Claims for Patent: 6,734,336

Summary for Patent: 6,734,336

Title:	Gene-targeted non-human mammal with human fad presenilin mutation and generational offspring
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 A.beta. 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.
Inventor(s):	Scott; Richard W. (West Chester, PA), Reaume; Andrew G. (Waterford, CT), Dorfman; Karen (Waterford, CT)
Assignee:	Cephalon, Inc. (West Chester, PA)
Application Number:	09/621,897
Patent Claims:	1. A gene-targeted mouse heterozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), and a human transgene for Swedish APP695, wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 2. A gene-targeted mouse homozygous for a human Familial Alzheimer's Disease (FAD) mutation comprising a human mutation of the presenilin-1 (PS-1 gene), and a human transgene for Swedish APP695, wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 3. Generational offspring of the mouse of claim 1 wherein said mutant PS-1 gene is expressed. 4. Generational offspring of the mouse of claim 2 wherein said mutant PS-1 gene is expressed. 5. A method for screening chemical compounds for the ability to decrease in vivo levels of the A.beta. peptide, said method comprising the steps of: a) administering said chemical compound to the mouse of claim 1; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said A.beta. peptide. 6. A method for screening chemical compounds for the ability to decrease in vivo levels of the A.beta. peptide, said method comprising the steps of: a) administering said chemical compound to the mouse of claim 2; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said A.beta. peptide. 7. A method for screening chemical compounds for the ability to decrease in vivo levels of the A.beta. peptide, said method comprising the steps of: a) administering said chemical compound to the mouse of claim 3; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said A.beta. peptide. 8. A method for screening chemical compounds for the ability to decrease in vivo levels of the A.beta. peptide, said method comprising the steps of: a) administering said chemical compound to the mouse of claim 4; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a chemical compound that has the ability to decrease in vivo levels of said A.beta. peptide. 9. The method of claim 5 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 10. The method of claim 6 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 11. The method of claim 7 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 12. The method of claim 8 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 13. A method for identifying a compound for treating Alzheimer's disease comprising the steps of: a) administering a compound to the mouse of claim 1; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease. 14. A method for identifying a compound for treating Alzheimer's disease comprising the steps of: a) administering a compound to the mouse of claim 2; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease. 15. A method for identifying a compound for treating Alzheimer's disease comprising the steps of: a) administering a compound to the mouse of claim 3; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease. 16. A method for identifying a compound for treating Alzheimer's disease comprising the steps of: a) administering a compound to the mouse of claim 4; and b) measuring the amount of A.beta. peptide in a tissue sample from said mouse, wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that can be used to treat Alzheimer's disease. 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. The method of claim 15 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 20. The method of claim 16 wherein said tissue sample is selected from the group consisting of brain tissue, non-brain tissue and body fluids. 21. A gene-targeted mouse heterozygous for a human presenilin-1 (PS-1) mutation and comprising a human Swedish mutation, said mouse comprising in its genome: a DNA sequence encoding a PS-1 protein comprising the human P264L mutation; and a DNA sequence encoding a human amyloid precursor protein having the Swedish APP695 mutation; wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 22. The mouse of claim 21 wherein codon 264 of the PS-1 gene is changed from CCG to CTT, CTC, CTA, CTG, TTA, or TTG. 23. The mouse of claim 22 wherein codon 264 of the PS-1 gene is changed from CCG to CTT. 24. The mouse of claim 21 wherein codon 265 of the PS-1 gene is changed from AAA to AAG. 25. A generational offspring of the mouse of claim 21 wherein said offspring comprises in its genome: a DNA sequence encoding a PS-1 protein comprising the human P264L mutation; and a DNA sequence encoding a human amyloid precursor protein having the Swedish APP695 mutation; wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 26. A gene-targeted mouse homozygous for a human presenilin-1 (PS-1) mutation and comprising a human Swedish mutation, said mouse comprising in its genome: a DNA sequence encoding a PS-1 protein comprising the human P264L mutation; and a