Prevention and treatment of synucleinopathic and amyloidogenic disease

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.

1 . A method of effecting prophylaxis or treating a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, the method comprising administering to a patient having or at risk of the disease an effective regime of an antibody that specifically binds to an epitope within residues 1-20 of human alpha-synuclein, residues being numbered according to SEQ ID NO:1. 
     
     
         2 . The method of  claim 2 , wherein the antibody specifically binds to an epitope within residues 1-10 of human alpha synuclein. 
     
     
         3 . The method of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         4 . The method of  claim 3 , wherein the antibody is a chimeric antibody. 
     
     
         5 . The method of  claim 3 , wherein the antibody is human antibody. 
     
     
         6 . The method of  claim 3 , wherein the antibody is a humanized antibody. 
     
     
         7 . The method of  claim 1 , wherein the antibody competes with mouse monoclonal antibody 6H7 (ATCC accession number PTA-6910) for binding to human alpha-synuclein. 
     
     
         8 . The method of  claim 7 , wherein the antibody is a humanized version of mouse monoclonal antibody 6H7 (ATCC accession number PTA-6910). 
     
     
         9 . A method of effecting prophylaxis or treating a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, the method comprising administering to a patient having or at risk of the disease an effective regime of an antibody that specifically binds to an epitope within residues 70-140 of human alpha-synuclein, residues being numbered according to SEQ ID NO: 1. 
     
     
         10 . The method of  claim 9 , wherein the antibody specifically binds to an epitope within residues 120-140 of human alpha synuclein. 
     
     
         11 . The method of  claim 9 , wherein the antibody is a monoclonal antibody. 
     
     
         12 . The method of  claim 11 , wherein the antibody is a chimeric antibody. 
     
     
         13 . The method of  claim 11 , wherein the antibody is human antibody. 
     
     
         14 . The method of  claim 11 , wherein the antibody is a humanized antibody. 
     
     
         15 . The method of  claim 11 , wherein the antibody competes with mouse monoclonal antibody 8A5 (ATCC accession number PTA-6909) for binding to human alpha-synuclein. 
     
     
         16 . The method of  claim 10 , wherein the antibody is a humanized version of mouse monoclonal antibody 8A5 (ATCC accession number PTA-6909). 
     
     
         17 . The method of  claim 11 , wherein the antibody is an antibody of human IgG1 isotype. 
     
     
         18 . The method of  claim 9 , wherein the antibody is administered with a pharmaceutical carrier as a pharmaceutical composition. 
     
     
         19 . The method of  claim 18 , wherein the antibody is administered at a dosage of 0.0001 to 100 mg/kg, preferably, at least 1 mg/kg body weight antibody. 
     
     
         20 . The method of  claim 18 , wherein the antibody is administered in multiple dosages over at least six months. 
     
     
         21 . The method of  claim 9 , wherein the antibody is administered intraperitoneally, orally, subcutaneously, intracranially, intramuscularly, topically, intranasally or intravenously. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . The method of  claim 9 , wherein the disease is Parkinson's disease. 
     
     
         25 . A pharmaceutical composition comprising a chimeric or humanized antibody that specifically binds to an epitope within residues 1-40 of alpha-synuclein and a pharmaceutical carrier. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the antibody specifically binds to an epitope within residues 1-20 of alpha-synuclein. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein the antibody specifically binds to an epitope within residues 1-10 of alpha-synuclein. 
     
     
         28 . A pharmaceutical composition comprising a chimeric or humanized antibody that specifically binds to an epitope within residues 70-140 of alpha-synuclein and a pharmaceutical carrier. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the antibody specifically binds to an epitope within residues 120-140 of alpha-synuclein and a pharmaceutical carrier. 
     
     
         30 . A monoclonal antibody produced by hybridoma JH17.6H7.1.54.28 (ATCC accession number PTA-6910) or JH4.8A5.25.7.36 (ATCC accession number PTA-6909). 
     
     
         31 . A cell of hybridoma JH17.6H7.1.54.28 (ATCC accession number PTA-6910) or JH4.8A5.25.7.36 (ATCC accession number PTA-6909). 
     
     
         32 . A method of effecting prophylaxis or treating a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, the method comprising:
 administering to a patient having or at risk of the disease a polypeptide comprising an immunogenic fragment of alpha-synuclein effective to induce an immunogenic response comprising antibodies that specifically bind to an epitope within residues 70-140 of human alpha-synuclein, residues being numbered according to SEQ ID NO: 1, thereby effecting prophylaxis or treatment of the disease.   
     
