TRANSGENIC MICE

• US 20090098052A1
• Filed: 09/12/2008
• Published: 04/16/2009
• Est. Priority Date: 09/12/2007
• Status: Active Grant

• Current Assignee: Probiodrug AG
• Original Assignee: Probiodrug AG
• Inventors: Graubner, Sigrid, Jagla, Wolfgang, Demuth, Hans-Ulrich, Schilling, Stephan, Cynis, Holger
• Granted Patent: US 8,283,517 B2
• Time in Patent Office: Days
• US Class Current: 424/9.1
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0312 Animal model for Alzheimer's disease
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination
• CPC Class Codes: C12N 9/104 Aminoacyltransferases (2.3.2)
• CPC Class Codes: C12Y 203/02005 Glutaminyl-peptide cyclotransferase (2.3.2.5)

Abstract

A transgenic non-human animal, in particular a transgenic mouse encoding Aβ peptide proteins, which have been implicated in Aβ peptide-related diseases. Cells and cell lines comprising transgenes encoding for Aβ peptide. Methods and compositions for evaluating agents that affect Aβ peptide, for use in compositions for the treatment of Aβ peptide-related diseases.

Claims

1. A transgenic non-human animal for overexpressing Aβ

peptides comprising cells containing a DNA transgene encoding Aβ

peptide.

2. The transgenic non-human animal of claim 1, wherein the animal is heterozygous for the transgene.

3. The transgenic non-human animal of claim 1, wherein the animal is homozygous for the transgene.

4. The transgenic non-human animal of claim 1, wherein the animal is a mouse.

5. The transgenic non-human animal of claim 1, wherein the transgene is of murine origin.

6. The transgenic non-human animal of claim 1, wherein the transgene is of human origin.

7. The transgenic non-human animal of claim 1, wherein the transgene is a recombinant gene.

8. The transgenic non-human animal of claim 7, wherein the recombinant transgene encodes a chimeric or humanized polypeptide.

9. The transgenic non-human animal of claim 1, wherein the transgene encodes at least one of Aβ

N3E-42 (SEQ ID No;

     1), Aβ

N3Q-42 (SEQ ID No;

     2), Aβ

N3E-40 (SEQ ID No;

     3) and Aβ

N3Q-40 (SEQ ID No;

     4).

10. The transgenic non-human animal of claim 1, wherein the transgene encodes at least one of Aβ

N3E-42 (SEQ ID No;

     1) and Aβ

N3Q-42 (SEQ ID No;

     2).

11. The transgenic non-human animal according to claim 1, wherein the transgene is operably linked to a tissue-specific promoter.

12. The transgenic non-human animal of claim 1, further comprising cells containing a DNA transgene encoding glutaminyl cyclase or a glutaminyl-peptide cyclotransferase-like protein.

13. The transgenic non-human animal of claim 12, wherein said glutaminyl cyclase or a glutaminyl-peptide cyclotransferase-like protein is selected from from human isoQC (SEQ ID Nos:

14 or

     15) mouse (SEQ ID No;

     20), Macaca fascicularis (SEQ ID No;

     16), Macaca mulatta (SEQ ID No;

     17), cat (SEQ ID No;

     18), rat (SEQ ID No;

     19), cow (SEQ ID No;

     21) or an analogue thereof having at least 50%/75% sequence identity/similarity.

14. The transgenic non-human animal of claim 12, wherein said glutaminyl cyclase or a glutaminyl-peptide cyclotransferase-like protein is an isoform or spliceform of human QC or isoQC according to SEQ. ID Nos:

13 to 15, 22 or 23;

rat QC (SEQ. ID No;

     19) or mouse (SEQ. ID No;

     20).

15. The transgenic non-human animal of claim 12, wherein said glutaminyl cyclase or a glutaminyl-peptide cyclotransferase-like protein is one of SEQ. ID No:

13 or SEQ. ID No;

20.

16. A method for screening for biologically active agents that inhibit or promote Aβ

peptide effects in vivo, comprising;

a) administering a test agent to the transgenic non-human animal of claim 1; and

b) determining the effect of the agent on the effect of Aβ

peptide produced.

17. The method of claim 16, wherein the transgenic non-human animal is heterozygous for the transgene.

18. The method of claim 16, wherein the transgenic non-human animal is homozygous for the transgene.

19. The method of claim 16, wherein the animal is a mouse.

20. The method of claim 16, wherein the transgene is of murine origin.

21. The method of claim 16, wherein the transgene is of human origin.

22. The method of claim 16, wherein the transgene is a recombinant gene.

23. The method of claim 22, wherein the recombinant transgene encodes a chimeric or humanized polypeptide.

24. The method of claim 16, wherein the transgene encodes Aβ

N3E-42 (SEQ ID No;

     1), Aβ

N3Q-42 (SEQ ID No;

     2), Aβ

N3E-40 (SEQ ID No;

     3) and/or Aβ

N3Q-40 (SEQ ID No;

     4).

25. The method of claim 16, wherein the transgene encodes Aβ

N3E-42 (SEQ ID No;

     1) and/or Aβ

N3Q-42 (SEQ ID No;

     2).

25-1. A cell or cell line derived from the transgenic non-human animal of claim 1.

39. A method for screening for a target compound that is influenced by Aβ

peptide production, wherein said method comprises the evaluation of the effects of Aβ

peptide in vivo with the use of the transgenic non-human animal of claim 1 on a possible target compound.

26. A transgenic mouse comprising a transgenic nucleotide sequence encoding Aβ

peptide operably linked to a promoter, integrated into the genome of the mouse, wherein the mouse demonstrates a phenotype that can be reversed or ameliorated with an Aβ

peptide inhibitor of Aβ

peptide effects.

27. The mouse of claim 26, wherein the mouse overexpresses Aβ

peptide.

28. The mouse of claim 26, wherein the mouse is heterozygous for Aβ

peptide.

29. The mouse of claim 26, wherein the mouse is homozygous for Aβ

peptide.

30. The mouse of claim 26, wherein the transgenic sequence encodes murine Aβ

peptide.

31. The mouse of claim 26, wherein the transgenic sequence encodes human Aβ

peptide.

32. The mouse of claim 26, wherein the transgene encodes Aβ

N3E-42 (SEQ ID No;

     1), Aβ

N3Q-42 (SEQ ID No;

     2), Aβ

N3E-40 (SEQ ID No;

     3) and/or Aβ

N3Q-40 (SEQ ID No;

     4).

33. The mouse of claim 26, wherein the transgene encodes Aβ

N3E-42 (SEQ ID No;

     1) and/or Aβ

N3Q-42 (SEQ ID No;

     2).

34. A method for screening for therapeutic agents that inhibit or promote Aβ

peptide effects comprising;

a) administering test agents to the transgenic mouse of claim 26;

b) evaluating the effects of the test agent on the neurological phenotype of the mouse; and

c) selecting a test agent which inhibits or promotes Aβ

peptide effects.

35. A method for treatment or prevention of an Aβ

peptide-related disease comprising;

a) administering the selected test agent of claim 34; and

b) monitoring the patient for a decreased clinical index for Aβ

peptide-related diseases.

36. The method of claim 35, wherein the Aβ

peptide-related disease is Alzheimer'"'"'s disease.

37. A pharmaceutical composition comprising the selected test agent of claim 35.

40. A method for screening for a target compound that is influenced by Aβ

peptide production, wherein said method comprises the evaluation of the effects of Aβ

peptide in vivo with the use of the transgenic mouse of claim 26 on a possible target compound.

38. (canceled)