  Intercellular heterogeneity is a major obstacle to successful precision
medicine. Single-cell RNA sequencing (scRNA-seq) technology has enabled
in-depth analysis of intercellular heterogeneity in various diseases. However,
its full potential for precision medicine has yet to be reached. Towards this,
we propose a new drug recommendation system called: A Single-cell Guided
Pipeline to Aid Repurposing of Drugs (ASGARD). ASGARD defines a novel drug
score predicting drugs by considering all cell clusters to address the
intercellular heterogeneity within each patient. We tested ASGARD on multiple
diseases, including breast cancer, acute lymphoblastic leukemia, and
coronavirus disease 2019 (COVID-19). On single-drug therapy, ASGARD shows
significantly better average accuracy (AUC of 0.92) compared to two other
bulk-cell-based drug repurposing methods (AUC of 0.80 and 0.76). It is also
considerably better (AUC of 0.82) than other cell cluster level predicting
methods (AUC of 0.67 and 0.55). In addition, ASGARD is also validated by the
drug response prediction method TRANSACT with Triple-Negative-Breast-Cancer
patient samples. Many top-ranked drugs are either approved by FDA or in
clinical trials treating corresponding diseases. In silico cell-type specific
drop-out experiments using triple-negative breast cancers show the importance
of T cells in the tumor microenvironment in affecting drug predictions. In
conclusion, ASGARD is a promising drug repurposing recommendation tool guided
by single-cell RNA-seq for personalized medicine. ASGARD is free for
educational use at https://github.com/lanagarmire/ASGARD.
