ANTISENSE OLIGONUCLEIC ACID
FIG2 is a graph showing the results of hepatotoxicity of antisense oligonucleic acid evaluated in the Example described later
In the same manner as in the above-mentioned Example 1 except that #12, #98, #14 or derivatives thereof which induce strong hepatotoxicity by contribution of the above-mentioned hepatotoxicity induction mechanism (iii) were used instead of antisense oligonucleic acid #101, the hepatotoxicity was evaluated. The theoretical value of the molecular weight of #12 was 4614.73 and the measured value was 4614.27, the theoretical value of the molecular weight of #12-C2-10 was 4630.73 and the measured value was 4627.86, the theoretical value of the molecular weight of #98 was 4613.75 and the measured value was 4612.79, the theoretical value of the molecular weight of #98-C2-7 was 4629.75 and the measured value was 4631.10, the theoretical value of the molecular weight of #14 was 4606.71 and the measured value was 4605.66, and the theoretical value of the molecular weight of #14-C2-6 was 4622.71 and the measured value was 4619.72. The sequence of each antisense oligonucleic acid used in this Example is shown in Table 2, and the measurement results of the hepatotoxicity are shown in FIG2. In FIG2, "*" indicates presence of a significant difference at p<0.05.[Table 2]#12G T mC c g c a t g c c T A A#12-C2-10G T mC c g c a t g ζ c T A A#98G A T a t g c c c t a mC T A#98-C2-7G A T a t g ζ c c t a mC T A#14G T A t g c c t c c g T T A#14-C2-6G T A t g ζ c t c c g T T A As shown in the results of FIG2, the serum concentrations of AST and ALT could be reduced significantly only by changing cytosine, which is in one of the 2',4'-non-bridged nucleic acid residues in the middle part, to 5-hydroxycytosine also in other antisense oligonucleic acids #12, #98 and #14 having high hepatotoxicity. The serum concentrations of AST and ALT were reduced to several percents by the above-mentioned mutation, though not as much as that in #101 having particularly high hepatotoxicity.
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["1. An antisense oligonucleic acid having a base length of not less than 7nt and not more than 30nt, wherein nucleic acid residues of not less than 1nt and not more than 5nt respectively from the both terminals are 2',4'-bridged nucleic acids, 2',4'-non-bridged nucleic acid residue(s) is(are) present between the both terminals, and one or more bases in the nucleic acid residue(s) of the 2',4'-non-bridged nucleic acid residue(s) is/are modified."]