Antisense modulation of bcl-x expression

• US 7,148,204 B2
• Filed: 11/21/2002
• Issued: 12/12/2006
• Est. Priority Date: 10/07/1998
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Zhang, Vivian Q., Nickoloff, Brian J., Monia, Brett P., Dean, Nicholas M., Bennett, C. Frank
• Primary Examiner(s): EPPS -SMITH, JANET L
• Application Number:
  US10/302,262
• Publication Number:
  US 20030191300A1
• Time in Patent Office: 1,482 Days
• Field of Search: 536/24.5, 536/24.3, 536/24.1, 536/24.31, 536/24.33, 536/23.1, 435/375, 514/44
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/3181 Peptide nucleic acid, PNA
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/334 Modified C
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

Compositions and methods are provided for modulating the expression of bcl-x. Antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding bcl-x are preferred. Methods of using these compounds for modulation of bcl-x expression and for treatment of diseases associated with expression of bcl-x are also provided. Methods of sensitizing cells to apoptotic stimuli are also provided.

Claims

1. An antisense compound 20 to 30 nucleobases in length targeted to nucleobases 876 through 895 or 907 through 926 of a 3′

untranslated region of a nucleic acid molecule encoding a human bcl-x of SEQ ID NO;

1.

2. The antisense compound of claim 1 which is an antisense oligonucleotide.

3. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified intemucleoside linkage.

4. The antisense compound of claim 3 wherein the modified intemucleoside linkage of the antisense oligonucleotide is a phosphorothioate linkage, a morpholino linkage or a peptide-nucleic acid linkage.

5. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

6. The antisense compound of claim 5 wherein the modified sugar moiety of the antisense oligonucleotide is a 2′

-O-methoxyethyl sugar moiety or a 2′

-dimethylaminooxyethoxy sugar moiety.

7. The antisense compound of claim 5 wherein more than one of the sugar moieties of the antisense oligonucleotide are modified sugar moieties.

8. The antisense compound of claim 3 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

9. The antisense compound of claim 8 wherein the modified nucleobase of to antisense oligonucleotide is a 5-methylcytosine.

10. The antisense compound of claim 8 wherein each modified nucleobase of the antisense oligonucleotide is a 5-methylcytosine.

11. The antisense compound of claim 1 which is a chimeric oligonucleotide.

12. A pharmaceutical composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

13. The pharmaceutical composition of claim 12 further comprising a colloidal dispersion system.

14. The pharmaceutical composition of claim 12 wherein the antisense compound is an antisense oligonucleotide.

15. The antisense compound of claim 1 which is targeted to bcl-xl.

16. The pharmaceutical composition of claim 12 further comprising a chemotherapeutic agent for the treatment of cancer.