Antisense oligonucleotides (aso) for efficient and precise rna editing with endogenous adenosine deaminase acting on rna (adar)

A chemically modified oligoribonucleotide for use in site-directed A-to-I editing of a target RNA inside a cell with endogenous ADAR, comprising a sequence with a length from 25 to 80 nucleotides, capable of binding to a target sequence in the target RNA, comprising a Central Base Triplet (CBT) of 3 nucleotides with the central nucleotide opposite to the target adenosine in the target RNA which is to be edited to an inosine, characterized in that

• a) at least 90% of the pyrimidine nucleosides outside the CBT are chemically modified at the 2′ position of the sugar moiety with a mixture of 2′-fluoro and 2′-O-methyl modifications,
• b) no more than 6 consecutive nucleosides are chemically modified with 2′-O-methyl at the 2′ position of the sugar moiety, and
• c) at least two of the three nucleosides of the CBT are chemically modified at the 2′ position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof;
• and
• wherein at least 30% of the linkages between the nucleosides are phosphorothioate (PS) linkages.

A chemically modified oligoribonucleotide for use in site-directed A-to-I editing of a target RNA inside a cell with endogenous ADAR, comprising a sequence with a length from 25 to 80 nucleotides, capable of binding to a target sequence in the target RNA, comprising a Central Base Triplet (CBT) of 3 nucleotides with the central nucleotide opposite to the target adenosine in the target RNA, which is to be edited to an inosine, characterized in that

• a) at least 90% of the pyrimidine nucleosides outside the CBT are chemically modified, either at the 2′ position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof,
• b) no more than 6 consecutive nucleosides are chemically modified with 2′-O-methyl at the 2′ position of the sugar moiety,
• c) at least two of the three nucleosides of the CBT are chemically modified at the 2′ position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof, and
• d) wherein said pyrimidine nucleosides do not comprise 2′-O-methoxyethyl (2′-MOE)-modifications;
• and
• wherein at least 30% of the linkages between the nucleosides are phosphorothioate (PS) linkages.