Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex
| Autor: | Elidia Tafoya, Joyce M.C. Teng, Ramrada Lekwuttikarn, Monica Martin, Gun Ho Lee, Kavita Y. Sarin |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Keratinocytes Male Adolescent Biopsy Pilot Projects Dermatology Bioinformatics Administration Cutaneous Biochemistry Transcriptome Epidermolysis bullosa simplex Phosphatidylinositol 3-Kinases Young Adult medicine Humans RNA-Seq skin and connective tissue diseases Child Molecular Biology PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Sirolimus integumentary system business.industry TOR Serine-Threonine Kinases Drug Repositioning Computational Biology Cell Biology MTOR Inhibitors Middle Aged medicine.disease Discovery and development of mTOR inhibitors Drug repositioning Treatment Outcome Gene Expression Regulation Child Preschool Epidermolysis Bullosa Simplex Female Epidermolysis bullosa Epidermis business |
| Zdroj: | The Journal of investigative dermatology. 142(2) |
| ISSN: | 1523-1747 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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