Compounds and methods for enhanced cellular uptake

Patent metadata

Field	Value
Publication number	US-10240151-B2
Application number	US-201615295646-A
Country	US
Kind code	B2
Filing date	Oct 17, 2016
Priority date	May 1, 2013
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

Described herein are conjugated modified oligonucleotides that are complementary to a target RNA. The conjugate facilitates cellular uptake of the modified oligonucleotide, resulting improved potency.

First claim

What is claimed:

1. A compound comprising the structure:

wherein each N of N m is, independently, a modified or unmodified nucleoside and m is 1, 2, or 3; at least one of X 1 and X 2 is a phosphodiester linkage; MO is a modified oligonucleotide; wherein when m is greater than 1, each modified or unmodified nucleoside of N m is connected to adjacent modified or unmodified nucleosides of N m by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage; and wherein the modified oligonucleotide consists of 8 to 25 linked nucleosides.

2. The compound of claim 1 , wherein each of X 1 and X 2 is a phosphodiester linkage.

3. The compound of claim 1 , wherein N m is N′ p N″, wherein each N′ is, independently, a modified or unmodified nucleoside and p is from 0 to 2; and N″ is a nucleoside comprising an unmodified sugar moiety; and wherein each pair of adjacent N′ nucleosides are connected by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage and N″ is connected to an adjacent N′ by a phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

4. The compound of claim 3 , wherein p is 0 or 1.

5. The compound of claim 4 , wherein each N of N m is linked by a phosphodiester internucleoside linkage.

6. The compound of claim 3 , wherein each N′ comprises an unmodified sugar moiety.

7. The compound of claim 3 , wherein N″ is a β-D-deoxyriboadenosine or a β-D-deoxyriboguanosine.

8. The compound of claim 1 , wherein the sugar moiety of each N of N m is independently selected from a β-D-ribose, a β-D-deoxyribose, a 2′-O-methoxy sugar, a 2′-O-methyl sugar, a 2′-fluoro sugar, and a bicyclic sugar moiety.

9. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is complementary to a target RNA.

10. The compound of claim 9 , wherein the target RNA is selected from a microRNA, a messenger RNA, a pre-messenger RNA, and a long non-coding RNA.

11. The compound of claim 9 , wherein the target RNA is a human target RNA.

12. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% identical to the nucleobase sequence of a microRNA.

13. The compound of claim 12 , wherein the modified oligonucleotide is hybridized to a second modified oligonucleotide, wherein the nucleobase sequence of the second modified oligonucleotide is complementary to the nucleobase sequence of the modified oligonucleotide.

14. The compound of claim 12 , wherein the microRNA is a human microRNA.

15. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one nucleoside with a modified sugar moiety.

16. The compound of claim 1 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety.

17. The compound of claim 1 , wherein the modified oligonucleotide comprises a plurality of nucleosides with a modified sugar moiety, and a plurality of nucleosides with an unmodified sugar moiety.

18. The compound of claim 15 , wherein each modified sugar moiety is independently selected from a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, a 2′-fluoro sugar moiety, and a bicyclic sugar moiety.

19. The compound of claim 18 , wherein each bicyclic sugar moiety is independently selected from a cEt sugar moiety and an LNA sugar moiety.

20. The compound of claim 1 , wherein the modified oligonucleotide comprises a plurality of non-bicyclic nucleosides and a plurality of bicyclic nucleosides.

21. The compound of claim 1 , wherein at least one linkage of the modified oligonucleotide is a modified internucleoside linkage.

Assignees

• Regulus Therapeutics Inc

Inventors

• Bhat Balkrishen

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title

• C12N2310/113

  targeting other non-coding nucleic acids, e.g. antagomirs · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/315

  Phosphorothioates · CPC title