Compounds and methods for enhanced cellular uptake
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Publication Number
US-10941400-B2
Publication Date
2021-03-09
Expiration 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.
Core Innovation
The invention relates to modified oligonucleotides and conjugated modified oligonucleotide compounds having defined linker/scaffold attachment options and substituent definitions. The described framework includes linker scaffold element B, scaffold attachment elements S, linking groups selected from Q, Q′, Q″, and combinations such as Q/Q′/Q″, as well as ligand attachment structures represented by L and Ln-linker structures.
The modified oligonucleotide backbone composition includes unmodified nucleosides with m=1, phosphodiester linkages defined by X1 and X2, and modified oligonucleotide embodiments with linked nucleosides in a length range of 8–30 linked nucleosides. The disclosure further includes gapmer motif configurations, siRNA and microRNA mimic forms, phosphorothioate internucleoside linkages, non-phosphorus modified linkers, and sugar-moiety options including 2′-O-methyl, 2′-O-methoxyethyl, 2′-fluoro, and bicyclic sugar moieties such as cEt/LNA/ENA.
A targeting and therapeutic context is described using carbohydrate ligands, including N-acetylgalactosamine and galactose-family ligands, with ASGPR targeting associated with galactose or GalNAc. The conjugated modified oligonucleotides are complementary to target RNA, including microRNA, and are described in relation to diseases associated with target RNAs in liver and hepatocytes and with expression in macrophages and dendritic cells.
Claims Coverage
The consolidated claim coverage centers on modified oligonucleotide compounds defined by unmodified nucleosides, phosphodiester linkages, and MO as a modified oligonucleotide, with dependent refinements for microRNA targeting and specified structural variants. The inventive features include the structural nucleoside-phosphodiester definition, microRNA complementarity or identity, allowed sugar moieties, nucleoside-type plurality, and phosphorothioate linkage refinement.
Unmodified nucleosides with m=1 in the nucleoside-phosphodiester structure
Each N is an unmodified nucleoside and m is 1.
Phosphodiester linkage definition for X1 and X2
Each of X1 and X2 is a phosphodiester linkage.
Modified oligonucleotide as MO
MO is a modified oligonucleotide.
MicroRNA complementarity targeting
The nucleobase sequence of a modified oligonucleotide is complementary to a human microRNA.
MicroRNA nucleobase sequence identity constraint
The nucleobase sequence of a modified oligonucleotide is at least 90% identical to a microRNA nucleobase sequence.
Allowed modified sugar moieties for modified oligonucleotide
Each modified sugar moiety is independently one of 2′-O-methyl, 2′-O-methoxyethyl, 2′-fluoro, or bicyclic sugar moieties.
Mixture of non-bicyclic and bicyclic nucleosides
The modified oligonucleotide includes both non-bicyclic and bicyclic nucleosides in plurality.
Phosphorothioate internucleoside linkage for essentially all linkages
Every linkage in the modified oligonucleotide is a phosphorothioate internucleoside linkage.
Overall, the claim coverage focuses on modified oligonucleotide structures defined by unmodified nucleosides and phosphodiester linkages, with dependent refinements for microRNA complementarity or identity, specified modified sugar moieties, mixtures of nucleoside types, and phosphorothioate linkage refinement.
Stated Advantages
Improved cellular uptake and potency relative to oligonucleotides, as stated in the provided description.
Improved in vivo potency and duration with measured effects in mice for GalNAc- or cholesterol-conjugated modified oligonucleotides.
Documented Applications
Treatment or use for diseases in which a target RNA, including microRNA, is present in liver cells, as described at a high level.
Use of GalNAc-conjugated anti-miR examples in connection with in vivo potency and liver concentration, as described in the provided content.
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