UNA oligomers for therapeutics with prolonged stability

• US 10,457,945 B2
• Filed: 04/13/2018
• Issued: 10/29/2019
• Est. Priority Date: 05/22/2007
• Status: Active Grant

• Current Assignee: Arcturus Therapeutics, Inc. (Arcturus Therapeutics Holdings, Inc.)
• Original Assignee: Arcturus Therapeutics, Inc. (Arcturus Therapeutics Holdings, Inc.)
• Inventors: Wengel, Jesper
• Primary Examiner(s): Angell, J. E.
• Application Number:
  US15/952,680
• Publication Number:
  US 20180237780A1
• Time in Patent Office: 564 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• 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 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2320/51 modulating the chemical stability, e.g. nuclease-resistance

Abstract

This invention provides UNA oligomers for therapeutics having prolonged stability. The UNA oligomers can be composed of one or more 2′-3′-seco-nucleomonomers and one or more natural or non-natural nucleotide monomers. Embodiments include UNA oligomers with phosphorothioate or boranophosphate intermonomer linkages. The UNA oligomers can be used for therapeutics that target oligonucleotides, nucleic acids, or RNAs to reduce their activity.

Claims

1. A ribonucleotide oligomer comprising one or more 2′

-3′

-seco-nucleomonomers and one or more natural or non-natural nucleotide monomers, wherein the oligomer is a duplex having a ribonucleotide sense strand and ribonucleotide antisense strand, wherein one or more of the 2′

-3′

-seco-nucleomonomers are in the antisense strand in positions 1-8 counted from the 5′

end, and wherein the 2′

-3′

-seco-nucleomonomers are monomer D

2. The oligomer of claim 1, wherein the nucleobase is adenine, thymine, uracil, guanine, cytosine, inosine, or a nucleobase of a non-natural nucleotide.

3. The oligomer of claim 1, each strand comprising from 8 to 62 monomers in length.

4. The oligomer of claim 1, each strand comprising from one to five 2′

-3′

-seco-nucleomonomers.

5. The oligomer of claim 1, wherein one or more of the nucleotide monomers is selected from the group consisting of 2′

-O-alkyl-RNA monomers, 2′

-amino-DNA monomers, 2′

-fluoro-DNA monomers, LNA monomers, PNA monomers, HNA monomers, ANA monomers, FANA monomers, CeNA monomers, ENA monomers, DNA monomers, and INA monomers.

6. The oligomer of claim 1, wherein one or more of the nucleotide monomers is 2′

-O-alkyl-RNA nucleotide analogues.

7. The oligomer of claim 1, further comprising a phosphorothioate linkage or a boranophosphate linkage.

8. The oligomer of claim 1, wherein the oligomer is capable of mediating RISC dependent translational repression or degradation of a target nucleotide sequence complementary to a portion of the oligomer.

9. The oligomer of claim 1, wherein the oligomer is capable of mediating DICER dependent translational repression or degradation of a target nucleotide sequence complementary to a portion of the oligomer.

10. The oligomer of claim 1, comprising a number of base pairs from 14 to 26 base pairs.

11. The oligomer of claim 1, comprising at least one overhang.

12. The oligomer of claim 1, comprising an overhang of from 1 to 14 monomers.

13. The oligomer of claim 1, comprising at least one 3′

-overhang.

14. The oligomer of claim 1, comprising at least one 3′

-overhang of from 1 to 14 nucleotides.

15. The oligomer of claim 1, comprising at least one blunt end.

16. The oligomer of claim 1, comprising a monomer sequence that is complementary to a target nucleotide sequence.

17. The oligomer of claim 1, wherein the oligomer has reduced off-target effects as compared to an oligonucleotide having the same target nucleotide sequence, wherein the oligonucleotide is composed of only natural RNA monomers.

18. The oligomer of claim 1, wherein the oligomer has increased or prolonged potency for gene silencing as compared to an oligonucleotide having the same target nucleotide sequence, wherein the oligonucleotide is composed of only natural RNA monomers.

19. The oligomer of claim 1, wherein the oligomer has improved stability towards enzymatic degradation as compared to an oligonucleotide having the same target nucleotide sequence, wherein the oligonucleotide is composed of only natural RNA monomers.

20. The oligomer of claim 1, wherein the oligomer has reduced immune stimulation as compared to an oligonucleotide having the same target nucleotide sequence, wherein the oligonucleotide is composed of only natural RNA monomers.