ASOCompass: Context- and Chemistry-Aware Activity Prediction for Transferable Antisense Oligonucleotide Screening

Abstract

Antisense oligonucleotide (ASO) activity is jointly influenced by nucleotide sequence, chemical modification, target-RNA context, dose, delivery protocol, and cellular environment. Most existing computational screening methods model only a subset of these factors, limiting their ability to predict experimentally measured activity across heterogeneous screening conditions and previously unseen biological contexts. We introduce ASOCompass, a context-and chemistry-aware framework for ASO activity prediction and candidate ranking. ASOCompass integrates contextualized ASO and target-RNA sequence representations with position-specific molecular representations of chemical modifications. It further incorporates dose and delivery information together with prototype-adapted transcriptomic representations of target genes and cell lines. To encourage chemically and biophysically informative representations, the model is jointly trained on auxiliary molecular-property and sequence-derived thermodynamic prediction tasks. We evaluate ASOCompass on ASO Atlas, a large patent-derived dataset of RNase H-mediated gapmer ASOs, under held-out drug, target-gene, cell line, and joint gene-cell line settings. ASOCompass achieves an overall Spearman correlation of 0.5970, improving over the strongest ASO-specific baseline by 0.0421, and consistently performs best across all four distribution shifts. When adapted to unseen SOD1 and KLKB1 targets, ASOCompass also provides more accurate candidate ranking across different annotation budgets, reaching correlations of 0.830 and 0.696 with 1,024 target-specific labels. Additional analyses suggest that molecular-property supervision improves modification-specific ranking, while the auxiliary thermodynamic task produces representations more closely aligned with measured inhibition. These results demonstrate the potential of jointly modeling sequence, chemistry, and experimental-biological context for transferable ASO screening.