Reduction of matched and nearly complementary unintended transcripts was evaluated for 96 antisense oligonucleotides (ASOs) and 832 nearly matched unintended transcripts. The ASOs were 16–20 nucleotide “gapmers” with a gap of 8–10 DNA residues and 2′-O-methoxy-ethyl or constrained-ethyl substitutions in the wings. Most unintended transcripts were not reduced or were reduced with a potency more than 10-fold weaker than the intended transcript. For the unintended transcripts that were reduced, a strong correlation between relative potency of the intended versus the unintended transcript with predicted free energy of hybridization was observed. These results suggest ASO selectivity should be evaluated by testing for reduction of the unintended transcripts predicted to bind most stably to the ASO.

中文翻译：

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Gapmer 反义寡核苷酸的非特异性活性的可能性与相对杂交自由能有关。

对 96 个反义寡核苷酸 (ASO) 和 832 个几乎匹配的非预期转录物的匹配和几乎互补的非预期转录物的减少进行了评估。ASO 是 16-20 个核苷酸的“间隙聚体”，具有 8-10 个 DNA 残基的间隙和 2'-O-甲氧基-乙基或限制性乙基取代。大多数非预期的转录本没有减少或以比预期的转录本弱 10 倍以上的效力减少。对于减少的非预期转录物，观察到预期与非预期转录物的相对效力与预测的杂交自由能之间的强相关性。这些结果表明 ASO 的选择性应该通过测试预测与 ASO 最稳定结合的非预期转录本的减少来评估。