Computational Drug Repurposing for All EBS Cases

NCT03269474 | Recruiting

• 1 other identifier: 41142
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The study will compare gene expression differences between blistered and non-blistered skin from individuals with all subtypes of EB, as well as normal skin from non-EB subjects. State of the art computational analysis will be performed to help identify new drugs that might help all EB wound healing and reduce pain. Researchers will focus on drugs that have already been approved for treatment of other dermatologic or non-dermatologic diseases, and therefore be repurposed for treatment of EB. Drug development is a very expensive process taking decades for execution. Drug repurposing on the other hand, significantly reduces the cost and shortens the amount of time that is needed to bring effective treatments to clinical use. To date, there is no specific treatment targeting the physiology and immunologic response in EB patients during wound healing. Market availability of repurposed medications will provide all EB patients rapid access to treatments, thus improving their quality of life.

Conditions

Epidermolysis Bullosa; Healthy; Genetic Skin Disease; Epidermolysis Bullosa Simplex; Epidermolysis Bullosa, Junctional; Epidermolysis Bullosa Dystrophica

Keywords

epidermolysis bullosa; genetic expression; drug repurposing; computational approaches; drug discovery

Outcome Measures

Primary Outcomes (1)

• Characterize gene expression changes in EB using RNA sequencing (RNA-seq) and Computational Profiling Potential Drug Targets

  Using bioinformatic algorithms to identify changes in gene expression and review of over 2000 FDA-approved drugs based on predicted modulation of gene expression changes using a computational evolutionary algorithm system.

  Through the completion of study in 1 year.

Study Arms (2)

Experimental Group

Blood and tissue specimen will be collected from subjects with an EB diagnosis. Tissue specimen will be collected from blistered and nonblistered skin.

Procedure: Experimental Group

Control Group

Blood and tissue specimen will be collected from healthy subjects with non-EB. Tissue specimen will be collected from an inconspicuous skin area.

Procedure: Experimental Group

Interventions

Experimental Group PROCEDURE

Subjects with EB diagnosis

Control Group; Experimental Group

Eligibility Criteria

• Age: 0 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Subject of all ages with either 1) a diagnosis of EB subjects or 2) healthy, non-EB subjects

You may qualify if:

• Subjects of all ages
• Diagnosis of all subtypes of EB subjects
• Healthy, non-EB subjects
• Ability to complete study visit to collect tissue and blood specimen

You may not qualify if:

• Pregnancy, breast feeding
• Prior history of liver disease
• Serious known concurrent medical illness or infection, which could potentially present a safety risk and/or prevent tissue collection from subjects

Sponsors & Collaborators

• Joyce Teng: lead

Study Sites (1)

Pediatric Dermatology Clinic at Stanford Children's Hospital

Palo Alto, California, 94304, United States

RECRUITING

Related Publications (17)

• McLaren PJ, Mayne M, Rosser S, Moffatt T, Becker KG, Plummer FA, Fowke KR. Antigen-specific gene expression profiles of peripheral blood mononuclear cells do not reflect those of T-lymphocyte subsets. Clin Diagn Lab Immunol. 2004 Sep;11(5):977-82. doi: 10.1128/CDLI.11.5.977-982.2004.

  PMID: 15358662 BACKGROUND

• Sleasman JW, Leon BH, Aleixo LF, Rojas M, Goodenow MM. Immunomagnetic selection of purified monocyte and lymphocyte populations from peripheral blood mononuclear cells following cryopreservation. Clin Diagn Lab Immunol. 1997 Nov;4(6):653-8. doi: 10.1128/cdli.4.6.653-658.1997.

  PMID: 9384284 BACKGROUND

• Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016 May;34(5):525-7. doi: 10.1038/nbt.3519. Epub 2016 Apr 4.

  PMID: 27043002 BACKGROUND

• Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010 Jan 1;26(1):139-40. doi: 10.1093/bioinformatics/btp616. Epub 2009 Nov 11.

  PMID: 19910308 BACKGROUND

• Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, Maciejewski A, Arndt D, Wilson M, Neveu V, Tang A, Gabriel G, Ly C, Adamjee S, Dame ZT, Han B, Zhou Y, Wishart DS. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2014 Jan;42(Database issue):D1091-7. doi: 10.1093/nar/gkt1068. Epub 2013 Nov 6.

  PMID: 24203711 BACKGROUND

• Sugaya N, Kanai S, Furuya T. Dr. PIAS 2.0: an update of a database of predicted druggable protein-protein interactions. Database (Oxford). 2012 Oct 10;2012:bas034. doi: 10.1093/database/bas034. Print 2012.

