Prevention and treatment of synucleinopathic and amyloidogenic disease

• US 8,697,082 B2
• Filed: 08/09/2004
• Issued: 04/15/2014
• Est. Priority Date: 11/01/2002
• Status: Active Grant

• Current Assignee: Prothena Biosciences Limited, Regents of the University of California (University of California)
• Original Assignee: Neotope Biosciences Limited (Prothena Corp. Plc), Regents of the University of California (University of California)
• Inventors: Schenk, Dale B., Masliah, Eliezer
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US10/915,214
• Publication Number:
  US 20050037013A1
• Time in Patent Office: 3,536 Days
• Field of Search: None
• US Class Current: 424/185.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions

Abstract

The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson'"'"'s disease.

Claims

1. A method of reducing the risk of, lessening the severity of, delaying or treating a disease characterized by Lewy bodies in the brain, the method comprising:

administering to a patient having or at risk of the disease an immunogenic fragment of alpha-synuclein effective to induce an immunogenic response comprising antibodies that specifically bind to one or more epitopes in the C-terminal region of human alpha-synuclein, wherein said fragment of alpha-synuclein consists of a total of 5 to 9 contiguous amino acids beginning between positions 132 and 136 and ending between positions 136 and 140 of human alpha-synuclein, residues being numbered according to SEQ ID NO;

1, optionally wherein said fragment is linked to a carrier to form a conjugate, wherein the carrier helps elicit the immunogenic response, thereby reducing the risk of, lessening the severity of, delaying, inhibiting or treating the disease.

2. The method of claim 1, wherein the C-terminal amino acid of the polypeptide is the C-terminal amino acid of full-length human alpha-synuclein.

3. The method of claim 1, wherein the immunogenic response is free of antibodies that specifically bind to residues of human alpha synuclein outside residues 124-140.

4. The method of claim 1, wherein one or more epitopes are within amino acids 135-140 of alpha synuclein, residues being numbered according to SEQ ID NO:

1.

5. The method of claim 1, wherein the immunogenic fragment of alpha synuclein consists of SN132-140, residues being numbered according to SEQ ID NO:

1.

6. The method of claim 1, wherein the immunogenic fragment is linked to a carrier to form a conjugate.

7. The method of claim 6, wherein the polypeptide comprises the immunogenic fragment fused to the carrier.

8. The method of claim 6, wherein the immunogenic fragment is linked to the carrier at the N-terminus of the alpha-synuclein fragment.

9. The method of claim 8, wherein multiple copies of the fragment are interlinked with multiple copies of the carrier.

10. The method of claim 1, wherein the polypeptide is administered with an adjuvant.

11. The method of claim 1, wherein administering step effects at least partial clearance of Lewy Bodies.

12. The method of claim 1, wherein the administering step disaggregates Lewy bodies.

13. The method of claim 1, wherein the administering step reduces levels of alpha synuclein oligomers in synapses.

14. The method of claim 1, wherein the administering step clears alpha-synuclein by activation of a lysosomal pathway.

15. The method of claim 1, wherein the patient is diagnosed with Parkinson'"'"'s Disease.