Methods and compositions for the treatment of neurological diseases and disorders

• US 20070232556A1
• Filed: 03/31/2006
• Published: 10/04/2007
• Est. Priority Date: 03/31/2006
• Status: Abandoned Application

• Current Assignee: University of Washington
• Original Assignee: University of Washington
• Inventors: Montine, Thomas, Shie, Feng-Shiun
• Application Number:
  US11/396,212
• Publication Number:
  US 20070232556A1
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/88 involving prostaglandins or their receptors

Abstract

Methods and compositions are provided for preventing or treating neurodegenerative disease and other related diseases and disorders in a mammalian subject. The method provides administering to the mammalian subject a compound capable of inhibiting a PGE2 receptor, e.g., subtype EP2, wherein the compound is administered in an amount effective to treat the neurodegenerative disease or to prevent its occurrence or recurrence. A method for identifying compounds capable of inhibiting neurodegenerative disease is also provided.

Claims

1. A method for preventing or treating a neurological disease in a mammalian subject comprising administering to the mammalian subject a compound capable of inhibiting prostaglandin E2 (PGE2) receptor, wherein the compound is administered in an amount effective to treat the neurological disease or to prevent its occurrence or recurrence.

2. The method of claim 1 wherein the PGE2 receptor is subtype EP2.

3. The method of claim 1 wherein the inhibitor is a small chemical compound, short interfering RNA, dominant-negative molecule, short hairpin RNA, ribozyme, antisense oligonucleotide, antibody, peptide or peptidomimetic.

4. The method of claim 1 wherein the neurological disease is Alzheimer'"'"'s disease or Parkinson'"'"'s disease.

5. The method of claim 1 wherein the compound promotes β

amyloid (Aβ

) clearance.

6. The method of claim 1 wherein the compound enhances microglial phagocytosis of pathogenic proteins associated with neurological diseases and disorders.

7. The method of claim 6 wherein the pathogenic proteins are Aβ

proteins associated with the initiation and progression of Alzheimer'"'"'s disease.

8. The method of claim 6 wherein the pathogenic proteins are α

-synuclein proteins associated with the initiation and progression of Parkinson'"'"'s disease.

9. An in vitro method of screening for an inhibitor of PGE2 receptor biological activity comprising:

contacting a cell with a test compound; and

detecting an increase or a decrease in activation, thereby identifying the test compound as an inhibitor of EP receptor biological activity.

10. The method of claim 9 wherein the PGE2 receptor is EP2.

11. The method of claim 9 wherein the cell is an astrocyte, microglia or neuron.

12. A compound identified by the method of claim 9.

13. A method for identifying a compound capable of inhibiting PGE2 receptor signaling comprising:

contacting a test compound with a cell-based assay system comprising a cell expressing a PGE2 receptor capable of signaling responsiveness to PGE2 receptor signaling, and

detecting an effect of the test compound on PGE2 receptor signaling in the assay system as an increase or a decrease in second messenger signaling or physiologic outcome such as increase or decrease in phagocytosis, effectiveness of the test compound in the assay being indicative of the inhibition EP receptor signaling.

14. The method of claim 13, wherein the physiologic outcome is an increase or decrease in phagocytosis.

15. The method of claim 13, wherein the test compound is a small chemical molecule, interfering RNA, short hairpin RNA, ribozyme, antisense oligonucleotide, protein inhibitor, monoclonal antibody, a polyclonal antibody, a peptide, or a nucleic acid.

16. The method of claim 13 wherein the PGE2 receptor is subtype EP2.

17. A compound identified according to the method of claim 15.

18. The compound of claim 17 wherein the compound is an E2 receptor subtype antagonist.

19. The compound of claim 17 wherein the compound alters the biological activity of the EP2 receptor subtype.

20. The compound of claim 17 wherein the compound is an EP2 receptor subtype antagonist.

21. The compound of claim 17 wherein the compound alters the biological activity of the EP2 receptor subtype.

22. A pharmaceutical composition comprising an PGE2 inhibitor for the treatment of a neurological disease or disorder in a mammalian subject.

23. The composition of claim 22 wherein the PGE2 is subtype EP2.

24. The composition of claim 22 wherein the inhibitor is a small chemical compound, interfering RNA, dominant-negative molecule, short hairpin RNA, ribozyme, antisense oligonucleotide, or protein inhibitor.

25. The composition of claim 22 wherein the neurological disease is Alzheimer'"'"'s disease or Parkinson'"'"'s disease.

26. The composition of claim 22 wherein the composition promotes Aβ

clearance from the brain.

27. The composition of claim 22 wherein the composition promotes synuclein clearance from the brain.

28. The composition of claim 27 wherein synuclein is α

-synuclein.