RNA-editing oligonucleotides and uses thereof
The present disclosure features useful compositions and methods to treat disorders for which deamination of an adenosine in an mRNA produces a therapeutic result, e.g., in a subject in need thereof.
1. An oligonucleotide comprising the structure:
[A m ]-X 1 -X 2 -X 3 —[B n ]
wherein each of A and B is a nucleotide;
m and n are each, independently, an integer from 5 to 40;
X 1 , X 2 , and X 3 are each, independently, a nucleotide, wherein at least one of X 1 , X 2 , or X 3 has the structure of Formula IV:
wherein N 1 is hydrogen or a nucleobase; and
R 12 is hydrogen, hydroxy, fluoro, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, or C 1 -C 6 alkoxy.
2. The oligonucleotide of claim 1 , wherein at least 80% of the nucleotides of [A m ] and/or [B n ] include a nucleobase, a sugar, and an internucleoside linkage.
3. The oligonucleotide of claim 1 , wherein R 12 is hydrogen, halogen, or C 1 -C 6 heteroalkyl.
4. The oligonucleotide of claim 1 , wherein R 12 is fluoro.
5. The oligonucleotide of claim 1 , wherein R 12 is hydrogen.
6. The oligonucleotide of claim 1 , wherein at least one of X 1 , X 2 , and X 3 has the structure of Formula I:
and N 1 is a nucleobase.
7. The oligonucleotide of claim 1 , wherein at least one of X 1 , X 2 , and X 3 has the structure of Formula II:
and N 1 is a nucleobase.
8. The oligonucleotide of claim 1 , wherein N 1 is a nucleobase.
9. The oligonucleotide of claim 1 , wherein at least one of X 1 , X 2 , and X 3 has the structure of Formula III:
and N 1 is a nucleobase.
10. The oligonucleotide of claim 1 , wherein at least 20% of the nucleotides of [A m ] and [B n ] combined are 2′-O-methyl-nucleotides.
11. The oligonucleotide of claim 1 , wherein A and B combined consist of 18 to 80 nucleotides.
12. The oligonucleotide of claim 1 , wherein m and n are each, independently, an integer from 5 to 40; at least one of X 1 , X 2 , and X 3 has the structure of Formula IV, wherein N 1 is a nucleobase and each of X 1 , X 2 , and X 3 that does not have the structure of Formula IV is a ribonucleotide; [A m ] and [B n ] each include at least five terminal 2′-O-methyl-nucleotides and at least four terminal phosphorothioate linkages; and at least 20% of the nucleotides of [A m ] and [B n ] combined are 2′-O-methyl-nucleotides.
13. The oligonucleotide of claim 1 , wherein the oligonucleotide further comprises one or more adenosine deaminase acting on RNA (ADAR)-recruiting domains.
14. A conjugate comprising an oligonucleotide of claim 1 conjugated to a targeting moiety.
15. A complex comprising:
an oligonucleotide of claim 1 or a conjugate comprising an oligonucleotide of claim 1 conjugated to a targeting moiety; and
an mRNA,
wherein the oligonucleotide or conjugate and mRNA are hybridized to each other and the complex comprises a first mismatch at an adenosine of the mRNA.
16. A method of producing a complex, the method comprising contacting a cell with an oligonucleotide of claim 1 .
17. A method for deamination of an adenosine in an mRNA, the method comprising contacting a cell with an oligonucleotide of claim 1 .