Method and medicament for inhibiting the expression of a given gene

• US 8,101,742 B2
• Filed: 10/31/2007
• Issued: 01/24/2012
• Est. Priority Date: 01/30/1999
• Status: Expired due to Term

• Current Assignee: Alnylam Pharmaceuticals Incorporated
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: Kreutzer, Roland, Limmer, Stefan
• Primary Examiner(s): Vivlemore, Tracy
• Application Number:
  US11/982,305
• Publication Number:
  US 20080182981A1
• Time in Patent Office: 1,546 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• 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 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/53 partially self-complementary or closed
• CPC Class Codes: C12N 2330/30 chemically synthesised
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to an isolated RNA that mediates RNA interference of an mRNA to which it corresponds and a method of mediating RNA interference of mRNA of a gene in a cell or organism using the isolated RNA.

Claims

1. A medicament comprising:

an isolated double stranded RNA (dsRNA) consisting of two separate complementary oligoribonucleotide strands that are linked by a linker, wherein said linker comprises a covalent linker,

wherein each of said strands consists of 21 nucleotides in length,

wherein the dsRNA does not comprise a full length RNA transcript of a mammalian target gene,

wherein one strand of said dsRNA is complementary to less than the full length of an RNA transcript of said mammalian target gene,

and wherein said dsRNA is capable of specifically inhibiting the expression of said mammalian target gene.

2. The medicament of claim 1, wherein said separate oligoribonucleotide strands are chemically linked by the linker to reduce dissociation as compared to non-linked oligoribonucleotide strands.

3. The medicament of claim 1, wherein at least one of said oligoribonucleotide strands comprises at least one chemically modified nucleotide.

4. The medicament of claim 3, wherein said chemically modified nucleotide is a 2′

-modified nucleotide.

5. The medicament of claim 4, wherein said 2′

-modified nucleotide is a 2′

-methyl substituted nucleotide.

6. The medicament of claim 4, wherein said 2′

-modified nucleotide is a 2′

-amino substituted nucleotide.

7. The medicament of claim 3, wherein said chemically modified nucleotide is a locked nucleotide.

8. The medicament of claim 1, wherein said dsRNA is modified so as to be resistant to RNA degradation.

9. The medicament of claim 1, wherein said two separate complementary strands are fully complementary to each other.

10. The medicament of claim 1, wherein only one nucleotide of at least one of said oligoribonucleotide strands is a chemically modified nucleotide.

11. The medicament of claim 1, wherein said dsRNA is capable of specifically inhibiting the expression of said mammalian target gene using dsRNA-mediated interference.

12. The medicament of claim 1, wherein said covalent linker is a C18 linker.

13. A medicament comprising:

an isolated double stranded RNA (dsRNA) consisting of two separate complementary oligoribonucleotide strands that are linked by a linker, wherein said linker comprises a labile linker,

wherein each of said strands consists of 21 nucleotides in length,

wherein the dsRNA does not comprise a full length RNA transcript of a mammalian target gene,

wherein one strand of said dsRNA is complementary to less than the full length of an RNA transcript of said mammalian target gene,

and wherein said dsRNA is capable of specifically inhibiting the expression of said mammalian target gene.

14. The medicament of claim 13, wherein said separate oligoribonucleotide strands are chemically linked by the linker to reduce dissociation as compared to non-linked oligoribonucleotide strands.

15. The medicament of claim 13, wherein at least one of said oligoribonucleotide strands comprises at least one chemically modified nucleotide.

16. The medicament of claim 15, wherein said chemically modified nucleotide is a 2′

-modified nucleotide.

17. The medicament of claim 16, wherein said 2′

-modified nucleotide is a 2′

-methyl substituted nucleotide.

18. The medicament of claim 16, wherein said 2′

-modified nucleotide is a 2′

-amino substituted nucleotide.

19. The medicament of claim 15, wherein said chemically modified nucleotide is a locked nucleotide.

20. The medicament of claim 13, wherein said dsRNA is modified so as to be resistant to RNA degradation.

21. The medicament of claim 13, wherein said two separate complementary strands are fully complementary to each other.

22. The medicament of claim 13, wherein only one nucleotide of at least one of said oligoribonucleotide strands is a chemically modified nucleotide.

23. The medicament of claim 13, wherein said dsRNA is capable of specifically inhibiting the expression of said mammalian target gene using dsRNA-mediated interference.

24. The medicament of claim 13, wherein said labile linker is a disulfide bridge.