Modulation of apolipoprotein (A) expression

• US 8,138,328 B2
• Filed: 04/22/2010
• Issued: 03/20/2012
• Est. Priority Date: 08/07/2001
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Crooke, Rosanne M., Graham, Mark J.
• Primary Examiner(s): Bowman, Amy
• Application Number:
  US12/765,647
• Publication Number:
  US 20100273860A1
• Time in Patent Office: 698 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 compound comprising an antisense oligonucleotide 12 to 30 nucleobases in length targeting apolipoprotein(a), wherein said oligonucleotide comprises at least an 8-nucleobase portion of the nucleobase sequence of SEQ ID NO:

11.

2. The compound of claim 1, wherein said oligonucleotide is 90% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO:

3).

3. The compound of claim 1, wherein said oligonucleotide is 95% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO:

3).

4. The compound of claim 1, wherein said oligonucleotide is 20 nucleobases in length.

5. The compound of claim 1, wherein said oligonucleotide is a chimeric oligonucleotide.

6. The compound of claim 1, wherein said oligonucleotide comprises at least one modified internucleoside linkage.

7. The compound of claim 6, wherein the modified internucleoside linkage is a phosphorothioate linkage.

8. The compound of claim 1, wherein said oligonucleotide comprises at least one modified sugar moiety.

9. The compound of claim 8, wherein said modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

10. The compound of claim 1, wherein said oligonucleotide comprises at least one modified nucleobase.

11. The compound of claim 10, wherein said modified nucleobase is a 5-methylcytosine.

12. The compound of claim 5, wherein said chimeric oligonucleotide comprises a gap segment of linked 2′

-deoxynucleotides which is flanked on each side by at least one 2′

-O-methoxyethyl nucleotide.

13. The compound of claim 12, wherein said gap segment is ten 2′

-deoxynucleotides in length.

14. The compound of claim 12, wherein said gap segment is flanked on each side by five 2′

-O-methoxyethyl nucleotides.

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

16. The compound of claim 1, having at least 12 linked nucleobases of SEQ ID NO:

11.

17. The compound of claim 5, wherein said oligonucleotide comprises at least one modified internucleoside linkage, wherein the modified internucleoside linkage is a phosphorothioate linkage, wherein said oligonucleotide comprises a gap segment of linked 2′

-deoxynucleotides which is flanked on each side by at least one 2′

-O-methoxyethyl nucleotide, wherein each cytosine is a 5-methylcytosine, and wherein said oligonucleotide is 95% complementary to a nucleic acid molecule encoding human apolipoprotein(a) (SEQ ID NO;

     3).

18. A compound comprising an antisense oligonucleotide 20 nucleobases in length, wherein said oligonucleotide comprises at least an 8-nucleobase portion of the nucleobase sequence of SEQ ID NO:

11, wherein said oligonucleotide comprises a gap segment of ten linked 2′

-deoxynucleotides which is flanked on each side by five 2′

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