Modulation of apolipoprotein (a) expression

• US 8,673,632 B2
• Filed: 03/17/2010
• Issued: 03/18/2014
• Est. Priority Date: 06/02/2003
• 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:
  US12/726,286
• Publication Number:
  US 20110039910A1
• Time in Patent Office: 1,462 Days
• Field of Search: None
• US Class Current: 435/325
• 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 of inhibiting the expression of apolipoprotein(a) in a cell or tissue comprising contacting said cell or tissue with a compound 15 to 30 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein(a) (SEQ ID NO:

4), wherein said compound comprises at least 8 consecutive nucleobases of SEQ ID NO;

86 and is at least 70% complementary to said nucleic acid molecule encoding apolipoprotein(a), so that expression of apolipoprotein(a) is inhibited.

2. The method of claim 1, wherein the compound is at least 80%, at least 90%, at least 95% or at least 99% complementary with said nucleic acid molecule encoding apolipoprotein(a).

3. The method of claim 1, wherein the compound has at least one modified internucleoside linkage, sugar moiety, or nucleobase.

4. The method of claim 1, wherein the compound has at least one 2′

-O-methoxyethyl sugar moiety, phosphorothioate internucleoside linkage or 5-methylcytosine.