Development of a pathogenesis‐based therapy for peeling skin syndrome type 1*

Abstract

Summary Background Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory. Objectives The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell–cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. Methods Human CDSN was recombinantly expressed in Escherichia coli. A liposome‐based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated. Results The liposomes showed an accumulation at the membranes of keratinocytes. CDSN‐deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN‐deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN. Conclusions This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.

A novel pathogenic variant in the corneodesmosin gene causing generalized inflammatory peeling skin syndrome with marked eosinophilia and trichorrhexis invaginata

“…In a mouse model, PSS CDSN iep −/− mice were treated with anakinra, an IL‐1 receptor antagonist, with significant improvement in clinical findings and histological inflammation 22 . A recent study explored using a liposomal delivery system for topical application of recombinant CDSN 23 …”

“…22 A recent study explored using a liposomal delivery system for topical application of recombinant CDSN. 23 These studies pave the way for a potential treatment for…”

Advancing novel therapies for ichthyoses

“…In this issue, Dr Oji's group presents compelling evidence of successful liposome-based delivery of recombinantly synthesized corneodesmosin to patient-derived PSS-1 keratinocytes both in monolayer and in three-dimensional (3D) cultures. 2 Aside from choosing protein supplementation as the method of disease modification, the efficient and precise delivery of the compounds to the crime scenethe tissue or the cellrepresents a major hurdle. The carrier system used by Valentin et al consists of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine, mimicking cellular lipid membranes.…”

“…Optimization for enhanced Table 1 Targeted therapies for ichthyoses At the DNA level, mutations can be excised or corrected, or expression vectors can be introduced 3,4 Small molecules modulate relevant signalling pathways, e.g. nitric oxide synthase inhibitors or Janus kinase inhibitors improve tissue models of harlequin ichthyosis 5 Protease inhibitors are being developed to antagonize protease overactivity in Netherton syndrome 6 Monoclonal antibodies neutralize mediators of skin inflammation in patients with ichthyosis 7,8 Deficient lipid components that are essential for the epidermal barrier have been exogenously added and shown to improve the scaling phenotype in ichthyosis 9 Decreased or absent proteins can be delivered to diseased skin grafts 2,10…”

“…1 Recent observational studies have paradoxically shown that patients with NSV have a decreased lifetime risk of developing both melanoma and keratinocytic skin cancers (KSCs). 2 In this issue of the BJD, Brahmbhatt et al reveal a molecular mechanism in lesional vitiligo keratinocytes that may account for this observation, which protects keratinocytes from ultraviolet (UV)-induced DNA damage. 3 The authors studied RNA in lesional and nonlesional epidermal vitiligo skin biopsies in five patients.…”