Intercellular heterogeneity is a major obstacle to successful personalized medicine. Single-cell RNA sequencing (scRNA-seq) technology has enabled in-depth analysis of intercellular heterogeneity in various diseases. However, its full potentials for personalized medicine are yet to be reached. Towards this, we propose A Single-cell Guided pipeline to Aid Repurposing of Drugs (ASGARD). ASGARD can repurpose single drugs for each cell cluster and for multiple cell clusters at individual patient levels; it can also predict personalized drug combinations to address the intercellular heterogeneity within each patient. We tested ASGARD on three independent datasets, including advanced metastatic breast cancer, acute lymphoblastic leukemia, and coronavirus disease 2019 (COVID-19). On single-drug therapy, ASGARD shows significantly better average accuracy (AUC=0.95) compared to two other single-cell pipelines (AUC 0.69 and 0.57) and two other bulk-cell-based drug repurposing methods (AUC 0.80 and 0.75). The top-ranked drugs, such as fulvestrant and neratinib for breast cancer, tretinoin and vorinostat for leukemia, and chloroquine and enalapril for severe COVID19, are either approved by FDA or in clinical trials treating corresponding diseases. In conclusion, ASGARD is a promising pipeline guided by single-cell RNA-seq data, for repurposing personalized drugs and drug combinations. ASGARD is free for academic use at https://github.com/lanagarmire/ASGARD.
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