From sequences to therapeutics: Using machine learning to predict chemically modified siRNA activity

Small interfering RNAs (siRNAs) exemplify the promise of genetic medicine in the discovery of novel therapeutic modalities. Their ability to selectively suppress gene expression makes them ideal candidates for the development of oligonucleotide pharmaceuticals. Recent advancements in machine learning (ML) have facilitated the design of unmodified siRNA and efficacy prediction. However, a model trained to predict the silencing activity of siRNAs with diverse chemical modification patterns is yet to be published despite the importance of such modifications in designing siRNAs with the potential to reach the level of clinical use. This study presents the first application of ML to efficiently classify chemically modified siRNAs on the basis of sequence and chemical modification patterns alone. Three algorithms were evaluated at three classification thresholds and compared according to sensitivity, specificity, consistency of feature weights with empirical knowledge, and performance using an external validation dataset. Finally, possible directions for future research were proposed.