Prevention and treatment of amyloidogenic disease

Abstract

The invention provides compositions and methods for treatment of amyloidogenic diseases. Such methods entail administering an agent that induces a beneficial immune response against an amyloid deposit in the patient. The methods are particularly useful for prophylactic and therapeutic treatment of Alzheimer's disease. In such methods, a suitable agent is Aβ peptide or an antibody thereto.

1 . A pharmaceutical composition comprising a nucleic acid encoding and capable of expressing Aβ or an immunogenic fragment thereof effective to induce an immune response comprising antibodies against Aβ, and a pharmaceutically acceptable carrier.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein Aβ is Aβ43, Aβ42, Aβ41, Aβ40, or Aβ39.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the immunogenic Aβ fragment comprises an N-terminal segment of at least residues 1-5 of Aβ, wherein the N-terminal segment is free of a C-terminal segment of Aβ.  
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the immunogenic fragment is Aβ1-5.  
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein the immunogenic fragment is Aβ1-6.  
     
     
         6 . The pharmaceutical composition of  claim 1 , further comprising a pharmaceutically acceptable adjuvant, wherein the adjuvant enhances the immune response to Aβ.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the adjuvant is alum, 3 De-O-acylated monophosphoryl lipid A (MPL), Stimulon QS-21, or GM-CSF.  
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the adjuvant is GM-CSF.  
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the Aβ or immunogenic fragment thereof is expressed with a carrier as a fusion protein, wherein the carrier enhances the immune response to Aβ.  
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the carrier is a serum albumin, keyhole limpet hemocyanin, an immunoglobulin molecule, thyroglobulin, ovalbumin, or a toxoid from a pathogenic bacteria.  
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the carrier is a toxoid from pathogenic bacteria.  
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the carrier is selected from the group consisting of tetanus toxoid, diphtheria toxoid,  E. coli  cholera toxoid, and  H. pylori  toxoid.  
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the carrier is  E. coli  cholera toxoid.  
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the nucleic acid is DNA or RNA.  
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the nucleic acid encoding the Aβ or immunogenic fragment thereof is linked to regulatory elements.  
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the nucleic acid encoding the Aβ or immunogenic fragment thereof and the linked regulatory elements are cloned into a vector.  
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the nucleic acid is a viral vector.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the viral vector is herpes, adenovirus, adenoassociated virus, a retrovirus, sindbis, Semliki Forest virus, vaccinia, or avian pox.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the viral vector is adenovirus, adenoassociated virus, or a retrovirus.  
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the viral vector is adenoassociated virus.  
     
     
         21 . A method of treating a disease characterized by an amyloid deposit of Aβ in a patient, comprising administering to a patient having the disease an effective dosage of a nucleic acid encoding Aβ or an immunogenic fragment thereof, wherein the Aβ or immunogenic fragment is expressed to induce an immune response comprising antibodies against Aβ and thereby treating the disease.  
     
     
         22 . The method of  claim 21 , wherein Aβ is Aβ43, Aβ42, Aβ41, Aβ40, or Aβ39.  
     
     
         23 . The method of  claim 21 , wherein the immunogenic Aβ fragment comprises an N-terminal segment of at least residues 1-5 of Aβ, wherein the N-terminal segment is free of a C-terminal segment of Aβ.  
     
     
         24 . The method of  claim 23 , wherein the immunogenic fragment is Aβ1-5.  
     
     
         25 . The method of  claim 23 , wherein the immunogenic fragment is Aβ1-6.  
     
     
         26 . The method of  claim 21 , wherein the disease is Alzheimer's disease.  
     
     
         27 . The method of  claim 21 , further comprising administering an adjuvant, wherein the adjuvant enhances the immune response to Aβ.  
     
     
         28 . The method of  claim 27 , wherein the adjuvant is alum, 3 De-O-acylated monophosphoryl lipid A (MPL), Stimulon QS-21, or GM-CSF.  
     
     
         29 . The method of  claim 28 , wherein the adjuvant is GM-CSF.  
     
     
         30 . The method of  claim 21 , wherein the Aβ or immunogenic fragment thereof is expressed with a carrier as a fusion protein, wherein the carrier enhances the immune response to Aβ.  
     
     
         31 . The method of  claim 30 , wherein the carrier is a serum albumin, keyhole limpet hemocyanin, an immunoglobulin molecule, thyroglobulin, ovalbumin, or a toxoid from a pathogenic bacteria.  
     
     
         32 . The method of  claim 31 , wherein the carrier is a toxoid from pathogenic bacteria.  
     
     
         33 . The method of  claim 32 , wherein the carrier is selected from the group consisting of tetanus toxoid, diphtheria toxoid,  E. coli  cholera toxoid, and  H. pylori  toxoid.  
     
     
         34 . The method of  claim 33 , wherein the carrier is  E. coli  cholera toxoid.  
     
     
         35 . The method of  claim 21 , wherein the nucleic acid is administered through the skin.  
     
     
         36 . The method of  claim 35 , wherein the nucleic acid is applied to the skin by patch.  
     
     
         37 . A method of prophylaxis of a disease characterized by an amyloid deposit of Aβ in a patient, comprising administering to a patient susceptible to the disease an effective dosage of a nucleic acid encoding Aβ or an immunogenic fragment thereof, wherein the Aβ or immunogenic fragment is expressed to induce an immune response comprising antibodies against Aβ and thereby effecting prophylaxis of the disease.  
     
     
         38 . The method of  claim 37 , wherein Aβ is Aβ43, Aβ42, Aβ41, Aβ40, or Aβ39.  
     
     
         39 . The method of  claim 37 , wherein the immunogenic Aβ fragment comprises an N-terminal segment of at least residues 1-5 of Aβ, wherein the N-terminal segment is free of a C-terminal segment of Aβ.  
     
     
         40 . The method of  claim 39 , wherein the immunogenic fragment is Aβ1-5.  
     
     
         41 . The method of  claim 39 , wherein the immunogenic fragment is Aβ1-6.  
     
     
         42 . The method of  claim 37 , wherein the disease is Alzheimer's disease.  
     
     
         43 . The method of  claim 37 , further comprising administering an adjuvant, wherein the adjuvant enhances the immune response to Aβ.  
     
     
         44 . The method of  claim 43 , wherein the adjuvant is alum, 3 De-O-acylated monophosphoryl lipid A (MPL), Stimulon QS-21, or GM-CSF.  
     
     
         45 . The method of  claim 44 , wherein the adjuvant is GM-CSF.  
     
     
         46 . The method of  claim 37 , wherein the Aβ or immunogenic fragment thereof is expressed with a carrier as a fusion protein, wherein the carrier enhances the immune response to Aβ.  
     
     
         47 . The method of  claim 46 , wherein the carrier is a serum albumin, keyhole limpet hemocyanin, an immunoglobulin molecule, thyroglobulin, ovalbumin, or a toxoid from a pathogenic bacteria.  
     
     
         48 . The method of  claim 47 , wherein the carrier is a toxoid from pathogenic bacteria.  
     
     
         49 . The method of  claim 48 , wherein the carrier is selected from the group consisting of tetanus toxoid, diphtheria toxoid,  E. coli  cholera toxoid, and  H. pylori  toxoid.  
     
     
         50 . The method of  claim 49 , wherein the carrier is  E. Coli  cholera toxoid.  
     
     
         51 . The method of  claim 37 , wherein the nucleic acid is administered through the skin.  
     
     
         52 . The method of  claim 51 , wherein the nucleic acid is applied to the skin by patch.