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. 2021 Jun;184(6):1123-1131.
doi: 10.1111/bjd.19546. Epub 2020 Nov 2.

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

F Valentin  1   2 , H Wiegmann  1 , T Tarinski  1 , H Nikolenko  3 , H Traupe  1 , E Liebau  4 , M Dathe  3 , V Oji  1
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Development of a pathogenesis-based therapy for peeling skin syndrome type 1

F Valentin et al. Br J Dermatol. 2021 Jun.

Abstract

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.

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Comment in

  • Advancing novel therapies for ichthyoses.
    Schmuth M, Reichelt J, Gruber R. Schmuth M, et al. Br J Dermatol. 2021 Jun;184(6):998-999. doi: 10.1111/bjd.19698. Epub 2020 Dec 30. Br J Dermatol. 2021. PMID: 33378090 Free PMC article.

References

    1. Oji V, Tadini G, Akiyama M et al. Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol 2010; 63:607-41.
    1. Traupe H. Peeling-skin syndrome: clinical and morphological evidence for two types. In: The Ichthyoses: a Guide to Clinical Diagnosis, Genetic Counseling, and Therapy. Berlin: Springer, 1989; 207-10.
    1. Oji V, Eckl KM, Aufenvenne K et al. Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. Am J Hum Genet 2010; 87:274-81.
    1. Cabral RM, Kurban M, Wajid M et al. Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome. Genomics 2012; 99:202-8.
    1. Pigors M, Sarig O, Heinz L et al. Loss-of-function mutations in SERPINB8 linked to exfoliative ichthyosis with impaired mechanical stability of intercellular adhesions. Am J Hum Genet 2016; 99:430-6.

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