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.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising an agent effective to induce an immunogenic response against Aβ in a patient, and a pharmaceutically acceptable adjuvant.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the agent is Aβ or an active fragment thereof.  
     
     
         3 . The pharmaceutical composition of  claim 1  or  2 , wherein the adjuvant comprises alum.  
     
     
         4 . The pharmaceutical composition of  claim 1  or  2 , wherein the adjuvant comprises monophosphoryl lipid (MPL)  
     
     
         5 . The pharmaceutical composition of  claim 1  or  2 , wherein the adjuvant comprises QS21.  
     
     
         6 . The pharmaceutical composition of any of the preceding claims, wherein the Aβ or fragment is a component of a particle.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.  
     
     
         8 . A method of preventing or treating a disease characterized by amyloid deposit in a patient, comprising: 
 administering an agent effective to induce an immune response against a peptide component of an amyloid deposit in the patient.    
     
     
         9 . The method of  claim 8 , wherein the amyloid deposit comprises aggregated Aβ peptide.  
     
     
         10 . The method of  claim 8  or  9 , wherein the patient is a human.  
     
     
         11 . The method of any of the preceding claims, wherein the disease is Alzheimer's disease.  
     
     
         12 . The method of any of the preceding claims, wherein the patient is asymptomatic.  
     
     
         13 . The method of any of the preceding claims, wherein the patient is under 50.  
     
     
         14 . The method of any of the preceding claims, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer's disease.  
     
     
         15 . The method of any of claims  8 - 13 , wherein the patient has no known risk factors for Alzheimer's disease.  
     
     
         16 . The method of any of the preceding claims, wherein the agent comprises Aβ peptide or an active fragment thereof.  
     
     
         17 . The method of any of the preceding claims, wherein the agent is Aβ peptide or an active fragment thereof.  
     
     
         18 . The method of  claim 17 , wherein the dose of Aβ peptide administered to the patient at least 50 μg.  
     
     
         19 . The method of  claim 17 , wherein the dose of Aβ peptide administered to the patient is at least 100 μg.  
     
     
         20 . The method of any of the preceding claims, wherein the Aβ peptide is Aβ42.  
     
     
         21 . The method of  claim 20 , wherein the Aβ peptide is administered in aggregated form.  
     
     
         22 . The method of claim any of the preceding claims, wherein the immune response comprises antibodies that bind to the Aβ peptide.  
     
     
         23 . The method of any of the preceding claims, wherein the immune response comprises T-cells that bind to the Aβ peptide as a component of an MHC I or MHC II complex.  
     
     
         24 . The method of any one of claims  8 , or  10 - 15  wherein agent is an antibody to Aβ which induces an immune response by binding to Aβ in the patient.  
     
     
         25 . The method of claims  8  or  10 - 15 , wherein T-cells are removed from the patient, contacted with Aβ peptide under conditions in which the T-cells are primed, and the primed T-cells are administered to the patient.  
     
     
         26 . The method of any of the preceding claims, wherein the agent is administered orally, subcutaneously, intramuscularly, topically or intravenously.  
     
     
         27 . The method of any of the preceding claims, wherein the agent is administered intramuscularly or subcutaneously.  
     
     
         28 . The method of any of the preceding claims, further comprising screening a library of compounds to identify a compound reactive with antibodies to Aβ, and administering the  
     
     
         29 . The method of any one of claims  8 ,  10 - 15 ,  26  or  27 , wherein the agent is an effective dose of a nucleic acid encoding Aβ or an active fragment thereof, whereby the nucleic acid is expressed in the patient to produce Aβ or the active fragment thereof, which induces the immune response.  
     
     
         30 . The method of  claim 29 , wherein the nucleic acid is administered through the skin.  
     
     
         31 . The method of  claim 30 , wherein the nucleic acid is applied to the skin by a patch.  
     
     
         32 . The method of any of the preceding claims, further comprising monitoring the patient for the immune response.  
     
     
         33 . The method of any of the preceding claims, further comprising administering an adjuvant that enhances the immune response to the Aβ peptide.  
     
     
         34 . The method of  claim 33 , wherein the adjuvant and the agent are administered together as a composition.  
     
     
         35 . The method of  claim 33 , wherein the adjuvant is administered before the agent.  
     
     
         36 . The method of  claim 33 , wherein the adjuvant is administered after the agent.  
     
     
         37 . The method of any one of claims  33 - 36 , wherein the adjuvant is alum.  
     
     
         38 . The method of any one of claims  33 - 36 , wherein the adjuvant is MPL.  
     
     
         39 . The method of any one of claims  33 - 36 , wherein the adjuvant is QS21.  
     
     
         40 . The method of anyone of claims  33 - 36 , wherein the dose of Aβ peptide is greater than 10 μg.  
     
     
         41 . A method of preventing or treating Alzheimer's disease comprising administering an effective dose of Aβ peptide to a patient.  
     
