Gene expression and pain

• US 8,093,225 B2
• Filed: 03/15/2011
• Issued: 01/10/2012
• Est. Priority Date: 05/11/2007
• Status: Active Grant

• Current Assignee: Adynxx Sub, Inc.
• Original Assignee: Adynxx, Inc
• Inventors: Mamet, Julien
• Primary Examiner(s): Schultz, Doug
• Application Number:
  US13/048,793
• Publication Number:
  US 20110166212A1
• Time in Patent Office: 301 Days
• Field of Search: None
• US Class Current: 514/44.R
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• 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 2310/13 Decoys
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

The present invention relates to double-stranded oligonucleotides, pharmaceutical compositions thereof, and use of such double-stranded oligonucleotides and pharmaceutical compositions to modulate nociceptive signaling in a cell or prevent and/or treat pain in a patient.

Claims

1. A method for treating or managing pain in a patient comprising administering to said patient a therapeutically effective amount of an oligonucleotide decoy, wherein the decoy comprises an EGR1 binding site is less than 65 base pairs in length, wherein the EGR1 binding site comprises a sequence capable of competing with SEQ ID NO:

41 for EGR1 binding in a quantitative competition ELISA assay.

2. The method of claim 1, wherein the EGR1 binding site comprises SEQ ID NO:

41.

3. The method of claim 1, wherein the EGR1 binding site further comprises a 5′

flanking sequence and a 3′

flanking sequence, wherein the 5′

flanking sequence starts with a G/C base pair and optionally wherein the 3′

flanking sequence terminates in a G/C base pair.

4. The method of claim 1, wherein the EGR1 binding site is a single consensus sequence for EGR1.

5. The method of claim 1, wherein the decoy is less than 35 base pairs in length.

6. The method of claim 1, wherein the decoy further comprises a second transcription factor binding site, wherein the second transcription factor binding site binds to a transcription factor selected from the group consisting of POU 1F 1, POU2F, POU3F, POUSF 1, USF, EGR1, CREB/ATF, AP1, CEBP, SRF, ETS1, MEF2, SP 1, RUNX, NFAT, ELK1, ternary complex factors, STAT, GATA1, ELF 1, nuclear factor—

granulocyte/macrophage a, POU4F 1, HNF 1, ZFHX3, IRF, TEAD 1, TBP, NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST, HSF, KCNIP3 and PPAR transcription factors.

7. The method of claim 1, wherein the pain is post-operative pain.

8. An oligonucleotide decoy comprising the sequence of SEQ ID NO:

41.

9. A pharmaceutical composition comprising an oligonucleotide decoy of claim 8 and a pharmaceutically acceptable carrier.

10. A kit comprising an oligonucleotide decoy of claim 8 and optionally an instruction for using said oligonucleotide decoy.

11. A method for treating or managing pain in a patient comprising administering to said patient a therapeutically effective amount of an oligonucleotide decoy, wherein the decoy comprises an EGR1 binding site and is less than 65 base pairs in length, wherein the EGR1 binding site has an affinity for EGR1 at least equivalent to SEQ ID NO:

41 as measured in a quantitative competition binding assay.

12. The method of claim 11, wherein the EGR1 binding site comprises SEQ ID NO:

41.

13. The method of claim 11, wherein the EGR1 binding site further comprises a 5′

flanking sequence and a 3′

flanking sequence, wherein the 5′

flanking sequence starts with a G/C base pair and optionally wherein the 3′

flanking sequence terminates in a G/C base pair.

14. The method of claim 11, wherein the EGR1 binding site is a single consensus sequence for EGR1.

15. The method of claim 11, wherein the decoy is less than 35 base pairs in length.

16. The method of claim 11, wherein the decoy further comprises a second transcription factor binding site, wherein the second transcription factor binding site binds to a transcription factor selected from the group consisting of POU 1F 1, POU2F, POU3F, POU5F1, USF, EGR1, CREB/ATF, AP1, CEBP, SRF, ETS1, MEF2, SP 1, RUNX, NFAT, ELK1, ternary complex factors, STAT, GATA1, ELF 1, nuclear factor—

granulocyte/macrophage a, POU4F 1, HNF 1, ZFHX3, IRF, TEAD 1, TBP, NFY, caccc-box binding factors, KLF4, KLF7, IKZF, MAF, REST, HSF, KCNIP3 and PPAR transcription factors.

17. The method of claim 11, wherein the pain is post-operative pain.