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. 2019 Nov/Dec;17(8):352-363.
doi: 10.1089/adt.2019.950. Epub 2019 Nov 26.

Systematically Prioritizing Candidates in Genome-Based Drug Repurposing

Anup P Challa  1 , Robert R Lavieri  1 , Judith T Lewis  1 , Nicole M Zaleski  1 , Jana K Shirey-Rice  1 , Paul A Harris  2 , David M Aronoff  3   4 , Jill M Pulley  1
Affiliations

Systematically Prioritizing Candidates in Genome-Based Drug Repurposing

Anup P Challa et al. Assay Drug Dev Technol. 2019 Nov/Dec.

Abstract

Drug repurposing is the application of approved drugs to treat diseases separate and distinct from their original indications. Herein, we define the scope of all practical precision drug repurposing using DrugBank, a publicly available database of pharmacological agents, and BioVU, a large, de-identified DNA repository linked to longitudinal electronic health records at Vanderbilt University Medical Center. We present a method of repurposing candidate prioritization through integration of pharmacodynamic and marketing variables from DrugBank with quality control thresholds for genomic data derived from the DNA samples within BioVU. Through the synergy of delineated "target-action pairs," along with target genomics, we identify ∼230 "pairs" that represent all practical opportunities for genomic drug repurposing. From this analysis, we present a pipeline of 14 repurposing candidates across 7 disease areas that link to our repurposability platform and present high potential for randomized controlled trial startup in upcoming months.

Keywords: drug repurposing; genomics; informatics; phenome-wide association study (PheWAS); precision medicine.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Appendix Fig. A1.
Appendix Fig. A1.
A summary representation of the pharmacodynamic and genomics-inspired workflow developed for the selection of optimal repurposing candidates: attrition at each step is defined through genomic and chemical profiling of ideal small molecule candidates. MAF, minor allele frequency; rsID, reference cluster ID number; SNP, single-nucleotide polymorphism.
Appendix Fig. A2.
Appendix Fig. A2.
Our repurposability screens define the current scope of the genomic drug repurposing space (227 “target-action pairs” of 147 unique targets) within the entirety of the druggable genome.,
Appendix Fig. A3.
Appendix Fig. A3.
A summary of the trial design of NCT03617172, a phase II repurposing randomized controlled trial for the potency and efficacy of misoprostol to treat recurrent Clostridioides difficile infection. BID, twice per day; CDI, C. difficile infection; QID, four times per day; SAE, serious adverse event; SOC, standard of care.
See this image and copyright information in PMC

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Appendix References

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