Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa...

Area of Science:

• Dermatology
• Genomics
• Pharmacology

Background:

• Epidermolysis bullosa simplex (EBS) is a group of genetic skin disorders characterized by blistering.
• Current treatments for EBS focus on symptom management, with limited options for addressing underlying mechanisms.

Purpose of the Study:

• To identify novel therapeutic targets for epidermolysis bullosa simplex (EBS) using expression-based drug repositioning.
• To evaluate the potential of mTOR inhibitors as a treatment for EBS.

Main Methods:

• RNA sequencing was performed on skin biopsies from EBS patients to identify dysregulated genes and pathways.
• A 1,276-gene EBS blister signature was integrated with a drug-treated cell line database (Connectivity Map CLUE platform).
• A pilot study investigated the efficacy of topical sirolimus (an mTOR inhibitor) in two EBS patients with plantar keratoderma.

Main Results:

• Transcriptomic analysis revealed significant gene dysregulation in EBS blisters, with upregulation of IL-6, IL-8, and IL-10 pathways.
• mTOR and phosphatidylinositol 3-kinase inhibitors were identified as drugs that most opposed the EBS molecular signature.
• Topical sirolimus treatment resulted in marked clinical improvement and reduced keratoderma in both EBS patients.

Conclusions:

• Expression-based drug repositioning is a viable strategy for identifying novel EBS therapies.
• mTOR inhibitors, specifically topical sirolimus, demonstrate potential as an effective treatment for EBS and associated complications like keratoderma.