O-methyl rich fully stabilized oligonucleotides

Patent metadata

Field	Value
Publication number	US-12297430-B2
Application number	US-202217580269-A
Country	US
Kind code	B2
Filing date	Jan 20, 2022
Priority date	Aug 23, 2018
Publication date	May 13, 2025
Grant date	May 13, 2025

Abstract

Novel oligonucleotides that are fully chemically stabilized are provided. Methods of using oligonucleotides that are fully chemically stabilized are also provided.

First claim

What is claimed:

1. An oligonucleotide comprising,
at least 14 contiguous nucleotides, a 5′ end and a 3′ end; and
at least 85% 2′-O-methyl nucleotide modifications,
wherein the nucleotides at positions 2, 14, and 20 from the 5′ end of the oligonucleotide comprise a non-2′-O-methyl modification.

2. The oligonucleotide of claim 1 , wherein the nucleotides at positions 2, 14, and 20 from the 5′ end of the oligonucleotide comprise a 2′-F modification, a 2′-H modification, or a 2′-OH moiety.

3. The oligonucleotide of claim 1 , further comprising a complementary second oligonucleotide comprising at least 13 contiguous nucleotides, and a 5′ end and a 3′ end.

4. The oligonucleotide of claim 3 , wherein the second oligonucleotide comprises between 15 and 20 contiguous nucleotides, 15 contiguous nucleotides, 18 contiguous nucleotides, or 20 contiguous nucleotides.

5. The oligonucleotide of claim 3 , wherein the second oligonucleotide comprises one or more nucleotide mismatches between the first oligonucleotide and the second oligonucleotide.

6. The oligonucleotide of claim 1 , comprising between 15 and 22 contiguous nucleotides, 20 contiguous nucleotides, or 22 contiguous nucleotides.

7. A pharmaceutical composition comprising one or more oligonucleotides of claim 1 , and a pharmaceutically acceptable carrier.

8. A method of treating or managing a disease or disorder comprising administering to a subject in need of such treatment or management a therapeutically effective amount of the pharmaceutical composition of claim 7 .

9. A double-stranded nucleic acid structure comprising an antisense strand and a sense strand, wherein:
the antisense strand comprises at least 14 contiguous nucleotides, a 5′ end and a 3′ end, and has complementarity to a target;
the sense strand comprises at least 13 contiguous nucleotides, a 5′ end and a 3′ end, and has complementarity to the antisense strand;
the antisense strand comprises at least 85% 2′-O-methyl modifications; and
the nucleotides at positions 2, 14, and 20 from the 5′ end of the antisense strand comprise a non-2′-O-methyl modification or are modified with 2′-F.

10. The double-stranded nucleic acid of claim 9 , wherein the nucleotides at positions 2, 14, and 20 from the 5′ end of the antisense strand comprise a 2′-F modification, a 2′-H modification, or a 2′-OH moiety.

11. The double-stranded nucleic acid of claim 9 , wherein the antisense strand comprises between 15 and 22 contiguous nucleotides, 20 contiguous nucleotides, or 22 contiguous nucleotides.

12. The double-stranded nucleic acid of claim 9 , wherein the sense strand comprises between 15 and 20 contiguous nucleotides, 15 contiguous nucleotides, 18 contiguous nucleotides, or 20 contiguous nucleotides.

13. The double-stranded nucleic acid of claim 9 , wherein the sense strand comprises one or more nucleotide mismatches between the antisense strand and the sense strand.

14. The double-stranded nucleic acid of claim 9 , wherein the antisense strand comprises a 5′ phosphate, a 5′-alkyl phosphonate, a 5′ alkylene phosphonate, or a 5′ alkenyl phosphonate.

15. A pharmaceutical composition comprising one or more double-stranded, chemically-modified nucleic acids of claim 9 , and a pharmaceutically acceptable carrier.

16. A method of treating or managing a disease or disorder comprising administering to a subject in need of such treatment or management a therapeutically effective amount of the pharmaceutical composition of claim 15 .

17. A branched oligonucleotide compound capable of mediating RNA silencing in a cell, comprising two or more double-stranded nucleic acids,
wherein the nucleic acids (N) are connected to one another by one or more moieties selected from a linker (L), a spacer (S), and optionally a branching point (B),
wherein each double-stranded nucleic acid comprises an antisense strand and a sense strand, wherein each antisense strand comprises at least 14 contiguous nucleotides, a 5′ end and a 3′ end, and at least one antisense strand comprises at least 85% 2′-O-methyl modifications,
wherein the nucleotides at positions 2, 14, and 20 from the 5′ end of the at least one antisense strand comprise a non-2′-O-methyl modification, and
wherein one or more nucleotides at positions 1-7 from the 3′ end of at least one antisense strand are connected to adjacent nucleotides via phosphorothioate linkages.

18. The branched oligonucleotide compound of claim 17 , wherein the compound further comprises a hydrophobic moiety attached to the terminal 5′ position of the branched oligonucleotide compound.

19. The branched oligonucleotide compound of claim 17 , wherein the non-2′-O-methyl modification comprises a 2′-F modification, a 2′-H modification, or a 2′-OH moiety.

20. The branched oligonucleotide compound of claim 17 , wherein the antisense strand comprises at least 90% 2′-O-methyl modified nucleotides.

Assignees

• Univ Massachusetts

Inventors

• Khvorova Anastasia
• Alterman Julia
• Davis Sarah
• Turanov Anton

Classifications

• C12N2310/322

  2'-R Modification · CPC title

• C12N2310/52

  branched · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/315

  Phosphorothioates · CPC title