31-LB: Identification of Repurposable Drug Candidate for Diabetic Peripheral Neuropathy Using High-Throughput Drug-Perturbation Data

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of prediabetes and type 2 diabetes (T2D) for which there are limited treatment options. We recently demonstrated that dietary reversal (DR) corrects the DPN phenotype using mouse models of prediabetes and T2D. However, it is still important to develop therapeutic agents for treating DPN in addition to life style changes such as DR. In this study, we employed an in silico omics-based systems approach to identify small-molecule drugs with a high potential of reversing or halting DPN. The NIH Library of Integrated Network-based Cellular Signatures (LINCS) drug-perturbation transcriptomic data were obtained, which measured gene expression changes after treatment of 83 human cells with over 20,000 small-molecule compounds using the L1000 assay platform. Gene expression signature of DPN, consisting of highly up- or down-regulated genes, was defined based on the dysregulated genes, identified from sciatic nerves RNA-Seq data of C57BL/6J mice fed with high-fat diet (60% kcal fat for 19 weeks). This DPN signature was compared against the LINCS perturbation data using the CLUE Query app from the Broad Institute and our in-house analysis pipeline. The top small-molecule drugs, demonstrating opposite expression profiles of the DPN signature, included various protein synthesis inhibitors, calcium channel blockers, and adrenergic receptor antagonists such as cephaeline, levetiracetam, and esmolol, respectively. Although the anti-DPN effects of these drugs need to be systematically examined, our systems approach provides a list of drugs with a potential for being used to treat DPN. Disclosure K. Guo: None. E.L. Feldman: None. J. Hur: None. Funding National Institutes of Health (R24DK082841); University of Michigan