Modified compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-12234447-B2
Application number	US-202217697577-A
Country	US
Kind code	B2
Filing date	Mar 17, 2022
Priority date	Feb 12, 2018
Publication date	Feb 25, 2025
Grant date	Feb 25, 2025

Abstract

The present disclosure provides oligomeric compound comprising a modified oligonucleotide having a central region comprising one or more modifications. In certain embodiments, the present disclosure provides oligomeric compounds having an improved therapeutic index or an increased maximum tolerated dose.

First claim

What is claimed:

1. An oligomeric compound comprising a modified oligonucleotide consisting of 16-20 linked nucleosides, wherein the modified oligonucleotide has a 5′-region, a central region, and a 3′-region, wherein:
the 5′-region consists of 3-5 linked nucleosides, each comprising modified sugar moiety;
the 3′ region consists of 3-5 linked nucleosides, each comprising a modified sugar moiety;
and the central region consists of 8-10 linked nucleosides, wherein the central region has the following formula:
(N d )(N x )(N d ) n

wherein N x is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety and each N d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety;
and n is 6-8.

2. The oligomeric compound of claim 1 , wherein each modified sugar moiety is selected from a 2′-substituted sugar moiety and a 4′-to-2′ linked bicyclic sugar moiety.

3. The oligomeric compound of claim 2 , wherein each 4′-to-2′ linked bicyclic sugar moiety is independently selected from cEt, LNA, and ENA.

4. The oligomeric compound of claim 2 , wherein each 4′-to-2′ linked bicyclic sugar moiety is cEt.

5. The oligomeric compound of claim 2 , wherein each 2′-substituted sugar moiety has a 2′-substituent independently selected from 2′-MOE, 2′-OMe, and 2′-NMA.

6. The oligomeric compound of claim 2 , wherein each 2′-substituted sugar moiety has a 2′-MOE substituent.

7. The oligomeric compound of claim 1 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.

8. The oligomeric compound of claim 1 , wherein each internucleoside linkage is independently selected from phosphodiester and phosphorothioate internucleoside linkages.

9. The oligomeric compound of claim 1 , wherein at least one internucleoside linkage within the central region is a modified internucleoside linkage other than phosphorothioate and each remaining internucleoside linkage in the modified oligonucleotide is independently selected from phosphodiester and phosphorothioate internucleoside linkages.

10. The oligomeric compound of claim 9 , wherein the central region contains exactly one modified internucleoside linkage other than phosphorothioate.

11. The oligomeric compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to a target RNA.

12. The oligomeric compound of claim 11 , wherein the target RNA is a target mRNA or a target pre-mRNA.

13. The oligomeric compound of claim 12 , wherein the target RNA is expressed in the liver, in the central nervous system, and/or in muscle cells.

14. The oligomeric compound of claim 1 , comprising a conjugate group.

15. The oligomeric compound of claim 14 , wherein the conjugate group comprises GalNAc.

16. A method comprising administering the oligomeric compound of claim 1 to a subject.

17. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of the motif eeeee-d-m-d (8)-eeeee, wherein each e is a nucleoside comprising a 2′-MOE sugar moiety, wherein each d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety, and wherein m is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety.

18. The oligomeric compound of claim 17 , wherein each internucleoside linkage is independently selected from phosphodiester and phosphorothioate internucleoside linkages.

19. The oligomeric compound of claim 17 , comprising a conjugate group.

20. The oligomeric compound of claim 19 , wherein the conjugate group comprises GalNAc.

21. A method comprising administering the oligomeric compound of claim 17 to a subject.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Oestergaard Michael
• Migawa Michael T
• Liang xue-hai
• Shen Wen
• Crooke Stanley T
• Swayze Eric E

Classifications

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N15/113 Primary

  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 title

• C12N2310/336

  Modified G · CPC title

• C12N2310/335

  Modified T or U · CPC title