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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.