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Title
Japanese:Gapmer型ASOにおけるオフターゲット効果のリスク評価手法の提案 
English: 
Author
Japanese: 玉野史結, 伊澤和輝, 柳澤渓甫, 大上雅史, 秋山泰.  
English: Shiyu Tamano, Kazuki Izawa, Keisuke Yanagisawa, Masahito Ohue, Yutaka Akiyama.  
Language Japanese 
Journal/Book name
Japanese:研究報告バイオ情報学（BIO） 
English: 
Volume, Number, Page 2022-BIO-69    7    1-7
Published date Mar. 3, 2022 
Publisher
Japanese:情報処理学会 
English: 
Conference name
Japanese: 
English: 
Conference site
Japanese: 
English: 
Official URL https://ipsj.ixsq.nii.ac.jp/ej/?action=pages_view_main&active_action=repository_view_main_item_detail&item_id=216917&item_no=1&page_id=13&block_id=8
 
Abstract In the development of gapmer ASOs, there is a problem that not only the on-target gene but also off-target genes are down-regulated. Evaluating the off-target effects by experimental screening tests is time-consuming and economically burdensome. Therefore, computational risk assessment is needed. In this study, we proposed a risk score in terms of cleavage by RNase H1, binding energy between an ASO and an mRNA, and the secondary structure of mRNAs. For the evaluation, we used the 13-mer gapmer targeting human APOB (gap-A13) and the 13-mer gapmer targeting human PCSK9 (gap-P13) used in previous study. For each gapmer ASO, Pearson correlation coefficients between the experimental values of log fold-change (logFC) and the assessed risk scores were calculated for a large number of genes. The results of the calculations were r = -0.091 for gap-A13 and r = -0.124 for gap-P13. This result indicates that the risk score is not practical as a valid risk measure. However, there was a statistically significant difference in gene expression intensity before the introduction of ASO between the gene groups with overestimated risk scores and the others. This suggests that the gene expression intensity before ASO introduction is important for evaluating off-target effects.

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