     
         33 . The method of  claim 32 , wherein the immunogenic fragment comprises SN130-136 and contains no more than 40 contiguous residues in total of alpha synuclein, residues being numbered according to SEQ ID NO: 1. 
     
     
         34 . The method of  claim 33 , wherein the immunogenic fragment is selected from a group consisting of SN124-140, SN125-140, SN126-140, SN127-140, SN128-140, SN 129-140, SN130-140, SN131-140, SN132-140, SN133-140, SN134-140, SN135-140, SN136-140, SN137-140, SN124-139, SN125-139, SN126-139, SN127-139, SN128-139, SN124-139, SN125-139, SN126-139, SN127-139, SN128-139, SN129-139, SN130-139, SN131-139, SN132-139, SN133-139, SN134-139, SN135-139, SN136-139, SN137-139, SN124-138, SN124-138, SN125-138, SN126-138, SN127-138, SN128-138, SN129-138, SN130-138, SN131-138, SN132-138, SN133-138, SN134-138, SN135-138, SN136-138, S SN124-137, SN125-137, SN126-137, SN127-137, SN128-137, SN129-137, SN130-137, SN131-137, SN132-137, SN133-137, SN134-137, SN135-137, SN124-136, SN125-136, SN126-136, SN127-136, SN128-136, SN129-136, SN130-136, SN131-136, SN132-136, SN133-136, and SN134-136, residues being numbered according to SEQ ID NO: 1. 
     
     
         35 . A method of effecting prophylaxis or treating a disease characterized by Lewy bodies or alpha-synuclein aggregation in the brain, the method comprising:
 administering to a patient having or at risk of the disease a polypeptide comprising an immunogenic fragment of alpha-synuclein effective to induce an immunogenic response comprising antibodies that specifically bind to an epitope within residues 1-40 of human alpha-synuclein, residues being numbered according to SEQ ID NO: 1, thereby effecting prophylaxis or treatment of the disease.   
     
     
         36 . The method of  claim 35 , wherein the immunogenic fragment comprises SN1-5 and contains no more than 40 contiguous residues in total of alpha synuclein, residues being numbered according to SEQ ID NO: 1. 
     
     
         37 . The method of  claim 35 , wherein the immunogenic fragment is selected from the group consisting of consisting of SN1-5, SN1-6, SN1-7, SN1-8, SN1-9, SN1-10, SN1-11, SN1-12, SN1-13, and SN1-14 SN1-15, SN1-16, SN1-17, SN1-18, SN1-19, and SN1-20. 
     
     
         38 . The method of  claim 35  comprising:
 administering to a patient having or at risk of the disease a polypeptide comprising an immunogenic fragment of alpha-synuclein effective to induce an immunogenic response comprising antibodies that specifically bind to an epitope within residues 1-20 of human alpha-synuclein, residues being numbered according to SEQ ID NO:1,   wherein the immunogenic fragment of alpha-synuclein is free of at least residues 25-69, residues 70-140, residues 41-140, or residues 25-140 of alpha synuclein,   thereby effecting prophylaxis or treatment of the disease.   
     
     
         39 . The method of  claim 38 , wherein the immunogenic fragment is linked to a carrier to form a conjugate. 
     
     
         40 - 41 . (canceled) 
     
     
         42 . A method of screening an agent to determine whether the agent has activity useful in treating a disease characterized by Lewy Bodies, comprising contacting the agent with a transgenic nonhuman animal disposed to develop a characteristic of a Lewy Body disease with the agent; determining whether the agent affects the extent or rate of development of the characteristic relative to a control transgenic nonhuman animal; wherein the agent is (i) a fragment of alpha synuclein that induces antibodies that specifically bind to at least one epitope within residues 70-140 of human alpha synuclein; (ii) a fragment of alpha synuclein that induces antibodies that specifically bind to at least one epitope within residues 1-20 of human alpha synuclein; (iii) an antibody that specifically binds to an epitope with residues 70-140 of human alpha synuclein; or (iv) an antibody that specifically binds to an epitope with residues 1-20 of human alpha synuclein; residues being numbered according to SEQ ID NO: 1. 
     
     
         43 . The method of  claim 9 , wherein the disease is Parkinson's disease. 
     
     
         44 . A pharmaceutical composition comprising a first immunogenic fragment of alpha-synuclein, said first fragment effective to induce an immunogenic response comprising antibodies that specifically bind to an epitope within residues 1-20 of human alpha-synuclein, and a pharmaceutical carrier. 
     
     
         45 - 47 . (canceled)