vivo or in vitro.

4. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 in mammalian cells or tissues according to claim 3 comprising;

contacting said mammalian cell with at least one antisense oligonucleotide 12 to 30 nucleotides in length wherein said at least one oligonucleotide has at least 90% sequence identity to a reverse complement of a polynucleotide comprising 12 to 30 consecutive nucleotides within the natural antisense transcript nucleotides 1 to 3774 of SEQ ID NO;

2;

thereby upregulating a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

5. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 in a mammalian system comprising;

contacting said system with at least one antisense oligonucleotide of 12 to 28 nucleotides in length that specifically targets and hybridizes to a region of a natural antisense polynucleotide of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide;

thereby upregulating a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

6. The method of claim 5, wherein a function of and/or the expression of the Methionine Sulfoxide Reductase A (MSRA) is increased in vivo or in vitro with respect to a control.

7. The method of claim 5, wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

2.

8. The method of claim 5, wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide antisense to coding and/or non-coding nucleic acid sequences of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

9. The method of claim 5, wherein the at least one antisense oligonucleotide targets a natural antisense polynucleotide having overlapping sequences with a Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

10. The method of claim 5, 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.

11. The method of claim 10, 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.

12. The method of claim 10, 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.

13. The method of claim 10, 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.

15. A method of upregulating a function of and/or the expression of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 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 12 to 30 nucleotides in length, said at least one siRNA oligonucleotide being specific for a natural antisense polynucleotide of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide, wherein said at least one siRNA oligonucleotide has at least 90% sequence complementarity to at least about 19 nucleotides of the natural antisense polynucleotide of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide; and

, upregulating a function of and/or the expression of Methionine Sulfoxide Reductase A (MSRA) in mammalian cells or tissues in vivo or in vitro.

16. The method of claim 15, wherein said oligonucleotide has sequence complementarity to a sequence of at least about 19 nucleotides of the natural antisense polynucleotide of the Methionine Sulfoxide Reductase A (MSRA) polynucleotide.

17. A method of upregulating a function of and/or the expression of Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1 in mammalian cells or tissues in vivo or in vitro comprising;

contacting said cells or tissues with at least one antisense oligonucleotide of about 12 to 30 nucleotides in length specific for noncoding and/or coding sequences of a natural antisense strand of a Methionine Sulfoxide Reductase A (MSRA) polynucleotide wherein said at least one antisense oligonucleotide has at least 90% sequence identity to a 12 to 30 nucleotide region of a nucleic acid sequence set forth as SEQ ID NO;

1; and

, upregulating the function and/or expression of the Methionine Sulfoxide Reductase A (MSRA) in mammalian cells or tissues in vivo or in vitro.

18. A method of treating a disease associated with at least one Methionine Sulfoxide Reductase A (MSRA) polynucleotide having SEQ ID NO:

1, comprising;

administering to a patient a therapeutically effective dose of at least one antisense oligonucleotide of 12 to 30 nucleotides in length that binds and specifically hybridizes to a natural antisense sequence of said at least one Methionine Sulfoxide Reductase A (MSRA) polynucleotide and upregulates expression of said at least one Methionine Sulfoxide Reductase A (MSRA) polynucleotide;

thereby treating the disease associated with the at least one Methionine Sulfoxide Reductase A (MSRA) polynucleotide and/or at least one encoded product thereof and wherein the disease or condition associated with the at least one Methionine Sulfoxide Reductase A (MSRA) polynucleotide is selected from cellular oxidative stress or a neurological disease or disorder or a retinal disease or disorder.