USE OF TOLL-LIKE RECEPTOR-9 AGONISTS, TOLL-LIKE RECEPTOR-4 ANTAGONISTS, AND/OR NUCLEAR OLIGOMERIZATION DOMAIN-2 AGONISTS FOR THE TREATMENT OR PREVENTION OF TOLL-LIKE RECEPTOR-4-ASSOCIATED DISORDERS

• US 20080311112A1
• Filed: 04/17/2008
• Published: 12/18/2008
• Est. Priority Date: 04/19/2007
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Ducruet, Alexander P., Hackam, David J., Gribar, Steven C., Richardson, Ward M.
• Granted Patent: US 8,188,058 B2
• Time in Patent Office: Days
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

The present invention relates to the use of a TLR9 agonist and/or a TLR4 antagonist and/or a NOD2 agonist for treatment or prevention of disorders involving TLR4 activation, such as systemic sepsis and necrotizing enterocolitis.

Claims

1. A method of treating necrotizing enterocolitis in a subject in need of such treatment comprising administering, to the subject, an effective amount of a TLR9 agonist.

2. The method of claim 1, wherein the TLR9 agonist is an oligonucleotide comprising an unmethylated CpG dinucleotide.

3. The method of claim 1, which further comprises administration of an antibiotic.

4. A method of treating a TLR4-associated disorder, comprising administering, to a subject in need of such treatment, an effective amount of a TLR9 agonist and a TLR4 antagonist.

5. The method of claim 4, wherein the disorder is necrotizing enterocolitis.

6. The method of claim 4, wherein the disorder is systemic sepsis.

7. The method of claim 4, 5 or 6 wherein the TLR9 agonist is an oligonucleotide comprising an unmethylated CpG dinucleotide.

8. The method of claim 4, 5 or 6 wherein the TLR4 antagonist is a lipopolysaccharide antagonist.

9. The method of claim 4, 5 or 6 wherein the TLR4 antagonist is an immunoglobulin molecule or fragment thereof.

10. The method of claim 4, 5, or 6 wherein the TLR4 antagonist is polymixin B.

11. A method comprising administering, to an infant, an effective amount of an agonist of NOD2 which reduces the risk of the infant developing necrotizing enterocolitis.

12. The method of claim 11, wherein the agonist of NOD2 is muramyl-di-peptide.

13. The method of claim 11 or 12, further comprising administering an effective amount of an agonist of TLR9.

14. The method of claim 11 or 12, further comprising administering an effective amount of an antagonist of TLR4.

15. The method of claim 13, further comprising administering an effective amount of an antagonist of TLR4.

16. A nutritional formulation comprising an effective amount of an agonist of NOD2.

17. The nutritional formulation of claim 16, wherein the agonist of NOD2 is muramyl-di-peptide.

18. The nutritional formulation of claim 16 or 17, further comprising an agonist of TLR9.

19. The nutritional formulation of claim 16 or 17, further comprising an antagonist of TLR4.

20. The nutritional formulation of claim 18, further comprising an antagonist of TLR4.

21. A method of reducing the severity of necrotizing enterocolitis in an infant suffering from the disease, comprising administering to the infant an effective amount of an agonist of NOD2.

22. The method of claim 21, wherein the agonist of NOD2 is muramyl-di-peptide.

23. The method of claim 21 or 22, further comprising administering an effective amount of an agonist of TLR9.

24. The method of claim 21 or 22, further comprising administering an effective amount of an antagonist of TLR4.

25. The method of claim 23, further comprising administering an effective amount of an antagonist of TLR4.