There have not been any major developments in the diagnosis and treatment of Bladder Pain Syndrome/ Interstitial Cystitis (BPS/ IC) in the last century. Bioinformatics has the potential to suggest new disease paradigms by collecting and analyzing complex biologic data at cellular and molecular levels. 
In this study, we compared disease signatures from a number of disrupted human cell lines to find prospective medications that may reverse the disease signature by targeting previously characterized differentially expressed genes (DEGs) in the disease state.

In a previous study, 3 publicly available datasets [GSE11783, GSE28242, GSE57560] supported by GEO DataSets were extracted, and analyzed with the online interactive web tool GEO2R to identify DEGs. Pooled data from BPS/ IC patients with Hunner's lesion disease (HLD), non-Hunner's lesion disease (non-HLD), and controls (CTL) were compared to extract the DEGs [1]. 
In this follow-up study, the up- and down-regulated DEGs between the same 3 groups (HLD, non-HLD, and CTL) were analyzed for drug repurposing on the L1000CDS2 and cMAP platforms [2]. 
The L1000CDS2 search engine provides prioritization of thousands of small-molecule signatures, and their pairwise combinations, predicts drugs and compounds that mimic or reverse an input gene expression signature, and provides an understandable heat map. For HLD vs. non-HLD and HLD vs. CTL comparisons, pairwise comparisons of the two groups predicted the top 50 chemicals.
The cMAP operates through the query app of the pattern-matching software Clue, which is a cloud-based software platform for the analysis of perturbational datasets generated using gene expression (L1000). The compounds with a connectivity score higher than '+/-90' were selected as the most probable drugs to investigate. The chemical properties, current utilization, and FDA status of the bioinformatically predicted compounds reversing the expression levels of DEGs were analyzed in PubChem and DrugBank.

The analysis revealed a total of 21 compounds and/or small molecules that reversed the disease signature.
The L1000CDS2 platform predicted 50 statistically significant compounds that reverse gene signatures; the top eight compounds [BRD-K94325918-Kinetin riboside; TG101348-Fedranitip, AZD8055; Selumetinib; S1057-Obatoclax; Saracatabip; Palbobiclib] were selected for further analysis. 
The Clue query revealed 13 compounds with a connectivity score higher than +/-90. Among these compounds, 7 [scoulerine, catechin, QL-XII-47, repaglinide, XMD-885, xanthoxylin, and chaetocin] reversed the disease signature by up-regulating gene expression levels. Whereas the other 6 compounds [etoposide, PI-828, KU-0063794, BRD-K30351863, vinorelbine, and levetiracetam] reversed the disease signature by down-regulating gene expression levels.

Among the 21 molecules/compounds, 11 were small molecules and the rest were chemical compounds; 3 were natural products, and 6 are FDA approved and actively utilized for several therapeutic purposes, including several cancers, myelofibrosis, and diabetes. Some of the predicted drugs have completed phase 1 and phase 2 clinical trials; others are investigational, while others have been discontinued. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication. The fast expansion of large-scale genome sequencing and expression studies for BPS/ IC will increase the chance of repurposing [3].

Bioinformatic approaches are useful in identifying novel therapeutic agents for BPS/ IC by accessing, and processing big and complex data on the molecular and cellular pathways of the disease. However, further work needs to be done to validate these results in prospective in-vivo experiments.

Inal-Gultekin G, Gormez Z, Mangir N. Defining Molecular Treatment Targets for Bladder Pain Syndrome/Interstitial Cystitis: Uncovering Adhesion Molecules. Front Pharmacol. 2022 Mar 25;13:780855. doi: 10.3389/fphar.2022.780855. PMID: 35401223; PMCID: PMC8990855.
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019 Jan;18(1):41-58. doi: 10.1038/nrd.2018.168. Epub 2018 Oct 12. PMID: 30310233.
Roessler HI, Knoers NVAM, van Haelst MM, van Haaften G. Drug Repurposing for Rare Diseases. Trends Pharmacol Sci. 2021 Apr;42(4):255-267. doi: 10.1016/j.tips.2021.01.003. Epub 2021 Feb 6. PMID: 33563480.

Continence 7S1 (2023) 100827
DOI: 10.1016/j.cont.2023.100827