Background/Purpose: Despite improvements in the understanding of the pathogenesis of Systemic Lupus Erythematosus (SLE), very few new treatments have proven their effectiveness. Drug development is long in this rare disease with its various clinical manifestations. Drug repositioning allows to identify pathophysiological pathways or molecules to target, by comparing the gene expression signature of a disease (genes differentially expressed in a given disease compared to healthy controls) and 1) the signature of expression of the action on different cell lines of drugs already evaluated in other indications or 2) the transcriptomic signature resulting from the knock-in or knock-out of a specific gene. Since these transcriptomic data are available and the safety profile of most drugs has already been assessed, this approach might help to repurpose drugs for SLE.

Methods: Inclusion criteria were the availability on GEO of transcriptomic data generated after 2014 in SLE patients and controls. To compare disease signature in each study to drug or knocked-in or knocked-out gene signatures, the CLUE database was used.

Results: Three thousand four hundred and thirty nine transcriptomes of SLE patients and 296 of controls were analyzed, generated in 7 studies on peripheral blood (5 on whole blood, 1 on B cells, 1 on PBMCs, accounting for 3233 SLE transcriptomes), 3 studies on skin biopsies (n=130 SLE) and 2 studies on kidney biopsies (n=76 SLE). Histone deacetylase (HDAC) and Rho kinase (ROCK) inhibitors were identified as potential treatments for SLE consistently across peripheral blood samples for HDAC inhibitors and in studies on PBMCs and skin biopsies for ROCK inhibitors. Overexpression of CD40, IFNG, IFNB1 and TNFRSF1A mimicked SLE signature in almost all studies.

Conclusion: A drug repositioning approach in 12 studies including more than 3400 transcriptomes identified two therapeutic classes, HDAC and ROCK inhibitors, with a potential interest to treat SLE. This study also confirms the potential therapeutic interest of inhibiting CD40-CD40L and interferon pathways.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-new-candidate-drugs-for-sle-using-a-drug-repurposing-transcriptomic-approach-on-blood-skin-and-kidney-samples-from-3439-patients/