Prevention and treatment of synucleinopathic and amyloidogenic disease
View Patent ↗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.
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.