sirolimus and Epidermolysis-Bullosa-Simplex

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, 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 old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-α, IL-1β, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.

Topics: Administration, Cutaneous; Adolescent; Adult; Biopsy; Child; Child, Preschool; Computational Biology; Drug Repositioning; Epidermis; Epidermolysis Bullosa Simplex; Female; Gene Expression Regulation; Humans; Keratinocytes; Male; Middle Aged; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pilot Projects; RNA-Seq; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult