Antisense modulation of microtubule-associated protein 4 expression

• US 5,998,148 A
• Filed: 04/08/1999
• Issued: 12/07/1999
• Est. Priority Date: 04/08/1999
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bennett, C. Frank, Ackermann, Elizabeth J.
• Primary Examiner(s): Elliot, George C.
• Assistant Examiner(s): WANG, ANDREW J
• Application Number:
  US09/289,368
• Time in Patent Office: 243 Days
• Field of Search: 435/6, 435/325, 536/245
• US Class Current: 435/6.11
• 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: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of microtubule-associated protein 4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding microtubule-associated protein 4. Methods of using these compounds for modulation of microtubule-associated protein 4 expression and for treatment of diseases associated with expression of microtubule-associated protein 4 are provided.

Claims

1. An antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human microtubule-associated protein 4, wherein said antisense compound specifically hybridizes with and inhibits the expression of human microtubule-associated protein 4.

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

3. The antisense compound of claim 2 wherein the antisense oligonucleotide has a sequence comprising SEQ ID NO:

9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 35, 37, 38, 40, 42, 44, 46, 47, 48, 50, 51, 52, 53, 54, 56, 57, 58, 59, 63, 66, 67, 68, 72, 73, 76, 77, 81, 84, 85 or 87.

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

5. The antisense compound of claim 4 wherein the modified internucleoside linkage is a phosphorothioate linkage.

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

7. The antisense compound of claim 6 wherein the modified sugar moiety is a 2'"'"'-O-methoxyethyl sugar moiety.

8. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

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

10. The antisense compound of claim 1 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

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

12. The composition of claim 11 further comprising a colloidal dispersion system.

13. The composition of claim 11 wherein the antisense compound is an antisense oligonucleotide.

14. A method of inhibiting the expression of microtubule-associated protein 4 in human cells or tissues comprising contacting said cells or tissues, in vitro, with the antisense compound of claim 1 so that expression of microtubule-associated protein 4 is inhibited.