Modulation of apolipoprotein (A) expression

• US 7,723,508 B2
• Filed: 06/02/2004
• Issued: 05/25/2010
• Est. Priority Date: 06/02/2003
• Status: Expired due to Term

• 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:
  US10/559,647
• Publication Number:
  US 20060281698A1
• Time in Patent Office: 2,183 Days
• Field of Search: None
• US Class Current: 536/24.5
• 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 single-stranded antisense compound 15 to 30 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein(a), wherein said compound is at least 94% complementary to nucleotides 12380-12438 as set forth in SEQ ID NO:

4.

2. The single-stranded antisense compound of claim 1 comprising an antisense oligonucleotide.

3. The single-stranded antisense compound of claim 2 comprising a chimeric antisense oligonucleotide.

4. The single-stranded antisense compound of claim 1 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.

5. The single-stranded antisense compound of claim 1 having at least one 2′

-O-methoxyethyl sugar moiety.

6. The single-stranded antisense compound of claim 1 having at least one phosphorothioate internucleoside linkage.

7. The single-stranded antisense compound of claim 1 having at least one 5-methylcytosine.

11. The single-stranded antisense compound of claim 1, wherein the antisense compound is at least 95% complementary to SEQ ID NO:

4.

12. The single-stranded antisense compound of claim 1, wherein the antisense compound is 100% complementary to SEQ ID NO:

4.

13. The single-stranded antisense compound of claim 1, wherein the antisense compound is 20 nucleobases in length.

8. A single-stranded antisense compound 15 to 30 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein(a), wherein said compound is at least 90% complementary to nucleotides 12380-12438 as set forth in SEQ ID NO:

4 and wherein the antisense compound comprises at least 8 contiguous nucleobases of SEQ ID NO;

87.

9. The single-stranded antisense compound of claim 8, wherein the antisense compound comprises SEQ ID NO:

87.

10. The single-stranded antisense compound of claim 8, wherein the antisense compound consists of SEQ ID NO:

87.

14. A chimeric antisense oligonucleotide 15 to 30 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein(a), wherein said chimeric antisense oligonucleotide is at least 90% complementary to nucleotides 12380-12438 as set forth in SEQ ID NO:

4.

15. The chimeric antisense oligonucleotide of claim 14, wherein said chimeric antisense oligonucleotide comprises a 2′

-deoxynucleotide gap segment positioned between a 5′

wing segment and a 3′

wing segment.

16. The chimeric antisense oligonucleotide of claim 15, wherein each nucleotide of each wing segment comprises a modified sugar moiety.

17. The chimeric antisense oligonucleotide of claim 16, wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

18. The chimeric antisense oligonucleotide of claim 16, wherein the modified sugar moiety is a bicyclic nucleic acid sugar moiety.

19. The chimeric antisense oligonucleotide of claim 14, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

20. The chimeric antisense oligonucleotide of claim 14, wherein each cytosine is a 5-methylcytosine.

21. The chimeric antisense oligonucleotide of claim 14, wherein the chimeric antisense oligonucleotide is at least 95% complementary to SEQ ID NO:

4.

22. The chimeric antisense oligonucleotide of claim 14, wherein the chimeric antisense oligonucleotide is 100% complementary to SEQ ID NO:

4.

23. The chimeric antisense oligonucleotide of claim 14, wherein the chimeric antisense oligonucleotide is 20 nucleobases in length.

24. The chimeric antisense oligonucleotide of claim 15, wherein the chimeric antisense oligonucleotide comprises:

a 5′

wing segment consisting of five linked 2′

-O-methoxyethyl nucleotides;

a 3′

wing segment consisting of five linked 2′

-O-methoxyethyl nucleotides;

a gap segment consisting often 2′

-deoxynucleotides positioned between the 5′

wing segment and the 3′

wing segment;

wherein each internucleoside linkage is a phosphorothioate internucleotide linkages, and wherein each cytosine is a 5-methylcytosine.