Modified compounds and uses thereof
Inventors
Seth, Punit P. • Oestergaard, Michael • Migawa, Michael T. • Liang, Xue-hai • Shen, Wen • Crooke, Stanley T. • Swayze, Eric E.
Assignees
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Publication Number
US-12234447-B2
Publication Date
2025-02-25
Expiration Date
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.
Core Innovation
The document describes an oligomeric compound comprising a modified oligonucleotide of 16-20 linked nucleosides organized into a 5′ region, a central region, and a 3′ region. The 5′ region and the 3′ region each consist of 3-5 linked nucleosides with modified sugar moieties, and the central region consists of 8-10 linked nucleosides with a specified nucleoside and sugar arrangement.
In the central region, Nx is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety and each Nd is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety, with n=6-8. The disclosure also describes motif-defined oligomeric compounds, including eeeee-d-m-d(8)-eeeee, and defines internucleoside linkage motifs, stereochemistry options, and neutral linkage chemistries.
The document further relates these structural organizations to target RNA modulation, including antisense mechanisms involving hybridizing to target nucleic acid and RNase H1 mediated cleavage. It also discusses target RNA expression in liver, central nervous system, and/or muscle cells, conjugate group architectures including GalNAc, and therapeutic use by administering the oligomeric compound to a human subject to modulate target RNA amount or activity.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a modified oligonucleotide with a defined 16-20 nucleoside architecture and a central-region nucleoside and sugar pattern. Dependent claim features refine the structure with complementarity thresholds, target expression context, a GalNAc conjugate group, a named sugar motif, and a quantitative constraint on modified internucleoside linkage count.
Region-defined modified oligonucleotide architecture
An oligomeric compound comprising a modified oligonucleotide of 16-20 linked nucleosides arranged into a 5′ region, a central region, and a 3′ region, with the 5′ region and 3′ region each consisting of 3-5 linked nucleosides with modified sugar moieties and the central region consisting of 8-10 linked nucleosides.
Central-region nucleoside and sugar formula using Nx and Nd
The central region has the formula with Nx and Nd units with n=6-8, wherein Nx is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety and each Nd is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety.
Motif-defined sugar arrangement in the modified oligonucleotide
A modified oligonucleotide having the motif eeeee-d-m-d(8)-eeeee, wherein each e is a nucleoside comprising a 2′-MOE sugar moiety, each d is a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety, and m is a nucleoside comprising a 2′-OMe-β-D-ribofuranosyl sugar moiety.
Central-region constraint on modified internucleoside linkage count
The central region contains exactly one modified internucleoside linkage other than phosphorothioate.
Nucleobase sequence complementary to target RNA
The nucleobase sequence is at least 85%, 90%, 95%, or 100% complementary to a target RNA.
Target RNA expressed in specific cell types
The target RNA is expressed in liver, central nervous system, and/or muscle cells.
GalNAc conjugate group
The conjugate group includes GalNAc.
Overall, the claim coverage centers on a region-defined modified oligonucleotide with a central-region sugar pattern defined by Nx and Nd nucleosides with n=6-8. The dependent features further include a named sugar motif, complementarity thresholds to target RNA, expression-location refinements, GalNAc conjugate group inclusion, and an exact-count constraint on modified internucleoside linkages in the central region.
Stated Advantages
Increased maximum tolerated dose compared with otherwise identical parent compounds lacking the altered central-region nucleotide(s).
Improved therapeutic index compared with otherwise identical parent compounds lacking the altered central-region nucleotide(s).
Reduced hepatotoxicity.
Safety improvement relative to otherwise identical parent compounds lacking the altered central-region nucleotide(s).
Comparative toxicity improvements from position-specific central-region modifications are described.
Therapeutic-index improvement supported by plasma ALT and AST thresholds in mice/humans.
Documented Applications
Antisense mechanisms are discussed, including hybridizing to target nucleic acid and RNase H1 mediated cleavage.
Target RNA expression-context refinements are described for liver, central nervous system, and/or muscle cells.
Conjugate group architectures are described, including conjugate moieties such as GalNAc.
Treating disorders associated with modulation of target RNA expression, including Alzheimer’s, ALS, Parkinson’s, spinocerebellar ataxia, Angelman syndrome, Alexander’s disease, Lafora disease, Charcot-Marie Tooth disease, Prion disease, dementia, neurodegeneration, MeCP2 Duplication Syndrome, encephalopathy, neuroinflammation, and multiple sclerosis.
In vitro evaluation of modified oligonucleotides complementary to mouse CXCL12, including caspase-3/7 activation in 3T3-L1 cells and RT-qPCR measurement of CXCL12 mRNA and P21 mRNA.
Confocal microscopy localization studies assessing p54nrb nucleolar positivity in connection with the tested modified oligonucleotides.
Evaluation of placement of chiral phosphorothioate or 2′-OMe modifications at specific central-region positions and conjugation to a 3′-THA-GalNAc conjugate.
In vitro and in vivo testing related to toxicity and biological effects, including liver toxicity assessed via ALT/AST, changes in liver mRNA assessed by RT-qPCR, caspase-related effects, and p54nrb nucleolar mislocalization.
Targeting a target RNA with complementarity thresholds, including embodiments where the target RNA is expressed in liver, central nervous system, and/or muscle cells.
Administration to a human subject to modulate target RNA amount or activity.
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