DNA sequence encoding a human amyloid precursor protein having the Swedish APP695 mutation; wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 27. The mouse of claim 26 wherein codon 264 of the PS-1 gene is changed from CCG to CTT, CTC, CTA, CTG, TTA, or TTG. 28. The mouse of claim 27 wherein codon 264 of the PS-1 gene is changed from CCG to CTT. 29. The mouse of claim 26 wherein codon 265 of the PS-1 gene is changed from AAA to AAG. 30. A generational offspring of the mouse of claim 26 wherein said offspring comprises in its genome: a DNA sequence encoding a PS-1 protein comprising the human P264L mutation; and a DNA sequence encoding a human amyloid precursor protein having the Swedish APP695 mutation; wherein the A.beta.42 protein level is elevated relative to the A.beta.42 protein level in a wild-type mouse. 31. A method for screening a compound for the ability to decrease in vivo levels of the A.beta. peptide comprising the steps of: administering said compound to the mouse of claim 21; and measuring the amount of A.beta. peptide in a tissue sample from said mouse; wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that has the ability to decrease in vivo levels of said A.beta. peptide. 32. A method for screening a compound for the ability to decrease in vivo levels of the A.beta. peptide comprising the steps of: administering said compound to the mouse of claim 25; and measuring the amount of A.beta. peptide in a tissue sample from said mouse; wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that has the ability to decrease in vivo levels of said A.beta. peptide. 33. A method for screening a compound for the ability to decrease in vivo levels of the A.beta. peptide comprising the steps of: administering said compound to the mouse of claim 26; and measuring the amount of A.beta. peptide in a tissue sample from said mouse; wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that has the ability to decrease in vivo levels of said A.beta. peptide. 34. A method for screening a compound for the ability to decrease in vivo levels of the A.beta. peptide comprising the steps of: administering said compound to the mouse of claim 30; and measuring the amount of A.beta. peptide in a tissue sample from said mouse; wherein a decrease in the amount of A.beta. peptide in said tissue sample is indicative of a compound that has the ability to decrease in vivo levels of said A.beta. peptide. 35. The method of claim 31 wherein said tissue sample is brain tissue, non-brain tissue, or a body fluid. 36. The method of claim 32 wherein said tissue sample is brain tissue, non-brain tissue, or a body fluid. 37. The method of claim 33 wherein said tissue sample is brain tissue, non-brain tissue, or a body fluid. 38. The method of claim 34 wherein said tissue sample is brain tissue, non-brain tissue, or a body fluid. 39. The mouse of claim 1 wherein said human mutation of the PS-1 gene is A79V, V82L, V96F, Y115C, E120D, E120K, M1391, M139T, M139V, I143F, I143T, M146I, M146L (A.fwdarw.T), H163Y, G209V, A231T, A231V, M233T, L235P, L250S, A260V, L262F, C263R, P264L, P267S, R269H, R278T, E280A, E280G, A285V, E318G, G378E, G384A, L392V, M146L (A.fwdarw.C), M146V, H163R, I213T, L286V, A246E, Y115H, T116N, P117L, L171P, E123L, N135D, C410Y, A426P, P436S, M139K, T147I, W165C, L173W, S390I, L166R, S169L, P436Q, S169P, E184D, G209R, L219P, M233L, A409T, E273A, L282R, G378A, N405S, A409T, L424R, a .DELTA. exon 9 splice acceptor site deletion mutation (G.fwdarw.T with S290C), a .DELTA. exon 9 splice acceptor site deletion mutation (G.fwdarw.A with S290C), a .DELTA. exon 9 Finn 4,555 basepair deletion, a .DELTA. intron 4 splice donor consensus sequence G deletion, a C.fwdarw.T mutation at position-48 in the 5' promoter, a C.fwdarw.G mutation at position-280 in the 5' promoter, or a A.fwdarw.G mutation at position-2818 in the 5' promoter. 40. The mouse of claim 2 wherein said human mutation of the PS-1 gene is A79V, V82L, V96F, Y115C, E120D, E120K, M139I, M139T, M139V, I143F, I143T, M146I, M146L (A.fwdarw.T), H163Y, G209V, A231T, A231V, M233T, L235P, L250S, A260V, L262F, C263R, P264L, P267S, R269H, R278T, E280A, E280G, A285V, E318G, G378E, G384A, L392V, M146L (A.fwdarw.C), M146V, H163R, I213T, L286V, A246E, Y115H, T116N, P117L, L171P, E123L, N135D, C410Y, A426P, P436S, M139K, T147I, W165C, L173W,S390I, L166R, S169L, P436Q, S169P, E184D, G209R, L219P, M233L, A409T, E273A, L282R, G378A, N405S, A409T, L424R, a .DELTA. exon 9 splice acceptor site deletion mutation (G.fwdarw.T with S290C), a .DELTA. exon 9 splice acceptor site deletion mutation (G.fwdarw.A with S290C), a .DELTA. exon 9 Finn 4,555 basepair deletion, a .DELTA. intron 4 splice donor consensus sequence G deletion, a C.fwdarw.T mutation at position-48 in the 5' promoter, a C.fwdarw.G mutation at position-280 in the 5' promoter, or a A.fwdarw.G mutation at position-2818 in the 5' promoter.

Details for Patent 6,734,336

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2017-08-29
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2017-08-29
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2017-08-29