The invention relates to modified
antisense oligonucleotides suitable for editing an
adenosine in a target
nucleic acid to
inosine (A-to-I editing), wherein the
oligonucleotide comprises: (I) a
nucleic acid sequence of 25 to 70 nucleotides (nt) that is an antisense sequence substantially complementary to the target
nucleic acid, (II) a central base triplet (CBT) (5'- N+1 e N0 f N-1 g -3') with the central
nucleotide (N0) directly opposite the target
adenosine to be edited when the antisense
oligonucleotide is hybridised to the target nucleic acid, and (III) the following core sequence: 5'- a N+4 b N+3 c N+2 d N+1 e N0 f N-1 g N-2 h N-3 i N-4 j N-5 k N-6 l N-7 m N-8 n N-9 -3';and wherein: (a) at least two of the three nucleotides of the CBT are chemically modified at the 2' position of the
sugar moiety, are deoxyribonucleosides, or a combination thereof and wherein d and e are internucleoside linkage modifications; (b) the N-2
nucleotide carries a 2'-O-
alkyl- modification; and wherein the N-3
nucleotide carries a 2´-fluoro (2'-F)-modification; (c) at least 10% of nucleotides of the
oligonucleotide are 2'-F-modified and at least 10% of nucleotides of the oligonucleotide are 2'-O-
alkyl-modified, wherein no more than 6 consecutive nucleotides have the same 2'-modification; and wherein the oligonucleotide comprises one or more nucleotide mismatches outside the CBT that is / are not complementary to the corresponding position in the target nucleic; and wherein the mismatch is: at position -7 (N-7), wherein there is a G or C directly 3' to the mismatch and an A or U directly 5' to the mismatch; at position -9 (N-9), wherein there is a G or C directly 3' to the mismatch and an A or U directly 5' to the mismatch; or at position -9 (N-9), wherein there is a G or C directly 3' to the mismatch and an A or U directly 5' to the mismatch, and at position +2 (N+2).