US2004154047A1PendingUtilityA1

Gene-targeted non-human mammal with human FAD presenilin mutation and generational offspring

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Assignee: CEPHALON INCPriority: Aug 29, 1997Filed: Mar 10, 2004Published: Aug 5, 2004
Est. expiryAug 29, 2017(expired)· nominal 20-yr term from priority
Inventors:Richard W. ScottAndrew G. ReaumeKaren Dorfman
A01K 2217/075A01K 67/0275C12N 2800/30C12N 15/8509G01N 33/6896A01K 2207/15A01K 2217/072A01K 2217/00A01K 2217/30G01N 33/5082A01K 2267/0312C07K 14/4711A01K 67/0278A01K 2217/05A01K 2227/105
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Claims

Abstract

The present invention provides a gene-targeted, non-human mammal having a gene encoding a mutant protein product of a mutated FAD presenilin-1 (PS-1) gene, a human FAD Swedish mutation, and a humanized Aβ mutation, and generational offspring thereof and a gene-targeted, non-human mammal having a gene encoding a mutant protein product of a mutated FAD PS-1 gene and a human Swedish APP695 mutation, and generational offspring thereof, as well as methods of identifying compounds useful in treating Alzheimer's disease, and to methods of treating Alzheimer's disease.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A gene-targeted, non-human mammal heterozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), a human FAD Swedish mutation, and a humanized Aβ gene.  
     
     
         2 . A gene-targeted, non-human mammal homozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), a human FAD Swedish mutation, and a humanized Aβ gene.  
     
     
         3 . The mammal of  claim 1  wherein said mutation of said PS-1 gene is P264L.  
     
     
         4 . The mammal of  claim 2  wherein said mutation of said PS-1 gene is P264L.  
     
     
         5 . The mammal of  claim 1  wherein said mammal is a rodent.  
     
     
         6 . The mammal of  claim 5  wherein said mammal is a mouse.  
     
     
         7 . The mammal of  claim 2  wherein said mammal is a rodent.  
     
     
         8 . The mammal of  claim 7  wherein said mammal is a mouse.  
     
     
         9 . Generational offspring of the mammal of  claim 1  wherein said mutant PS-1 gene is expressed.  
     
     
         10 . Generational offspring of the mammal of  claim 2  wherein said mutant PS-1 gene is expressed.  
     
     
         11 . A method for screening chemical compounds for the ability to decrease in vivo levels of Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 1;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         12 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 2;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         13 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 9;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         14 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 10;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         15 . The method of  claim 11  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         16 . The method of  claim 12  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         17 . The method of  claim 13  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         18 . The method of  claim 14  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         19 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 1;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         20 . A method for identifiing a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 2;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         21 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 9;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         22 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 10;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         23 . The method of  claim 19  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         24 . The method of  claim 20  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         25 . The method of  claim 21  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         26 . The method of  claim 22  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         27 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 19 .  
     
     
         28 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 20 .  
     
     
         29 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 21 .  
     
     
         30 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 22 .  
     
     
         31 . A compound identified by the method of  claim 11 .  
     
     
         32 . A compound identified by the method of  claim 12 .  
     
     
         33 . A compound identified by the method of  claim 13 .  
     
     
         34 . A compound identified by the method of  claim 14 .  
     
     
         35 . A compound identified by the method of  claim 19 .  
     
     
         36 . A compound identified by the method of  claim 20 .  
     
     
         37 . A compound identified by the method of  claim 21 .  
     
     
         38 . A compound identified by the method of  claim 22 .  
     
     
         39 . A gene-targeted, non-human mammal heterozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), and a human transgenic for Swedish APP695.  
     
     
         40 . A gene-targeted, non-human mammal homozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), and a human transgenic for Swedish APP695.  
     
     
         41 . The mammal of  claim 39  wherein said mutation of said PS-1 gene is P264L.  
     
     
         42 . The mammal of  claim 40  wherein said mutation of said PS-1 gene is P264L  
     
     
         43 . The mammal of  claim 39  wherein said mammal is a rodent.  
     
     
         44 . The mammal of  claim 43  wherein said mammal is a mouse.  
     
     
         45 . The mammal of  claim 40  wherein said mammal is a rodent.  
     
     
         46 . The mammal of  claim 45  wherein said mammal is a mouse.  
     
     
         47 . Generational offspring of the mammal of  claim 39  wherein said mutant PS-1 gene is expressed.  
     
     
         48 . Generational offspring of the mammal of  claim 40  wherein said mutant PS-1 gene is expressed.  
     
     
         49 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 39;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         50 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 40;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         51 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 47;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         52 . A method for screening chemical compounds for the ability to decrease in vivo levels of the Aβ peptide, said method comprising the steps of: 
 a) administering said chemical compound to the mammal of  claim 48;  and  
 b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said Aβ peptide.  
 
     
     
         53 . The method of  claim 49  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         54 . The method of  claim 50  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         55 . The method of  claim 51  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         56 . The method of  claim 52  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         57 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 39;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         58 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 40;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         59 . A method for identifying a compound for treating Atzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 47;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         60 . A method for identifying a compound for treating Alzheimer's disease comprising the steps of: 
 a) administering a compound to the mammal of  claim 48;  and    b) measuring the amount of Aβ peptide in a tissue sample from said mammal, wherein a decrease in the amount of Aβ peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease.    
     
     
         61 . The method of  claim 57  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         62 . The method of  claim 58  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         63 . The method of  claim 59  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         64 . The method of  claim 60  wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids.  
     
     
         65 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 57 .  
     
     
         66 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 58 .  
     
     
         67 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 59 .  
     
     
         68 . A method of treating an individual suspected of having Alzheimer's disease comprising administering to said individual an effective Alzheimer's disease treatment amount of a compound identified by the method of  claim 60 .  
     
     
         69 . A compound identified by the method of  claim 49 .  
     
     
         70 . A compound identified by the method of  claim 50 .  
     
     
         71 . A compound identified by the method of  claim 51 .  
     
     
         72 . A compound identified by the method of  claim 52 .  
     
     
         73 . A compound identified by the method of  claim 57 .  
     
     
         74 . A compound identified by the method of  claim 58 .  
     
     
         75 . A compound identified by the method of  claim 59 .  
     
     
         76 . A compound identified by the method of  claim 60.

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