Back to results
US 12,668,801 B2Granted
RNA-editing oligonucleotides and uses thereof
AssigneeKorro Bio, Inc.
InventorsVenkat Krishnamurthy, Christopher Brown, Tyson Moyer, Mallikarjuna Reddy Putta, Mateusz Maciejewski
Life of this patent
Estimating the term…
Abstract
The present disclosure features useful compositions and methods to treat disorders for which deamination of an adenosine in an RNA produces a therapeutic result in a subject in need thereof.
Claims29
An oligonucleotide capable of binding and recruiting an ADAR enzyme to perform editing on a target adenosine of a target RNA, the oligonucleotide comprising the structure:
- wherein
- m+n is 24 to 50, n is at least 4, and m is at least 20;
- -X1-X2-X3- is a Central Triplet of the oligonucleotide;
- X1 is position −1 of the oligonucleotide, X2 is position 0 of the oligonucleotide, and X3 is position +1 of the oligonucleotide;
- [A]m is a first domain at positions −(m+1) to −2 of the oligonucleotide;
- [B]n is a second domain at positions +2 to +(n+1) of the oligonucleotide;
- each A and B is a nucleotide comprising a nucleobase, a sugar (“an A/B sugar”), and an internucleotide linkage;
- each X1, X2, and X3 comprises a nucleobase, a sugar (“an X sugar”), and an internucleotide linkage;
- the A/B sugars and the X3 sugar are selected from 2′-methoxy-ribose, 2′-MOE-ribose, 2′-deoxy-2′-fluororibose, 2′-fluoro-arabinose, 2-methoxy-arabinose, 2′deoxyribose and a locked nucleic acid (LNA);
- the X1 sugar is 2′-deoxy-2′-fluororibose or 2′deoxyribose;
- the X2 sugar is a beta-homo-DNA sugar;
- the A/B sugars and the X sugars, collectively, are 10-70% 2′-deoxy-2′-fluororibose;
- the internucleotide linkages of the oligonucleotide are 30-100% phosphorothioate and mesyl phosphoramidate linkages, and 3, 4, 5, 6, 7, 8, 9, or 10 internucleotide linkages are mesyl phosphoramidate linkages;
- the internucleotide linkage (i) between the nucleotide at position −(m+1) and the nucleotide at position −(m) (the 5′end), (ii) between the nucleotide at position +(n) and the nucleotide at position +(n+1) (the 3′-end), or (iii) at each the 5′-end and 3′-end of the oligonucleotide is a mesyl phosphoramidate linkage;
- and
- the internucleotide linkage between the nucleotide at position −(m) and the nucleotide at position −(m−1) and the internucleotide linkage between the nucleotide at position +(n−1) and the nucleotide at position +(n) are independently a phosphorothioate or a mesyl phosphoramidate linkage.
13 more elements
An oligonucleotide capable of binding and recruiting an ADAR enzyme to perform editing on a target adenosine of a target RNA comprising the structure:
- wherein
- m+n is 29 to 50, n is at least 9, and m is at least 20;
- -X1-X2-X3- is a Central Triplet of the oligonucleotide;
- X1 is position −1 of the oligonucleotide, X2 is position 0 of the oligonucleotide, and X3 is position +1 of the oligonucleotide;
- [A]m is a first domain at positions −(m+1) to −2 of the oligonucleotide;
- [B]n is a second domain at positions +2 to +(n+1) of the oligonucleotide;
- each A and B is a nucleotide comprising a nucleobase, a sugar (“an A/B sugar”), and an internucleotide linkage;
- each X1, X2, and X3 comprises a nucleobase, a sugar (“an X sugar”), and an internucleotide linkage;
- the A/B sugars and the X3 sugar are selected from 2′-methoxy-ribose, 2′-MOE-ribose, 2′-deoxy-2′-fluororibose, 2′-fluoro-arabinose, 2-methoxy-arabinose, 2′deoxyribose and a locked nucleic acid (LNA);
- the X1 and X3 sugars are 2′deoxyribose;
- the X2 sugar is a beta-homo-DNA sugar;
- the A/B sugars and the X sugars, collectively, are 10-70% 2′-deoxy-2′-fluororibose;
- the internucleotide linkages of the oligonucleotide are 30-100% phosphorothioate and mesyl phosphoramidate linkages, and 5 internucleotide linkages are mesyl phosphoramidate linkages;
- the internucleotide linkage between the nucleotide at position −(m+1) and the nucleotide at position −(m) (the 5′end) is a mesyl phosphoramidate linkage,
- the internucleotide linkage between the nucleotide at position +(n) and the nucleotide at position +(n+1) (the 3′-end) is a mesyl phosphoramidate linkage;
- the internucleotide linkage between the nucleotide at position +1 and the nucleotide at position +2 is a mesyl phosphoramidate;
- the internucleotide linkage between the nucleotide at position −9 and the nucleotide at position −8 is a mesyl phosphoramidate;
- and
- the internucleotide linkage between the nucleotide at position −11 and the nucleotide at position −10 is a mesyl phosphoramidate.
16 more elements
Dependencies are inferred from the claim text.