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

Experimental Dermatology
William V J HaritonEliane J Müller

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.

References

Jul 27, 1999·The Journal of Investigative Dermatology·M G MahoneyJ R Stanley
Jul 28, 2006·The EMBO Journal·Lina WilliamsonEliane J Müller
Aug 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Paula BerkowitzDavid S Rubenstein
Oct 1, 2011·The Journal of Investigative Dermatology·Katja SchulzeEliane J Müller
May 10, 2013·The Journal of Investigative Dermatology·Xuming MaoAimee S Payne
Nov 26, 2015·Seminars in Immunopathology·Giovanni Di ZenzoLuca Borradori
Feb 18, 2017·Cell Death and Differentiation·Stéphanie SolierEric Solary

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Citations

Feb 17, 2018·Frontiers in Immunology·Volker Spindler, Jens Waschke
Aug 21, 2020·British Journal of Pharmacology·Imke A K BurmesterRalf J Ludwig
Nov 22, 2017·Experimental Dermatology·Frank Antonicelli, Ralf J Ludwig
Aug 27, 2021·Frontiers in Medicine·Thomas Schmitt, Jens Waschke

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