Transgenic animals and cell lines for screening drugs effective for the treatment or prevention of Alzheimer's disease

• US 7,045,616 B2
• Filed: 09/28/2001
• Issued: 05/16/2006
• Est. Priority Date: 02/26/1997
• Status: Expired due to Fees

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: de la Monte, Suzanne, Wands, Jack R
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US09/964,666
• Publication Number:
  US 20020104108A1
• Time in Patent Office: 1,691 Days
• Field of Search: 435/375, 435/377, 536/23.1, 536/24.1, 536/24.5, 514/44
• US Class Current: 536/24.5
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• 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 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: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

Disclosed are transgenic animals and transfected cell lines expressing a protein associated with Alzheimer'"'"'s Disease, neuroectodermal tumors, malignant astrocytomas, and glioblastomas. Also disclosed is the use of such transgenic animals and transfected cell lines to screen potential drug candidates for treating or preventing Alzheimer'"'"'s disease, neuroectodermal tumors, malignant astrocytomas, and glioblastomas. The invention also relates to new antisense oligonucleotides, ribozymes, triplex forming DNA and external guide sequences that can be used to treat or prevent Alzheimer'"'"'s disease, neuroectodermal tumors, malignant astrocytomas, and glioblastomas.

Claims

1. An antisense oligonucleotide which is complementary to an NTP mRNA sequence, wherein said antisense oligonucleotide is selected from the group consisting of SEQ ID NO:

9, SEQ ID NO;

10 and SEQ ID NO;

11.

2. The antisense oligonucleotide of claim 1, which is deoxyribonucleic acid.

3. The antisense oligonucleotide of claim 1, which is deoxyribonucleic acid phosphorothioate.

4. The antisense oligonucleotide of claim 1, which is a derivative of a deoxyribonucleic acid or a deoxyribonucleic acid phosphorothioate.

5. A pharmaceutical composition comprising the antisense oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.

6. A ribonucleotide external guide nucleic acid molecule comprising a 10-mer nucleotide sequence fused to a 3′

NCCA nucleotide sequence, wherein N is a purine, wherein said ribonucleotide external guide nucleic acid molecule is selected from the group consisting of SEQ ID NO;

12, SEQ ID NO;

13 and SEQ ID NO;

14.

7. A pharmaceutical composition comprising the ribonucleotide of claim 6 and a pharmaceutically acceptable carrier.

8. An antisense oligonucleotide, which is a 15 to 40 mer and is complementary to an NTP mRNA sequence corresponding to a region within nucleotides 150–

1139 of SEQ ID NO;

1, wherein said region includes one or more nucleotides selected from the group consisting of nucleotides 150, 194–

195, 240–

241, 243, 244, 255–

256, 266–

267, 269–

271, 276, 279–

280, 293–

295, 338–

340, 411, 459, 532–

533, 591, 633–

644, 795–

797, 828, 853–

854, 876–

877, 883, 884–

885, 898, 976, 979–

980, 999, 1037, 1043–

1044, 1092–

1096, 1099, and 1116–

1119 of SEQ ID NO;

1.

9. The antisense oligonucleotide of claim 8, which is deoxyribonucleic acid.

10. The anti sense oligonucleotide of claim 8, which is deoxyribonucleic acid phosphorothioate.

11. The antisense oligonucleotide of claim 8, which is a derivative of a deoxyribonucleic acid or a deoxyribonucleic acid phosphorothioate.

12. A pharmaceutical composition comprising the antisense oligonucleotide of claim 8 and a pharmaceutically acceptable carrier.