Interfering RNA molecules

• US 9,758,784 B1
• Filed: 05/08/2017
• Issued: 09/12/2017
• Est. Priority Date: 08/05/2002
• Status: Expired due to Term

• Current Assignee: Silence Therapeutics Gmbh (Silence Therapeutics plc)
• Original Assignee: Silence Therapeutics Gmbh (Silence Therapeutics plc)
• Inventors: Giese, Klaus, Kaufmann, Jrg, Klippel-Giese, Anke
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US15/589,971
• Publication Number:
  US 20170247698A1
• Time in Patent Office: 127 Days
• Field of Search: None
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 15/111 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 15/1137 : against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/13 : Decoys
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2310/317 : with an inverted bond, e.g. a cap structure
• CPC Class Codes: C12N 2310/3183 : Diol linkers, e.g. glycols or propanediols
• CPC Class Codes: C12N 2310/32 : of the sugar
• CPC Class Codes: C12N 2310/321 : 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 : 2'-R Modification
• CPC Class Codes: C12N 2310/332 : Abasic residue
• CPC Class Codes: C12N 2310/343 : having patterns, e.g. ==--==--==--
• 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 2310/3525 : MOE, methoxyethoxy
• CPC Class Codes: C12N 2310/53 : partially self-complementary or closed
• CPC Class Codes: C12N 2310/531 : Stem-loop; Hairpin
• CPC Class Codes: C12N 2320/50 : Methods for regulating/modulating their activity
• CPC Class Codes: C12N 2320/51 : modulating the chemical stability, e.g. nuclease-resistance
• CPC Class Codes: C12N 5/10 : Cells modified by introduction of foreign genetic material
• CPC Class Codes: C12Q 1/68 : involving nucleic acids
• CPC Class Codes: C12Y 207/11001 : Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
• CPC Class Codes: C12Y 301/03048 : Protein-tyrosine-phosphatase (3.1.3.48)

Abstract

The present invention is related to a ribonucleic acid comprising a double stranded structure whereby the double-stranded structure comprises a first strand and a second strand, whereby the first strand comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, and the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to a target nucleic acid, and whereby the double stranded structure is blunt ended.

Claims

1. A double-stranded siRNA molecule against a target nucleic acid, wherein the double-stranded siRNA molecule comprises a first strand and a second strand,

wherein the first strand comprises a first stretch that is complementary to the target nucleic acid,

wherein the second strand comprises a second stretch that is complementary to the first stretch,

wherein the first strand and the second strand form a double-stranded structure comprising the first stretch and the second stretch,

wherein the double-stranded siRNA molecule is blunt ended on at least one end, and

wherein each stretch consists of at least 15 and fewer than 30 ribonucleotides and wherein the first stretch and the second stretch each comprises contiguous alternating modified ribonucleotides, wherein the alternating modified ribonucleotides alternate with unmodified or differently modified ribonucleotides.

2. The double-stranded siRNA molecule of claim 1, wherein the double-stranded siRNA molecule is blunt ended on the end defined by the 5′

end of the first strand and the 3′

end of the second strand.

3. The double-stranded siRNA molecule of claim 1, wherein the double-stranded siRNA molecule is blunt ended on the end defined by the 3′

end of the first strand and the 5′

end of the second strand.

4. The double-stranded siRNA molecule of claim 1, wherein the double-stranded siRNA molecule is blunt ended on both ends.

5. The double-stranded siRNA molecule of claim 1, wherein each of the first strand and the second strand consists of 17 to 30 ribonucleotides.

6. The double-stranded siRNA molecule of claim 1, wherein the first stretch and the second stretch are of the same length.

7. The double-stranded siRNA molecule of claim 1, wherein each of the first strand and the second strand is 17 to 23 nucleotides long.

8. The double-stranded siRNA molecule of claim 1, wherein each of the first strand and the second strand is 19 nucleotides long.

9. The double-stranded siRNA molecule of claim 1, wherein each of the first strand and the second strand is 21 nucleotides long.

10. The double-stranded siRNA molecule of claim 1, wherein each of the first strand and the second strand is 23 nucleotides long.

11. The double-stranded siRNA molecule of claim 1, wherein the modified ribonucleotides are selected from the group consisting of 2′

-O-alkyl ribonucleotides, 2′

-fluoro ribonucleotides and 2′

-amino ribonucleotides.

12. The double-stranded siRNA molecule of claim 11, wherein the 2′

-O-alkyl ribonucleotides are selected from the group consisting of 2′

-O-methyl ribonucleotides and 2′

-O-ethyl ribonucleotides.

13. The double-stranded siRNA molecule of claim 1, wherein the modified ribonucleotides are 2′

-O-methyl ribonucleotides.

14. The double-stranded siRNA molecule of claim 13, wherein the 2′

-O-methyl ribonucleotides alternate with the unmodified ribonucleotides.

15. The double-stranded siRNA molecule of claim 13, wherein the 2′

-O-methyl ribonucleotides alternate with the differently modified ribonucleotides.

16. The double-stranded siRNA molecule of claim 15, wherein the differently modified ribonucleotides are 2′

-fluoro ribonucleotides.

17. The double-stranded siRNA molecule of claim 1, wherein the alternating modified ribonucleotides of the first strand are shifted by at least one ribonucleotide relative to the unmodified or differently modified ribonucleotides of the second strand.

18. The double-stranded siRNA molecule of claim 1, wherein the first stretch and the second stretch each comprises contiguous alternating single 2′

-O-alkyl modified ribonucleotides, and wherein the single 2′

-O-alkyl modified ribonucleotides alternate with the unmodified ribonucleotides.

19. The double-stranded siRNA molecule of claim 18, wherein the single 2′

-O-alkyl modified ribonucleotides of the first strand are shifted by one ribonucleotide relative to the single 2′

-O-alkyl modified ribonucleotides of the second strand.

20. The double-stranded siRNA molecule of claim 18, wherein the single 2′

-O-alkyl modified ribonucleotides are 2′

-O-methyl ribonucleotides.

21. The double-stranded siRNA molecule of claim 1, wherein the first stretch and the second stretch each comprises contiguous alternating single 2′

-O-alkyl modified ribonucleotides, and wherein the single 2′

-O-alkyl modified ribonucleotides alternate with the differently modified ribonucleotides.

22. The double-stranded siRNA molecule of claim 21, wherein the single 2′

-O-alkyl modified ribonucleotides of the first strand are shifted by one ribonucleotide relative to the single 2′

-O-alkyl modified ribonucleotides of the second strand.

23. The double-stranded siRNA molecule of claim 21, wherein the single 2′

-O-alkyl modified ribonucleotides are 2′

-O-methyl ribonucleotides.

24. The double-stranded siRNA molecule of claim 23, wherein the differently modified ribonucleotides are 2′

-fluoro ribonucleotides.