Feasibility study for clinical application of caspase-3 inhibitors in Pemphigus vulgaris.

Abstract:

:The potentially severe side effects of systemic corticosteroids and immunosuppressants used in Pemphigus vulgaris (PV) call for novel therapeutic approaches. In this context, pharmacological inhibition of major pathogenic signalling effectors represents a promising alternative. However, we have also shown that overinhibition of effectors required for epidermal homeostasis can exacerbate PV pathophysiology implicating transepidermal keratinocyte fragility. A feedforward target validation therefore preferentially includes studies on knockout mouse models. We previously reported on successful amelioration of PV blisters following inhibition of non-apoptotic, low-level caspase-3. Here, we use conditional, keratinocyte-specific caspase-3-deficient mice (casp3EKO ) to demonstrate (i) absence of keratinocyte fragility upon injection of the potent Dsg3-specific antibody AK23 and (ii) amelioration of blistering on the background of known signalling effectors. Our results provide the experimental proof of concept justifying translation of the caspase-3 inhibitor approach into PV clinical trials.

journal_name

Exp Dermatol

journal_title

Experimental dermatology

authors

Hariton WVJ,Galichet A,Vanden Berghe T,Overmiller AM,Mahoney MG,Declercq W,Müller EJ

doi

10.1111/exd.13458

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

1274-1277

issue

12

eissn

0906-6705

issn

1600-0625

journal_volume

26

pub_type

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