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  Drug repurposing as a successful principle to identify drugs that alleviate experimental epidermolysis bullosa acquisita (EBA)

Ghorbanalipoor, S., Veldkamp, W., Matsumoto, K., Bieber, K., Vidarsson, G., Gupta, Y., et al. (2018). Drug repurposing as a successful principle to identify drugs that alleviate experimental epidermolysis bullosa acquisita (EBA). Experimental Dermatology: an International Journal for Rapid Publication of Short Reports in Experimental Dermatology, 27(3), e67-e67. doi:10.1111/exd.13486.

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 Creators:
Ghorbanalipoor, S., Author
Veldkamp, W., Author
Matsumoto, K., Author
Bieber, K., Author
Vidarsson, G., Author
Gupta, Y., Author
Kuenzel, S.1, Author           
Schwaninger, M., Author
Kalies, K., Author
Ludwig, R. J., Author
Affiliations:
1Department Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445635              

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 Abstract: Epidermolysis bullosa acquisita (EBA) is a prototypic immunobullous disorder caused by autoantibodies directed against type VII collagen (COL7), which is the major component of the anchoring fibrils at the dermal epidermal junction. Treatment of EBA is difficult and more specifically relies on general immunosuppression. The molecular mechanisms of disease, required for the pathogenesis, are poorly understood limiting the clinical development of rational targeted therapies. Several studies indicated the pivotal role of neutrophils in both induction and effector phases of EBA; therefore, these cells are considered as potential therapeutic targets for treatment of EBA. Drug repurposing represents an alternative to drug discovery and exploits new molecular targets of a known drug for different medical indications. Here, we tested this hypothesis with screening of 1200 FDA- approved compounds for their suppression of generated reactive oxygen species (ROS) from immobilized immune complex (iIC)- activated human neutrophils. Among the tested compounds, thirty three compounds repressed ROS generation by more than 50%. This group of compounds were then investigated for their dose dependency and ROS scavenging activities. The cytotoxic drugs were also excluded from further study. Via complementary screening, six drugs were identified and subjected to the further elucidation of the clinical potential effect in an antibody transfer- induced mouse model of EBA. Four of these drugs indicated disease alleviating impact on this disease model, from which one drug was selected by its potency of effect on reduction of the disease severity. To identify the comparative transcriptional profiling, we performed RNA sequencing (RNA- seq) of skin tissues obtained from EBA mice treated with this drug and its vehicle. The result of our expression profiling would provide information about the genes of relevant immune cells affected by our drug which could be then considered as a therapeutic target for EBA treatment.

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Language(s): eng - English
 Dates: 2018-03-082018
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1111/exd.13486
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Title: 45th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF)
Place of Event: Zürich, Switzerland
Start-/End Date: 2018-03-07 - 2018-03-10

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Title: Experimental Dermatology : an International Journal for Rapid Publication of Short Reports in Experimental Dermatology
Source Genre: Journal
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Affiliations:
Publ. Info: Wiley
Pages: - Volume / Issue: 27 (3) Sequence Number: - Start / End Page: e67 - e67 Identifier: ISSN: 0906-6705
CoNE: https://pure.mpg.de/cone/journals/resource/954925562616