Compounds and methods for enhanced cellular uptake

Patent metadata

Field	Value
Publication number	US-10941400-B2
Application number	US-201916250529-A
Country	US
Kind code	B2
Filing date	Jan 17, 2019
Priority date	May 1, 2013
Publication date	Mar 9, 2021
Grant date	Mar 9, 2021

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 an unmodified nucleoside and m is 1; each of X 1 and X 2 is a phosphodiester linkage; and MO is a modified oligonucleotide.

2. The compound of claim 1 , wherein the unmodified nucleoside is a β-D-deoxyriboadenosine or a β-D-deoxyriboguanosine.

3. The compound of claim 1 , wherein the unmodified nucleoside is a β-D-deoxyriboadenosine.

4. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is complementary to a human microRNA.

5. 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.

6. The compound of claim 5 , 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.

7. The compound of claim 1 , wherein the modified oligonucleotide consists of 8 to 25 linked nucleosides.

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

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

10. 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.

11. The compound of claim 10 , 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.

12. The compound of claim 11 , wherein each bicyclic sugar moiety is independently selected from a cEt sugar moiety and an LNA sugar moiety.

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

14. The compound of claim 13 , wherein each non-bicyclic nucleoside is selected from a β-D-deoxyriboadenosine and a 2′-O-methoxyethyl nucleoside.

15. The compound of claim 13 , wherein each bicyclic nucleoside is an S-cEt nucleoside.

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

17. The compound of claim 1 , wherein each linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

Assignees

• Regulus Therapeutics Inc

Inventors

• Bhat Balkrishen

Classifications

• 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

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• C12N2310/346

  having a combination of backbone and sugar modifications · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N2310/11

  Antisense · CPC title