Compounds and Methods for Enhanced Cellular Uptake

Patent metadata

Field	Value
Publication number	US-2019309292-A1
Application number	US-201916250529-A
Country	US
Kind code	A1
Filing date	Jan 17, 2019
Priority date	May 1, 2013
Publication date	Oct 10, 2019
Grant date	—

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

1 .- 91 . (canceled)

92 . 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.

93 . The compound of claim 92 , wherein the unmodified nucleoside is a β-D-deoxyriboadenosine or a β-D-deoxyriboguanosine.

94 . The compound of claim 92 , wherein the unmodified nucleoside is a β-D-deoxyriboadenosine.

95 . The compound of claim 92 , wherein the nucleobase sequence of the modified oligonucleotide is complementary to a human microRNA.

96 . The compound of claim 92 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% identical to the nucleobase sequence of a microRNA.

97 . The compound of claim 96 , 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.

98 . The compound of claim 92 , wherein the modified oligonucleotide consists of 8 to 25 linked nucleosides.

99 . The compound of claim 92 , wherein the modified oligonucleotide comprises at least one nucleoside with a modified sugar moiety.

100 . The compound of claim 92 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety.

101 . The compound of claim 92 , wherein the modified oligonucleotide comprises a plurality of nucleosides with a modified sugar moiety, and a plurality of nucleosides with an unmodified sugar moiety.

102 . The compound of claim 101 , 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.

103 . The compound of claim 102 , wherein each bicyclic sugar moiety is independently selected from a cEt sugar moiety and an LNA sugar moiety.

104 . The compound of claim 101 , wherein each unmodified sugar moiety is selected from is a β-D-deoxyriboadenosine or a β-D-deoxyriboguanosine.

105 . The compound of claim 92 , wherein the modified oligonucleotide comprises a plurality of non-bicyclic nucleosides and a plurality of bicyclic nucleosides.

106 . The compound of claim 105 , wherein each non-bicyclic nucleoside is selected from a β-D-deoxyriboadenosine and a 2′-O-methoxyethyl nucleoside.

107 . The compound of claim 105 , wherein each bicyclic nucleoside is an S-cEt nucleoside.

108 . The compound of claim 92 , wherein at least one linkage of the modified oligonucleotide is a modified internucleoside linkage.

109 . The compound of claim 92 , wherein each linkage of the modified oligonucleotide is a phosphorothioate 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

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/113

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

• C12N2310/315

  Phosphorothioates · CPC title