METHODS AND COMPOSITIONS FOR THE TREATMENT OF PARKINSON'S DISEASE

• US 20090226401A1
• Filed: 02/15/2007
• Published: 09/10/2009
• Est. Priority Date: 02/16/2006
• Status: Active Grant

• Current Assignee: Mclean Hospital (Mass General Brigham, Inc.)
• Original Assignee: Mclean Hospital (Mass General Brigham, Inc.)
• Inventors: Kim, Kwang Soo, Kim, Deog Joong, Kim, Chun Hyung
• Granted Patent: US 8,114,892 B2
• Time in Patent Office: Days
• US Class Current: 424/93.700
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 33/06 Antimalarials

Abstract

The invention features methods and kits for treating or inhibiting the development of Parkinson'"'"'s Disease by administering 7-chloro-4-aminoquinoline compounds, e.g., amodiaquine or glafenine. Stem cells are also useful in the methods of the invention and may be administered separately from or together with 7-chloro-4-aminoquinoline compounds. The invention further features methods of identifying additional chemical compounds that are useful in the treatment or inhibition of the development of Parkinson'"'"'s Disease.

Claims

1. A method for treating or inhibiting the development of Parkinson'"'"'s Disease comprising the steps of:

(a) determining whether a patient has or is at risk of developing Parkinson'"'"'s Disease; and

(b) if said patient has or is at risk of developing Parkinson'"'"'s Disease, administering to said patient a 7-chloro-4-aminoquinoline compound in an amount sufficient to treat or inhibit the development of Parkinson'"'"'s Disease.

3. The method of claims 1 or 2, wherein said compound is amodiaquine.

4. The method of claims 1 or 2, wherein said compound is glafenine.

2. A method for treating or inhibiting the development of Parkinson'"'"'s Disease comprising the steps of:

(a) determining whether a patient has or is at risk of developing Parkinson'"'"'s Disease; and

(b) if said patient has or is at risk of developing Parkinson'"'"'s Disease, administering to said patient a 7-chloro-4-aminoquinoline compound in an amount sufficient to activate Nurr1 in cells of said patient.

5. A kit comprising:

(a) a 7-chloro-4-aminoquinoline compound; and

(b) instructions for administering said compound to a patient diagnosed with or at risk of developing Parkinson'"'"'s Disease.

6. The kit of claim 5, wherein said compound is amodiaquine.

7. The kit of claim 5, wherein said compound is glafenine.

8. A method for causing the differentiation of an ex vivo stem cell into a dopaminergic neuron, said method comprising contacting said ex vivo stem cell with a 7-chloro-4-aminoquinoline compound that is present in an amount sufficient to induce differentiation of said stem cell.

9. The method of claim 8, wherein said stem cell is a human embryonic stem cell.

10. The method of claim 8, wherein said compound is amodiaquine.

11. The method of claim 8, wherein said compound is glafenine.

12. A method for treating or inhibiting the development of Parkinson'"'"'s Disease comprising the steps of:

(a) injecting a composition comprising stem cells into the brain of a patient; and

(b) following step (a), administering to said patient a 7-chloro-4-aminoquinoline compound in an amount sufficient to induce differentiation of said stem cells.

13. The method of claim 12, wherein said stem cells are human embryonic stem cells.

14. The method of claim 12, wherein said compound is amodiaquine.

15. The method of claim 12, wherein said compound is glafenine.

16. A method for treating or inhibiting the development of Parkinson'"'"'s Disease comprising injecting into the brain of a patient a composition comprising stem cells and a 7-chloro-4-aminoquinoline compound.

17. The method of claim 16, wherein said stem cells are human embryonic stem cells.

18. The method of claim 16, wherein said compound is amodiaquine.

19. The method of claim 16, wherein said compound is glafenine.

20. A pharmaceutical composition comprising:

(a) stem cells; and

(b) a 7-chloro-4-aminoquinoline compound.

21. The pharmaceutical composition of claim 20, wherein said stem cells are human embryonic stem cells.

22. The pharmaceutical composition of claim 20, wherein said compound is amodiaquine.

23. The pharmaceutical composition of claim 20, wherein said compound is glafenine.

24. A method for identifying a chemical compound for therapeutic use in Parkinson'"'"'s Disease, said method comprising the steps of:

(a) cotransfecting a mammalian cell with a first plasmid comprising a domain of a Nurr1 gene and a second plasmid comprising a promoter operably linked to a reporter gene;

(b) contacting said cell with a candidate chemical compound;

(c) measuring the resulting level of expression of said reporter gene; and

(d) comparing said level to a control value, wherein, if said level is at least 20% greater than said control value, said candidate chemical compound is identified as a chemical compound for therapeutic use in Parkinson'"'"'s Disease.

25. The method of claim 24, wherein the mixture produced in step (b) is incubated for eighteen hours prior to step (c).

26. The method of claim 24, wherein said cell is an SK-N-BE(2)C cell.

27. The method of claim 24, wherein the molar ratio between said first plasmid and said second plasmid is between 0.1 and 10.

28. The method of claim 24, wherein said second plasmid comprises a 100 bases of a tyrosine hydroxylase promoter.

29. The method of claim 28, wherein said second plasmid comprises 2,600 bases of a tyrosine hydroxylase promoter.

30. The method of claim 24, wherein said reporter gene is firefly luciferase.

31. The method of claim 24, wherein said first plasmid comprises a GAL4 DNA-binding domain operably linked to said domain of a Nurr1 gene, and wherein said second plasmid comprises a GAL4 binding site operably linked to said reporter gene.

32. A method for identifying a chemical compound for therapeutic use in Parkinson'"'"'s Disease, said method comprising the steps of:

(a) providing;

(i) a mammalian cell capable of producing dopamine; and

(ii) a chemical compound identified using the method of claim 24;

(b) contacting said cell with said chemical compound;

(c) measuring the resulting level of expression of tyrosine hydroxylase or dopamine; and

(d) comparing said level to a control value, wherein, if said level is at least 20% greater than said control value, said chemical compound is identified as a chemical compound for therapeutic use in Parkinson'"'"'s Disease.

33. The method of claim 32, wherein said measuring comprises quantification of tyrosine hydroxylase using real time PCR.

34. The method of claim 32, wherein said measuring comprises quantification of dopamine using HPLC analysis.

35. The method of claim 32, wherein said measuring comprises quantification of tyrosine hydroxylase using immunostaining.