iRNA agents targeting VEGF

• US 7,947,659 B2
• Filed: 03/11/2005
• Issued: 05/24/2011
• Est. Priority Date: 03/12/2004
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: de Fougerolles, Antonin, Hadwiger, Philipp, Manoharan, Muthiah, Rajeev, Kallanthottathil G., Frank-Kamenetsky, Maria
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US11/078,073
• Publication Number:
  US 20060094032A1
• Time in Patent Office: 2,265 Days
• Field of Search: None
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/475 : Growth factors; Growth regulators
• CPC Class Codes: C12N 15/1136 : against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2310/533 : having a mismatch or nick in at least one of the strands
• CPC Class Codes: C12N 2320/30 : Special therapeutic applications
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific

Abstract

The features of the present invention relate to compounds, compositions and methods useful for modulating the expression of vascular endothelial growth factor (VEGF), such as by the mechanism of RNA interference (RNAi). The compounds and compositions include iRNA agents that can be unmodified or chemically-modified.

Claims

1. An isolated double stranded iRNA agent, consisting of SEQ ID NO:

609 and SEQ ID NO;

608.

8. A method of reducing the amount of VEGF RNA in a cell of a subject, comprising contacting the cell with an iRNA agent of claim 1.

9. A pharmaceutical composition comprising an iRNA agent of claim 1 and a pharmaceutically acceptable carrier.

10. A method of inhibiting VEGF expression in a subject comprising administering to said subject an effective amount of an iRNA agent of claim 1.

2. An isolated double stranded iRNA agent consisting of SEQ ID NO:

608 and SEQ ID NO;

609 and a non-nucleotide moiety.

3. The iRNA of claim 2, wherein the sense and antisense sequences are stabilized against nucleolytic degradation.

4. An isolated double stranded iRNA agent consisting of SEQ ID NO:

608 and SEQ ID NO;

609 and a phosphorothioate at the first internucleotide linkage at the 5′

end of the antisense and sense sequences.

5. An isolated double stranded iRNA agent consisting of SEQ ID NO:

608 and SEQ ID NO;

609 and a phosphorothioate at the first internucleotide linkage at the 5′

end of the antisense and sense sequences, and a phosphorothioate at the first internucleotide linkage at the 3′

end of the antisense and sense sequences.

6. An isolated double stranded iRNA agent consisting of SEQ ID NO:

608 and SEQ ID NO;

609 and wherein at least one nucleotide of at least one strand is a 2′

-modified nucleotide.

7. The iRNA agent of claim 6, wherein the 2′

-modified nucleotide comprises a modification selected from the group consisting of;

2′

-deoxy, 2′

-deoxy-2′

-fluoro, and 2′

-O-methyl.