Modulation of apolipoprotein (a) expression

• US 7,741,305 B2
• Filed: 07/30/2007
• Issued: 06/22/2010
• Est. Priority Date: 08/07/2001
• Status: Expired due to Fees

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Graham, Mark J., Crooke, Rosanne M.
• Primary Examiner(s): BOWMAN, AMY HUDSON
• Application Number:
  US11/830,734
• Publication Number:
  US 20090075924A1
• Time in Patent Office: 1,058 Days
• Field of Search: None
• US Class Current: 514/44.00R
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: 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
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Compounds, compositions and methods are provided for modulating the expression of apolipoprotein(a). The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein(a). Methods of using these compounds for modulation of apolipoprotein(a) expression and for diagnosis and treatment of disease associated with expression of apolipoprotein(a) are provided.

Claims

1. A method comprising administering to a human an antisense compound comprising an antisense oligonucleotide 12 to 30 nucleobases in length wherein the antisense oligonucleotide specifically hybridizes to at least 8 consecutive nucleotides selected from nucleotides 13711-13750 of SEQ ID NO:

4.

2. The method of claim 1, wherein the human has a cardiovascular disease.

3. The method of claim 1, wherein the human has elevated plasma lipoprotein(a) levels.

4. The method of claim 1, wherein the administering comprises intravenous administration or subcutaneous administration.

5. The method of claim 1, further comprising a step of measuring lipoprotein(a) levels in the plasma of the human.

6. The method of claim 1, wherein the antisense oligonucleotide comprises a gap segment having 2-deoxynucleotides positioned between 5′

and 3′

wing segments, wherein each nucleotide of each wing segment comprises a modified sugar moiety.

7. The method of claim 6, wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

8. The method of claim 6, wherein the modified sugar moiety is a bicyclic nucleic acid sugar moiety.

9. The method of claim 6, wherein the gap segment is ten 2′

-deoxynucleotides and each wing segment is five 2′

-O-methoxyethyl nucleotides.

10. The method of claim 6, wherein at least one intemucleoside linkage is a phosphorothioate intemucleoside linkage.

11. The method of claim 6, wherein at least one cytosine is a 5-methylcytosine.

12. The method of claim 1, wherein the antisense oligonucleotide is 100% complementary to SEQ ID NO:

4.

13. The method of claim 1, wherein the antisense oligonucleotide comprises SEQ ID NO:

39 or 40.

14. The method of claim 1, wherein the antisense oligonucleotide consists of SEQ ID NO:

39 or 40.

15. The method of claim 1, wherein the antisense oligonucleotide is 20 nucleobases in length.

25. The method of claim 2, wherein the human has atherosclerosis, hypercholesterolemia, or coronary artery disease.

16. A method comprising

administering to a human having a cardiovascular disease an antisense oligonucleotide 20 nucleobases in length comprising at least 8 consecutive nucleobases of SEQ ID NO:

39 or 40.

17. The method of claim 16, wherein the antisense oligonucleotide comprises a gap segment of ten 2′

-deoxynucleotides positioned between 5′ and

3′

wing segments of five nucleotides, wherein each nucleotide of each wing segment comprises a modified sugar moiety.

18. The method of claim 17, wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

19. The method of claim 17, wherein the modified sugar moiety is a bicyclic nucleic acid sugar moiety.

20. The method of claim 19, wherein each intemucleoside linkage is a phosphorothioate internucleoside linkage.

21. The method of claim 20, wherein each cytosine is a 5-methylcytosine.

22. The method of claim 16, further comprising measuring lipoprotein(a) levels in the serum of the human following the administering.

23. The method of claim 16, wherein the administering comprises intravenous administration or subcutaneous administration.

26. The method of claim 16, wherein the human has atherosclerosis, hypercholesterolemia, or coronary artery disease.

24. A method comprising

administering to a human having a cardiovascular disease an antisense oligonucleotide 20 nucleobases in length consisting of SEQ ID NO:

39 or 40, wherein the antisense oligonucleotide comprises a gap segment of ten 2′

-deoxynucleotides positioned between 5′ and

3′

wing segments of five 2′

-O-methoxyethyl-nucleotides, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein each cytosine is a 5-methylcytosine; and

measuring lipoprotein(a) levels in the serum of the human following the administering.

27. The method of claim 24, wherein the human has atherosclerosis, hypercholesterolemia, or coronary artery disease.