Transgenic mice expressing HPV early region oncogene develop progressive cervico-vaginal neoplasia

• US 5,709,844 A
• Filed: 06/07/1995
• Issued: 01/20/1998
• Est. Priority Date: 06/09/1994
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hanahan, Douglas, Arbeit, Jeffrey M.
• Primary Examiner(s): Crouch, Deborah
• Application Number:
  US08/484,997
• Time in Patent Office: 958 Days
• Field of Search: 424/9.2, 800/2, 800/DIG. 1, 514/182, 514/2, 435/320.1, 435/172.3, 935/22
• US Class Current: 800/3
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 2267/0393 Animal model comprising a reporter system for screening tests
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 49/0006 Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2710/20022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination

Abstract

The present invention relates to improved models for progressive epithelial neoplasias and methods for their use. In particular, the invention provides transgenic mice comprising a human papilloma virus early region oncogene operably linked to a promoter which directs expression of the oncogene in a transient amplifying cell in the mice.

Claims

1. A method for determining the efficacy of a composition in the inhibition of vaginal of cervical neoplasia, the method comprising,

providing a transgenic mouse, wherein the genome of the mouse has integrated into it an HPV early region oncogene operably linked to a promoter, wherein the promoter regulates expression of the oncogene in a transient amplifying epithelial cell,

administering an estrogenic compound to the mouse;

administering the test compound to the mouse; and

monitoring the mouse for the development of vaginal or cervical epithelium dysplasia or vaginal or cervical neoplasia.

2. The method of claim 1, wherein the oncogene is HPV-16 E6 or E7, or both HPV-16 E6 and E7.

3. The method of claim 1, wherein the mouse further comprises a β

-galactosidase gene operably linked to the keratin-14 promoter.

4. The method of claim 1, wherein the estrogenic compound is implanted subcutaneously.

5. The method of claim 1, wherein the estrogenic compound is 17-β

-estradiol.

6. The method of claim 1, wherein the estrogen is administered at a dose of about 0.25 mg to about 0.72 mg over about 60 days.

7. The method of claim 1, wherein the estrogenic compound is administered for a period from about 2 months to about 4 months.

8. A method of inducing vaginal or cervical squamous epithelium dysplasia, the method comprising,

providing a transgenic mouse, wherein the genome of the mouse has integrated into it an HPV early region oncogene operably linked to a promoter, wherein the promoter regulates expression of the oncogene in a transient amplifying epithelial cell,

administering a sufficient amount of an estrogenic compound to the mouse to cause dysplasia of the vaginal or cervical epithelium.

9. The method of claim 8, wherein the estrogenic compound is implanted subcutaneously.

10. The method of claim 8, wherein the estrogenic compound is 17-β

-estradiol.

11. The method of claim 8, wherein the estrogenic compound is administered at a dose of about 0.25 mg to about 0.72 mg over about 60 days.

12. The method of claim 8, wherein the estrogenic compound is administered for a period from about 2 months to about 4 months.

13. The method of claim 8, wherein the oncogene is HPV-16 E6 or E7, or both HPV-16 E6 and E7.

14. The method of claim 8, wherein the promoter is the keratin-14 promoter.

15. The method of claim 8, wherein the mouse further comprises a β

-galactosidase gene operably linked to a promoter which regulates expression of the β

-galactosidase gene in a transient amplifying epithelial cell.

16. The method of claim 15, wherein the promoter is the keratin-14-promoter.