Antisense inhibition of tumor necrosis factor alpha converting enzyme (TACE) expression

• US 6,180,403 B1
• Filed: 10/28/1999
• Issued: 01/30/2001
• Est. Priority Date: 10/28/1999
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Flournoy, Shin Cheng, Bennett, C. Frank
• Primary Examiner(s): Yucel, Remy
• Assistant Examiner(s): Lacourciere, Karen A
• Application Number:
  US09/429,093
• Time in Patent Office: 460 Days
• Field of Search: 435/6, 435/91.1, 435/91.3, 435/375, 435/325, 536/23.1, 536/23.2, 536/24.5, 536/24.3, 536/24.33, 536/24.31, 514/44
• US Class Current: 435/375
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• 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 2310/3525 : MOE, methoxyethoxy
• CPC Class Codes: Y02P 20/582 : Recycling of unreacted starting or intermediate materials

Abstract

Compositions and methods are provided for inhibiting the expression of human tumor necrosis factor-α-converting enzyme (TACE). Antisense oligonucleotides targeted to nucleic acids encoding TACE are preferred. Methods of using these oligonucleotides for inhibition of TACE expression and for treatment of diseases, particularly inflammatory and autoimmune diseases, associated with overexpression of TACE or TNF-α are provided.

Claims

1. An antisense compound 8 to 30 nucleobases in length targeted to nucleotides 2911 through 2930, nucleotides 2641 through 2660 or nucleotides 2681 through 2700 of a 3′

-untranslated region, nucleotides 2770 through 2603 of a stop codon region, nucleotides 131 through 150, nucleotides 2471 through 2490 or nucleotides 2531 through 2570 of a coding region, or nucleotides 114 through 133 of an AUG codon region of human TNF-α

converting enzyme SEQ ID NO;

1, wherein said antisense compound inhibits expression of human TNF-α

converting enzyme.

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

3. The antisense compound of claim 2 which comprises at least one modified internucleoside linkage.

4. The antisense compound of claim 3 wherein the modified internucleoside linkage is a phosphorothioate linkage.

5. The antisense compound of claim 2 which comprises at least one modified sugar moiety.

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

-O-methoxyethyl sugar moiety.

7. The antisense compound of claim 2 which comprises at least one modified nucleobase.

8. The antisense compound of claim 7 wherein the modified nucleobase is a 5-methylcytosine.

9. The antisense compound of claim 2 which is a chimeric oligonucleotide.

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

11. The composition of claim 10 further comprising a colloidal dispersion system.

12. A method of modulating processing of TNF-α

, in human cells or tissue, from its membrane bound form to its secreted form comprising contacting said cells or tissue in vitro with the antisense compound of claim 1 so that expression of TNF-α

converting enzyme is inhibited and processing of TNF-α

is inhibited.

13. A method of modulating the expression of TNF-α

converting enzyme in human cells or tissues comprising contacting said cells or tissue in vitro with the antisense compound of claim 1 so that expression of said TNF-α

converting enzyme is inhibited.

14. An antisense compound up to 30 nucleobases in length comprising at least an 8-nucleobase portion of SEQ ID NO:

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, or SEQ ID NO;

12 which inhibits the expression of human TNF-α

converting enzyme.