Antisense design

Patent metadata

Field	Value
Publication number	US-9994850-B2
Application number	US-201715619134-A
Country	US
Kind code	B2
Filing date	Jun 9, 2017
Priority date	Nov 18, 2002
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

A novel class of pharmaceuticals which comprises a Locked Nucleic Acid (LNA) which can be used in antisense therapy. These novel oligonucleotides have improved antisense properties. The novel oligonucleotides are composed of at least one LNA selected from beta-D-thio/amino-LNA or alpha-L-oxy/thio/amino-LNA. The oligonucleotides comprising LNA may also include DNA and/or RNA nucleotides.

First claim

The invention claimed is:

1. A gapmer oligonucleotide 12 26 nucleotide units in length of formula A-B-C-D, wherein:
A represents a sequence of locked nucleotide units;
B represents a sequence of at least 6 continuous DNA nucleotide units;
C represents a locked nucleotide unit or a sequence of locked nucleotide units;
D represents a non-locked nucleotide unit or a sequence of non-locked nucleotide units,
wherein the non-locked nucleotide unit of region D is a 2′ substituted non-locked nucleotide, wherein the 2′ substituent is selected from the group consisting of halogen or C 1 -C 9 alkoxy.

2. The gapmer oligonucleotide according to claim 1 , wherein at least one of the locked nucleotide units of regions A and/or C is a nucleotide of formula:

wherein X is O; one of the H's in (CH 2 )n is replaced with a C 1-6 alkyl substituent; n is 1; and Base is independently selected from the group consisting of cytosine, methyl cytosine, uracil, thymine, adenine and guanine.

3. The gapmer oligonucleotide according to claim 2 , wherein one of the H's in (CH 2 )n is replaced with methyl.

4. The gapmer oligonucleotide according to claim 1 wherein at least one of the internucleoside linkages is a phosphorothioate linkage.

5. The gapmer oligonucleotide of claim 1 wherein all of the internucleotide linkages are phosphorothioate linkages.

6. The gapmer oligonucleotide according to claim 2 wherein at least one of the internucleotide linkages is a phosphorothioate linkages.

7. The gapmer oligonucleotide according to claim 2 wherein all of the internucleotide linkages are phosphorothioate linkages.

8. The gapmer oligonucleotide of claim 1 wherein in the central region B is 8-12 DNA nucleotides.

9. The gapmer oligonucleotide of claim 2 wherein in the central region B is 8-12 DNA nucleotides.

10. The gapmer oligonucleotide of claim 1 , wherein region A has a length of 2-6 nucleotide units and region C has a length of 1-5 nucleotide units and region D has a length of 1-3 nucleotide units.

11. The gapmer oligonucleotide of claim 2 , wherein region A has a length of 2-6 nucleotide units and region C has a length of 1-5 nucleotide units and region D has a length of 1-3 nucleotide units.

12. The gapmer oligonucleotide of claim 1 , wherein region A has a length of 3-5 nucleotide units and region C has a length of 2-4 nucleotide units and region D has a length of 1-2 nucleotide units.

13. The gapmer oligonucleotide of claim 2 , wherein region A has a length of 3-5 nucleotide units and region C has a length of 2-4 nucleotide units and region D has a length of 1-2 nucleotide units.

14. The gapmer oligonucleotide of claim 1 , wherein the gapmer oligonucleotide has a length of 12-21 nucleotide units.

15. The gapmer oligonucleotide of claim 2 , wherein the gapmer oligonucleotide has a length of 12-21 nucleotide units.

16. The gapmer oligonucleotide of claim 1 , wherein the gapmer oligonucleotide has a length of 15-17 nucleotide units.

17. The gapmer oligonucleotide of claim 2 , wherein the gapmer oligonucleotide has a length of 15-17 nucleotide units.

18. The gapmer oligonucleotide of claim 1 , wherein the gapmer oligonucleotide has a length of 13, 14, 15, 16, 17 or 18 nucleotide units.

19. The gapmer oligonucleotide of claim 2 , wherein the gapmer oligonucleotide has a length of 13, 14, 15, 16, 17 or 18 nucleotide units in length.

Assignees

• Roche Innovation Ct Copenhagen As

Inventors

• Christensen Signe M
• Mikkelsen Nikolaj Dam
• Frieden Miriam
• Hansen Henrik Frydenlund
• Koch Troels
• Pedersen Daniel Sejer
• Rosenbohm Christoph
• Thrue Charlotte Albaek
• Westergaard Majken

Classifications

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C07H19/16

  Purine radicals · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title