Modulation of C-reactive protein expression

• US 7,425,545 B2
• Filed: 06/01/2004
• Issued: 09/16/2008
• Est. Priority Date: 07/25/2001
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Graham, Mark J., Crooke, Rosanne M.
• Primary Examiner(s): McGarry; Sean
• Application Number:
  US10/858,500
• Publication Number:
  US 20050014257A1
• Time in Patent Office: 1,568 Days
• Field of Search: None
• US Class Current: 514/44.00A
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 25/16 Anti-Parkinson drugs
• 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 27/02 Ophthalmic agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07H 21/02 : with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 : with deoxyribosyl as saccharide radical
• 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 2310/11 : Antisense
• 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

Abstract

Compounds, compositions and methods are provided for modulating the expression of C-reactive protein. The compositions comprise oligonucleotides, targeted to nucleic acid encoding C-reactive protein. Methods of using these compounds for modulation of C-reactive protein expression and for diagnosis and treatment of disease associated with expression of C-reactive protein are provided.

Claims

1. An antisense compound 15 to 30 nucleobases in length targeted to a nucleic acid molecule encoding C-reactive protein, wherein said compound comprises a 15 nucleobase portion having at least 90% complementarity to at least a 15 nucleobase portion of nucleotides 1719 to 1738 of SEQ ID NO. 4.

2. The antisense compound of claim 1, wherein said antisense compound has a nucleobase sequence that is at least 95% complementary to at least a 15 nucleobase portion of nucleotides 1719-1738 of SEQ ID NO:

4.

3. The antisense compound of claim 1, wherein said antisense compound has a nucleobase sequence that is 100% complementary to at least a 15 nucleobase portion of nucleotides 1719-1738 of SEQ ID NO:

4.

4. The antisense compound of claim 1, wherein said antisense compound comprises an antisense oligonucleotide.

5. The antisense compound of claim 4, wherein said antisense compound comprises a chimeric oligonucleotide.

6. The antisense compound of claim 1, wherein said antisense compound comprises at least one modified internucleoside linkage, modified sugar moiety, or modified nucleobase.

7. The antisense compound of claim 1, wherein said antisense compound comprises at least one 2′

-O-methoxyethyl sugar moiety.

8. The antisense compound of claim 1, wherein said antisense compound comprises at least one phosphorothioate internucleoside linkage.

9. The antisense compound of claim 1, wherein said antisense compound comprises at least one 5-methylcytosine.

10. The antisense compound of claim 5, wherein said chimeric oligonucleotide comprises a 2′

-deoxynucleotide segment positioned between wing segments, each wing segment having two to five nucleotides comprising modified sugar moieties, wherein each internucleoside linkage of said chimeric oligonucleotide is a phosphorothioate internucleoside linkage and wherein all cytidine residues are 5-methylcytidines.

11. The antisense compound of claim 1, wherein said antisense compound is single-stranded.

19. A method of treating an animal having a disease or condition treatable by reducing C-reactive protein comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of C-reactive protein is inhibited.

20. The method of claim 19, wherein said disease or condition is selected from the group consisting of:

coronary artery disease, unstable angina, stroke, atherosclerosis, myocardial infarction, thrombosis, obesity, metabolic syndrome, diabetes, hyperlipidemia, acute coronary syndrome, and coronary artery stenting.

21. The method according to claim 19 wherein said animal is a human.

22. The method according to claim 19, wherein said disease or condition is selected from the group consisting of:

coronary artery disease, unstable angina, atherosclerosis, myocardial infarction, hyperlipidemia, and coronary artery stenting.

23. The method according to claim 19, wherein said disease or condition is coronary artery disease.

24. The method according to claim 19, wherein said disease or condition is unstable angina.

25. The method according to claim 19, wherein said disease or condition is atherosclerosis.

26. The method according to claim 19, wherein said disease or condition is myocardial infarction.

27. The method according to claim 19, wherein said disease or condition is hyperlipidemia.

28. The method according to claim 19, wherein said disease or condition is coronary artery stenting.

29. The method according to claim 19, wherein said disease or condition is stroke.

30. The method according to claim 19, wherein said disease or condition is thrombosis.

31. The method according to claim 19, wherein said disease or condition is obesity.

32. The method according to claim 19, wherein said disease or condition is metabolic syndrome.

33. The method according to claim 19, wherein said disease or condition is diabetes.

34. The method according to claim 19, wherein said disease or condition is acute coronary syndrome.

35. The antisense compound of claim 1, wherein said antisense compound comprises at least one bicyclic nucleic acid sugar moiety.

41. The method of claim 19 wherein said antisense oligonucleotide consists of the nucleobase sequence of SEQ ID NO:

205, having a 2′

-deoxynucleotide portion fourteen nucleotides in length positioned between a 5′

terminus and a 3′

terminus, wherein said 5′

terminus has three 2′

-O-methoxyethylnucleotides, wherein said 3′

terminus has three 2′

-O-methoxyethylnucleotides, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein each cytosine is a 5-methylcytosine.

42. The method of claim 41 wherein said antisense oligonucleotide is in a pharmaceutically acceptable salt form.

12. An antisense compound 20 nucleobases in length targeted to a nucleic acid molecule encoding C-reactive protein, comprising:

at least 16 consecutive nucleotides of SEQ ID NO;

205;

a 5′

terminus having two to four 2′

-O-methoxyethyl nucleotides;

a 3′

terminus having two to four 2′

-O-methoxyethyl nucleotides; and

a 2′

-deoxynucleotide portion twelve to sixteen nucleotides in length disposed between said 5′

terminus and said 3′

terminus.

13. The antisense compound of claim 12, wherein all internucleoside linkages are phosphorothioate.

14. The antisense compound of claim 12, wherein all cytidine residues are 5-methylcytidines.

15. The antisense compound of claim 12, wherein each terminus is two nucleotides in length and said 2′

-deoxynucleotide portion is sixteen nucleobases in length.

16. The antisense compound of claim 12, wherein each terminus is three nucleotides in length and said 2′

-deoxynucleotide portion is fourteen nucleobases in length.

17. The antisense compound of claim 12, wherein each terminus is four nucleotides in length and said 2′

-deoxynucleotide portion is twelve nucleobases in length.

18. The antisense compound of claim 12, wherein said antisense compound has a nucleobase sequence consisting of SEQ ID NO:

205.

36. The antisense compound of claim 12, wherein said antisense compound comprises an antisense oligonucleotide.

37. An antisense oligonucleotide consisting the nucleobase sequence of SEQ ID NO:

205, having a 2′

-deoxynucleotide portion fourteen nucleotides in length positioned between a 5′

terminus and a 3′

terminus, wherein said 5′

terminus has three 2′

-O-methoxyethylnucleotides, wherein said 3′

terminus has three 2′

-O-methoxyethylnucleotides, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein each cytosine is a 5-methylcytosine.

38. The antisense oligonucleotide of claim 37, wherein the antisense oligonucleotide is in a pharmaceutically acceptable salt form.

39. A composition comprising the antisense oligonucleotide of claim 38 and a pharmaceutically acceptable carrier or excipient.

40. The antisense oligonucleotide of claim 38, wherein the salt is a sodium salt.