Oligonucleotide compositions and methods thereof
Inventors
Frank-Kamenetsky, Maria David • Yang, Hailin • MORRIS, Aaron Jay • Vargeese, Chandra • Francis, Christopher J.
Assignees
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Publication Number
US-11634710-B2
Publication Date
2023-04-25
Expiration Date
Abstract
Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.
Core Innovation
The invention relates to a method for characterizing a chirally controlled oligonucleotide composition by assessing complement activation by the chirally controlled oligonucleotide composition relative to a reference oligonucleotide composition. The chirally controlled oligonucleotide composition comprises a plurality of structurally identical oligonucleotides of a particular oligonucleotide type and is enriched relative to a substantially racemic preparation of oligonucleotides of the particular oligonucleotide type.
The chirally controlled oligonucleotide composition comprises 5 or more phosphorothioate internucleotidic linkages, wherein at least about 50% of the phosphorothioate internucleotidic linkages are Sp. The reference oligonucleotide composition is a substantially racemic preparation of oligonucleotides of the particular type and increases complement activation compared to absence of the reference oligonucleotide composition.
The disclosure further refines backbone chiral center patterning using Rp/Sp arrangements, including at least one Rp and at least one Sp, Rp(Sp)m, and (Np)t(Rp)(Sp)m. The characterization can include assessing the level of C3a and/or the level of Bb as complement readouts.
Claims Coverage
The consolidated claim coverage includes one independent claim centered on characterizing a chirally controlled oligonucleotide composition by assessing complement activation relative to a substantially racemic reference. The claim combines three inventive feature areas: complement-activation based characterization, chirality defined by phosphorothioate internucleotidic linkages enriched for Sp, and backbone chiral center stereopattern refinements with optional complement readouts.
Complement-activation characterization versus substantially racemic reference
Assessing complement activation by the chirally controlled oligonucleotide composition relative to a reference oligonucleotide composition, wherein the reference oligonucleotide composition is a substantially racemic preparation of oligonucleotides of the particular type and increases complement activation compared to absence of the reference.
Chirally controlled enrichment defined by phosphorothioate Sp internucleotidic linkages
A chirally controlled oligonucleotide composition comprising structurally identical oligonucleotides of a particular oligonucleotide type that are enriched, relative to a substantially racemic preparation, for oligonucleotides of the particular type, wherein the oligonucleotides comprise 5 or more phosphorothioate internucleotidic linkages and at least about 50% of the phosphorothioate internucleotidic linkages are Sp.
Backbone chiral center stereopattern constraints and complement readouts
Refining the backbone chiral center pattern using Rp/Sp arrangements, including at least one Rp and at least one Sp and stereopatterns such as Rp(Sp)m and (Np)t(Rp)(Sp)m, and optionally assessing the level of C3a and/or the level of Bb.
Overall, the claim coverage characterizes a chirally controlled oligonucleotide composition through complement activation relative to a substantially racemic reference, with chirality defined by enrichment for Sp phosphorothioate internucleotidic linkages. Dependent claims further constrain the backbone Rp/Sp stereopattern and can specify complement readouts via C3a and/or Bb.
Stated Advantages
Reduced complement activation/immune response associated with controlled backbone stereochemistry, including C3a and Bb.
Low toxicity associated with controlled backbone stereochemistry.
Improved protein binding and delivery associated with controlled backbone stereochemistry.
Reduced toxicity is associated with decreased complement activation, including alternative and classical complement pathways.
Improved delivery and uptake profiles are described for chirally controlled oligonucleotides.
Improved protein-binding profiles are described for chirally controlled oligonucleotides.
Reduced injection-site inflammation and drug-induced vascular injury are described.
Altered splicing is described as governed by controlled backbone chiral stereochemistry.
Documented Applications
Characterizing chirally controlled oligonucleotide compositions by assessing complement activation relative to substantially racemic reference oligonucleotide compositions.
Characterizing a chirally controlled oligonucleotide composition by assessing complement activation relative to a substantially racemic reference oligonucleotide composition, including optional complement readouts of C3a and/or Bb.
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