  PMID: 23060433 BACKGROUND

• Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007 Dec 1;23(23):3251-3. doi: 10.1093/bioinformatics/btm369. Epub 2007 Jul 20.

  PMID: 17644558 BACKGROUND

• Cohn HI, Teng JM. Advancement in management of epidermolysis bullosa. Curr Opin Pediatr. 2016 Aug;28(4):507-16. doi: 10.1097/MOP.0000000000000380.

  PMID: 27386970 RESULT

• Uitto J, Bruckner-Tuderman L, Christiano AM, McGrath JA, Has C, South AP, Kopelan B, Robinson EC. Progress toward Treatment and Cure of Epidermolysis Bullosa: Summary of the DEBRA International Research Symposium EB2015. J Invest Dermatol. 2016 Feb;136(2):352-358. doi: 10.1016/j.jid.2015.10.050.

  PMID: 26802230 RESULT

• Nystrom A, Thriene K, Mittapalli V, Kern JS, Kiritsi D, Dengjel J, Bruckner-Tuderman L. Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms. EMBO Mol Med. 2015 Sep;7(9):1211-28. doi: 10.15252/emmm.201505061.

  PMID: 26194911 RESULT

• Wally V, Kitzmueller S, Lagler F, Moder A, Hitzl W, Wolkersdorfer M, Hofbauer P, Felder TK, Dornauer M, Diem A, Eiler N, Bauer JW. Topical diacerein for epidermolysis bullosa: a randomized controlled pilot study. Orphanet J Rare Dis. 2013 May 7;8:69. doi: 10.1186/1750-1172-8-69.

  PMID: 23651789 RESULT

• Li J, Zheng S, Chen B, Butte AJ, Swamidass SJ, Lu Z. A survey of current trends in computational drug repositioning. Brief Bioinform. 2016 Jan;17(1):2-12. doi: 10.1093/bib/bbv020. Epub 2015 Mar 31.

  PMID: 25832646 RESULT

• Low YS, Daugherty AC, Schroeder EA, Chen W, Seto T, Weber S, Lim M, Hastie T, Mathur M, Desai M, Farrington C, Radin AA, Sirota M, Kenkare P, Thompson CA, Yu PP, Gomez SL, Sledge GW Jr, Kurian AW, Shah NH. Synergistic drug combinations from electronic health records and gene expression. J Am Med Inform Assoc. 2017 May 1;24(3):565-576. doi: 10.1093/jamia/ocw161.

  PMID: 27940607 RESULT

• Bchetnia M, Tremblay ML, Leclerc G, Duperee A, Powell J, McCuaig C, Morin C, Legendre-Guillemin V, Laprise C. Expression signature of epidermolysis bullosa simplex. Hum Genet. 2012 Mar;131(3):393-406. doi: 10.1007/s00439-011-1077-7. Epub 2011 Aug 30.

  PMID: 21877134 RESULT

• Roth W, Reuter U, Wohlenberg C, Bruckner-Tuderman L, Magin TM. Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex. Hum Mutat. 2009 May;30(5):832-41. doi: 10.1002/humu.20981.

  PMID: 19267394 RESULT

• Lee B, Geyfman M, Andersen B, Dai X. Analysis of gene expression in skin using laser capture microdissection. Methods Mol Biol. 2013;989:109-17. doi: 10.1007/978-1-62703-330-5_10.

  PMID: 23483391 RESULT

• Lovendorf MB, Mitsui H, Zibert JR, Ropke MA, Hafner M, Dyring-Andersen B, Bonefeld CM, Krueger JG, Skov L. Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis. Exp Dermatol. 2015 Mar;24(3):187-93. doi: 10.1111/exd.12604.

  PMID: 25431026 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Punch biopsies of non-blistering and blistering skin, and peripheral blood mononuclear cells (PBMCs): CD8+ cytotoxic T cells and CD4+ helper T cells.

MeSH Terms

Conditions

Epidermolysis Bullosa; Skin Diseases, Genetic; Epidermolysis Bullosa Simplex; Epidermolysis Bullosa, Junctional; Epidermolysis Bullosa Dystrophica

Condition Hierarchy (Ancestors)

Skin Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Vesiculobullous; Collagen Diseases; Connective Tissue Diseases

Study Officials

• Joyce M Teng, MD, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Monica Martin

CONTACT

650-723-0636; momartin@stanford.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of Pediatric Dermatology

Study Record Dates

• First Submitted: August 21, 2017
• First Posted: August 31, 2017
• Study Start: November 28, 2017
• Primary Completion: December 30, 2024
• Study Completion: December 31, 2024
• Last Updated: February 13, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)