Oligonucleotide sequences targeting transcription factor TSC22D4 for the treatment of insulin resistance

Patent metadata

Field	Value
Publication number	US-10676739-B2
Application number	US-201615545104-A
Country	US
Kind code	B2
Filing date	Feb 12, 2016
Priority date	Mar 23, 2015
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

The present invention relates to oligonucleotide inhibitors of the TSC22D4 activity or expression and their uses for the prevention, treatment, and/or regulation of insulin resistance, metabolic syndrome and/or diabetes and/or for improving insulin sensitivity in a mammal.

First claim

The invention claimed is:

1. An inhibitor of expression and/or biological activity of transforming growth factor beta1 stimulated clone 22 D4 (TSC22D4) wherein said inhibitor is selected from an oligonucleotide that is an interfering ribonucleic acid, PNA (protein nucleic acid) or LNA (locked nucleic acid), and wherein said oligonucleotide comprises at least one sequence selected from:
5′-GGAUGUUUACGAGAGAGAUdTdT-3′ (SEQ ID NO: 2);
5′-AGUCCCACCUCAUGUUUGCdTdT-3′ (SEQ ID NO: 3);
and complementary sequences thereof.

2. The inhibitor according to claim 1 , wherein the interfering ribonucleic acid is a small interfering ribonucleic acid (siRNA) or small hairpin ribonucleic acid (shRNA) or micro ribonucleic acid (miRNA) or a combination thereof.

3. The inhibitor according to claim 2 , wherein the siRNA has a length of 19 to 30 nucleotides.

4. The inhibitor according to claim 2 , wherein the siRNA consists of at least one of SEQ ID NOs: 2 and 3.

5. A recombinant vector, comprising an oligonucleotide according to claim 1 .

6. A recombinant cell, comprising an oligonucleotide according to claim 1 .

7. A pharmaceutical composition, comprising at least one of the inhibitor according to claim 1 , together with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7 , wherein said pharmaceutical composition is formulated for administration orally, rectally, transmucosally, transdermally, intestinally, parenterally, intramuscularly, intrathecally, direct intraventricularly, intravenously, intraperitoneally, intranasally, intraocularly, or subcutaneously.

9. A method for prevention, regulation, and/or treatment of a disease, and/or for improving insulin sensitivity, wherein said method comprises administering, to a subject in need of such prevention, regulation, treatment, and/or improvement, an inhibitor of TSC22D4 wherein said inhibitor is selected from an oligonucleotide that is an interfering ribonucleic acid, PNA (protein nucleic acid) or LNA (locked nucleic acid), and wherein said oligonucleotide comprises at least one sequence selected from:
5′-GGACGUGUGUGGAUGUUUAdTdT-3′ (SEQ ID NO: 1);
5′-GGAUGUUUACGAGAGAGAUdTdT-3′ (SEQ ID NO: 2);
5′-AGUCCCACCUCAUGUUUGCdTdT-3′ (SEQ ID NO: 3);
and complementary sequences thereof.

10. The method, according to claim 9 , wherein said disease is selected from insulin resistance, hypertension, dyslipidemia, coronary artery disease, metabolic syndrome and diabetes type 1.

11. The method, according to claim 9 , wherein the insulin resistance is diet-induced insulin resistance and/or obesity-induced insulin resistance.

12. A therapeutic kit, comprising the inhibitor according to claim 1 , optionally together with suitable buffers and excipients, and instructions for use.

13. The therapeutic kit according to claim 12 with instructions for use in the prevention, regulation, and/or treatment of a disease, wherein said disease is selected from insulin resistance, hypertension, dyslipidemia, coronary artery disease, metabolic syndrome and/or diabetes type 1 or 2, and/or for improving insulin sensitivity.

14. The method, according to claim 9 , for improving insulin sensitivity in the context of a tumorous disease.

15. The inhibitor according to claim 1 , wherein the oligonucleotide comprises SEQ ID NO: 2 or the complementary sequence thereof.

16. The inhibitor according to claim 1 , wherein the oligonucleotide comprises SEQ ID NO: 3 or the complementary sequence thereof.

17. The inhibitor according to claim 1 , wherein the interfering ribonucleic acid is a siRNA.

18. The inhibitor according to claim 17 , wherein the siRNA is a RNA duplex comprising at least one of:
1) SEQ ID NO: 2 and SEQ ID NO: 5; and
2) SEQ ID NO: 3 and SEQ ID NO: 6.

Assignees

• Deutsches Krebsforschungszentrum Stiftung Des Oeffentlichen Rechts

Inventors

• Herzig Stephan
• Berriel Diaz Mauricio
• Schafmeier Tobias

Classifications

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• C12N2310/3181

  Peptide nucleic acid, PNA · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N15/113 Primary

  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 title

• C12N2310/531

  Stem-loop; Hairpin · CPC title