     
         42 . Use of Aβ peptide, or an antibody thereto, in the manufacture of a medicament for prevention or treatment of Alzheimer's disease.  
     
     
         43 . The use of  claim 42 , wherein the Aβ peptide is combined with a pharmaceutically acceptable adjuvant in the manufacture of the medicament.  
     
     
         44 . A composition comprising Aβ or a fragment linked to a conjugate molecule that promotes delivery of Aβ to the bloodstream of a patient and/or promotes an immune response against Aβ.  
     
     
         45 . The composition of  claim 44 , wherein the conjugates promotes an immune response against Aβ.  
     
     
         46 . The composition of  claim 44  or  45 , wherein the conjugate is cholera toxin.  
     
     
         47 . The composition of  claim 44  or  45 , wherein the conjugate is an immunoglobulin.  
     
     
         48 . The composition of  claim 44  or  45 , wherein the conjugate is attenuated diphtheria toxin CRM 197.  
     
     
         49 . A pharmaceutical composition comprising an agent effect to induce an immunogenic response against Aβ in a patient with the proviso that the composition is free of Complete Freund's adjuvant.  
     
     
         50 . A composition comprising a viral vector encoding Aβ or a fragment thereof effective to induce an immune response against Aβ.  
     
     
         51 . A composition of  claim 50 , wherein the viral vector is herpes, adenovirus, adenoassociated virus, a retrovirus, sindbis, semiliki forest virus, vaccinia or avian pox.  
     
     
         52 . A method of assessing efficacy of an Alzheimer's treatment method in a patient, comprising 
 determining a baseline amount of antibody specific for Aβ peptide in tissue sample from the patient before treatment with an agent,    comparing an amount of antibody specific for Aβ peptide in the tissue sample from the patient after treatment with the agent to the baseline amount of Aβ peptide-specific antibody,    wherein an amount of Aβ peptide-specific antibody measured after the treatment that is significantly greater than the baseline amount of Aβ peptide-specific antibody indicates a positive treatment outcome.    
     
     
         53 . The method of  claim 52 , wherein the amounts of antibody are measured as antibody titers.  
     
     
         54 . The method of  claim 53 , wherein the amounts of antibody are measured by an ELISA assay.  
     
     
         55 . A method of assessing efficacy of an Alzheimer's treatment method in a patient, comprising 
 determining a baseline amount of antibody specific for Aβ peptide in tissue sample from a patient before treatment with an agent;    comparing an amount of antibody specific for Aβ peptide in the tissue sample from the subject after treatment with the agent to the baseline amount of Aβ peptide-specific antibody,    wherein a reduction or lack of significant difference between the amount of Aβ peptide-specific antibody measured after the treatment compared to the baseline amount of Aβ peptide-specific antibody indicates a negative treatment outcome.    
     
     
         56 . A method of assessing efficacy of an Alzheimer's treatment method in a patient, comprising 
 determining a control amount of antibody specific for Aβ peptide in tissue samples from a control population,    comparing an amount of antibody specific for Aβ peptide in a tissue sample from the patient after administering an agent to the control amount of Aβ peptide-specific antibody,    wherein an amount of Aβ peptide-specific antibody measured after the treatment that is significantly greater than the control amount of Aβ peptide-specific antibody indicates a positive treatment outcome.    
     
     
         57 . A method of assessing efficacy of an Alzheimer's treatment method in a patient, comprising 
 determining a control amount of antibody specific for Aβ peptide in tissues samples from a control population,    comparing an amount of antibody specific for Aβ peptide in a tissue sample from the patient after administering an agent to said control amount of Aβ peptide-specific antibody,    wherein a lack of significant difference between the amount of Aβ peptide-specific antibody measured after beginning said treatment compared to the control amount of Aβ peptide-specific antibody indicates a negative treatment outcome.    
     
     
         58 . A method of monitoring Alzheimer's disease or susceptibility thereto in a patient, comprising: 
 detecting an immune response against Aβ peptide in a sample from the patient.    
     
     
         59 . The method of  claim 58 , wherein the patient is being administered an agent effective to treat or prevent Alzheimer's disease, and the level of the response determines the future treatment regime of the patient.  
     
     
         60 . The method of  claim 59 , wherein the agent is Aβ peptide.  
     
     
         61 . The method of any one of claims  57 - 60 , wherein the detecting comprises detecting an antibody that specifically binds to Aβ peptide.  
     
     
         62 . The method of any one of claims  57 - 60 , wherein the detecting comprises detecting T-cells specifically reactive with Aβ peptide.  
     
     
         63 . A method of assessing efficacy of an Alzheimer's treatment method in a patient, comprising 
 determining a value for an amount of antibody specific for Aβ peptide in tissue sample from a patient who has been treated with an agent;    comparing the value with a control value determined from a population of patient experiencing amelioriation of, or freedom from, symptoms of Alzheimer's disease due to treatment with the agent;    wherein a value in the patient at least equal to the control value indicates a positive response to treatment.