Chemically modified double stranded nucleic acid molecules

• US 20050176018A1
• Filed: 11/17/2003
• Published: 08/11/2005
• Est. Priority Date: 04/20/1998
• Status: Abandoned Application

• Current Assignee: Sirna Therapeutics, Inc. (Alnylam Pharmaceuticals Incorporated)
• Original Assignee: Sirna Therapeutics, Inc. (Alnylam Pharmaceuticals Incorporated)
• Inventors: Zwick, Michael, Bellon, Laurent, Thompson, James, Beigelman, Leonid, Reynolds, Mark, McSwiggen, James, Haeberli, Peter, Matulic-Adamic, Jasenka, Jarvis, Thale, Karpeisky, Alexander, Woolf, Tod
• Application Number:
  US10/715,285
• Publication Number:
  US 20050176018A1
• Time in Patent Office: Days
• US Class Current: 435/6
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/30 Oestrogens
• 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 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/15 Nucleic acids forming more than 2 strands, e.g. TFOs
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/317 with an inverted bond, e.g. a cap structure
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/332 Abasic residue
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2310/3527 Other alkyl chain

Abstract

This invention relates to novel chemically-modified nucleic acid molecules having specified formulae that exhibit increased resistance to nucleases and increased binding affinity to target nucleic acid molecules. The invention further relates to methods of modulating gene expression using the novel chemically modified nucleic acid molecules, and compositions and cells comprising said molecules.

Claims

1. A chemically synthesized double stranded nucleic acid molecule comprising nucleotide sequence having between 14 and 24 nucleotides complementary to nucleotide sequence of a target RNA or a portion thereof, wherein one of the strands of said double stranded nucleic acid comprises a 5′

-cap, a 3′

-cap, or both a 5′ and

3′

-cap.

2. The double stranded nucleic acid molecule of claim 1, wherein said double stranded nucleic acid is an RNA molecule.

3. The double stranded nucleic acid molecule of claim 1, wherein said cap comprises an inverted nucleotide.

4. The double stranded nucleic acid molecule of claim 2, wherein said inverted nucleotide comprises an inverted deoxynucleotide.

5. The double stranded nucleic acid molecule of claim 1, wherein said cap comprises an inverted abasic moiety.

6. The double stranded nucleic acid molecule of claim 2, wherein said inverted abasic moiety comprises an inverted deoxyabasic moiety.

7. The double stranded nucleic acid molecule of claim 1, wherein said nucleic acid comprises one or more 2′

-O-alkyl modified nucleotides.

8. The double stranded nucleic acid molecule of claim 1, wherein said nucleic acid comprises one or more 2′

-deoxy nucleotides.

9. The double stranded nucleic acid molecule of claim 1, wherein said nucleic acid comprises ribonucleotides, 2′

-O-alkyl, 2′

-deoxy-2′

-fluoro, 2′

-deoxy nucleotides or a combination thereof.

10. The double stranded nucleic acid molecule of claim 4 or claim 6, wherein said 2′

-O-alkyl is 2′

-O-methyl.

11. The double stranded nucleic acid molecule of claim 4 or claim 6, wherein said 2′

-O-alkyl is 2′

-O-allyl.

12. The double stranded nucleic acid molecule of claim 11 further comprising one or more phosphorothioate internucleotide linkages.

13. The double stranded nucleic acid molecule of claim 1, wherein said nucleic acid comprises one or more phosphorothioate internucleotide linkages.

14. The double stranded nucleic acid molecule of claim 1, wherein said target RNA is encoded by a mammalian gene.

15. A composition comprising the double stranded nucleic acid molecule of claim 1 in a pharmaceutically acceptable carrier or diluent.