Abstract

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. Here, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week) (n=9) and non-blistered epidermis (n=11) obtained from 11 EBS patients. Transcriptomic analysis of blistered epidermis in EBS patients revealed a set of 1276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-alpha, IL-1beta, IL2, IL-6, PI3K, and mTOR. The 1276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2423 drugs using the ConnectivityMap CLUE platform. mTOR inhibitors and PI3K inhibitors most opposed the EBS signature. To determine if mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of 2 patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.

View details for DOI 10.1016/j.jid.2021.07.170

View details for PubMedID 34536484