Oligomeric compounds for the modulation of HIF-1A expression

• US 8,357,670 B2
• Filed: 05/22/2012
• Issued: 01/22/2013
• Est. Priority Date: 04/05/2002
• Status: Expired due to Fees

• Current Assignee: Roche Innovation Center Copenhagen A/S (Roche Holding AG)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC), Santaris Pharama A/S
• Inventors: Thrue, Charlotte Albaek, Hog, Anja Molhart, Kristjansen, Paul E. G.
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US13/477,825
• Publication Number:
  US 20120270924A1
• Time in Patent Office: 245 Days
• Field of Search: None
• US Class Current: 514/44
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• 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: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 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 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/331 Universal or degenerate base
• CPC Class Codes: C12N 2310/334 : Modified C
• CPC Class Codes: C12N 2310/3341 : 5-Methylcytosine
• CPC Class Codes: C12N 2310/335 : Modified T or U
• CPC Class Codes: C12N 2310/341 : Gapmers, i.e. of the type ===---===

Abstract

Oligonucleotides directed against the hypoxia-inducible factor-1α (HIF-1α) gene are provided for modulating the expression of HIF-1α. The compositions comprise oligonucleotides, particularly antisense oligonucleotides, targeted to nucleic acids encoding the HIF-1α. Methods of using these compounds for modulation of HIF-1α expression and for the treatment of diseases associated with the hypoxia-inducible factor-1α are provided. Examples of diseases are cancer and pre-eclampsia. The oligonucleotides may be composed of deoxyribonucleosides, a nucleic acid analogue, or Locked Nucleic Acid (LNA) or a combination thereof.

Claims

1. A method of treating a mammal suffering from cancer, comprising administering to the mammal a composition comprising a therapeutically effective amount of an oligonucleotide compound targeted to Hif-1alpha and having the base sequence set forth in SEQ ID NO:

3 and an agent selected from the group consisting of an antiinflammatory agent, a corticosteroid, an antiviral agent, a chemotherapeutic agent, and an immuno-modulating agent, wherein the cancer is selected from the group consisting of kidney cancer, melanoma, glioblastoma and prostate cancer, and wherein the oligonucleotide compound comprises one or more LNA units.

2. The method of claim 1, wherein the cancer is kidney cancer.

3. The method of claim 1, wherein the cancer is melanoma.

4. The method of claim 1, wherein the cancer is glioblastoma.

5. The method of claim 1, wherein the cancer is prostate cancer.

6. The method of claim 1, wherein the composition is administered parenterally.

7. The method of claim 1, wherein the composition is administered intravenously.

8. The method of claim 1, wherein the composition is administered by bolus injection into a target organ.

9. The method of claim 1, wherein the composition is administered intraperitoneally.