Chiral design
Inventors
Meena, Meena • Butler, David • Iwamoto, Naoki • Svrzikapa, Nenad • Verdine, Gregory L. • ZLATEV, Ivan
Assignees
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Publication Number
US-12180472-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention relates to chirally controlled oligonucleotides of select designs, chirally controlled oligonucleotide compositions, and methods of making and using the same. In some embodiments, a provided chirally controlled oligonucleotide composition provides different cleavage patterns of a nucleic acid polymer than a reference oligonucleotide composition. In some embodiments, a provided chirally controlled oligonucleotide composition provides single site cleavage within a complementary sequence of a nucleic acid polymer.
Core Innovation
The invention relates to chirally controlled oligonucleotide compositions used to contact a nucleic acid polymer for cleaving the nucleic acid polymer or inhibiting expression or reducing activity of a protein. The compositions comprise oligonucleotides of a particular oligonucleotide type defined by a common base sequence and length, a common pattern of backbone linkages, and a common pattern of backbone chiral centers, and are enriched, relative to a substantially racemic preparation having the same base sequence and length, for oligonucleotides of that type.
The chirally controlled oligonucleotide type is defined by a common base sequence having at least 17 bases, at least 50% of chiral internucleotidic linkages in each oligonucleotide being Sp, and a common pattern of backbone chiral centers comprising from 5′ to 3′ Rp(Sp)2. The disclosure describes phosphorothioate diester linkage configurations, phosphodiester linkages, phosphorothioate triester linkage configurations, and stereochemical phosphorus notation including Rp and Sp.
In the protein-directed use, the common base sequence is complementary to that of a nucleic acid encoding the protein. The disclosed framework also refers to chirally controlled oligonucleotides affecting cleavage patterns, including single site control and multiple site control, and to allele-specific transcript suppression, with example target genes and diseases including Huntington’s disease (HTT), PCSK9, and KRAS.
Claims Coverage
The consolidated claims coverage includes two independent methods. Both are directed to a chirally controlled oligonucleotide composition enriched relative to a substantially racemic preparation and defined by a common base sequence and length, a common pattern of backbone linkages, and a common pattern of backbone chiral centers; the claims require at least 17 bases, at least 50% Sp-configured chiral internucleotidic linkages in each oligonucleotide, and a 5′ to 3′ Rp(Sp)2 backbone chiral-center pattern.
Chirally controlled oligonucleotide composition for nucleic acid polymer cleavage
A method for cleaving a nucleic acid polymer by contacting the nucleic acid polymer with a chirally controlled oligonucleotide composition comprising oligonucleotides of a particular oligonucleotide type defined by a common base sequence and length, a common pattern of backbone linkages, and a common pattern of backbone chiral centers, wherein the composition is enriched relative to a substantially racemic preparation for oligonucleotides of the particular oligonucleotide type; the common base sequence has at least 17 bases; at least 50% of chiral internucleotidic linkages in each oligonucleotide are Sp; and the common pattern of backbone chiral centers comprises from 5′ to 3′ Rp(Sp)2.
Chirally controlled oligonucleotide composition for inhibiting expression or reducing protein activity
A method for inhibiting expression or reducing activity of a protein by contacting a nucleic acid polymer encoding the protein with a chirally controlled oligonucleotide composition comprising oligonucleotides of a particular oligonucleotide type defined by a common base sequence and length, a common pattern of backbone linkages, and a common pattern of backbone chiral centers, wherein the composition is enriched relative to a substantially racemic preparation for oligonucleotides of the particular oligonucleotide type; the common base sequence has at least 17 bases; at least 50% of chiral internucleotidic linkages in each oligonucleotide are Sp; and the common pattern of backbone chiral centers comprises from 5′ to 3′ Rp(Sp)2; wherein the common base sequence is complementary to that of a nucleic acid encoding the protein.
Across both independent claims, the inventive concept is the use of chirally controlled oligonucleotide compositions enriched over substantially racemic preparations and defined by shared sequence, linkage, and backbone chiral-center patterns. The claims center on the minimum base length, the Sp enrichment threshold, and the 5′ to 3′ Rp(Sp)2 backbone chiral-center pattern, applied either to cleavage of a nucleic acid polymer or to inhibition of expression or reduction of protein activity using a complementary sequence.
Stated Advantages
Provides single site control and multiple site control of cleavage patterns.
Enables allele-specific transcript suppression.
Increases stability, synthesis efficiency, yield, and product purity.
Inhibiting expression of a protein.
Reducing activity of a protein.
Documented Applications
Cleaving a nucleic acid polymer by contacting it with a chirally controlled oligonucleotide composition, including cleavage pattern control.
Inhibiting expression or reducing activity of a protein by contacting a nucleic acid polymer encoding the protein with a chirally controlled oligonucleotide composition, including allele-specific transcript suppression against target genes/diseases such as Huntington’s disease (HTT), PCSK9, and KRAS.
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