Development of a Pathogenesis‐Based Therapy for Peeling Skin Syndrome Type 1

BACKGROUND Peeling skin syndrome type 1 is a rare and severe autosomal recessive form of congenital ichthyosis. Patients suffer from pronounced erythroderma accompanied by tremendous pruritus and superficial generalised peeling of the skin. The disease is due to nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). It severely impairs the quality of life and therapeutic approaches are totally unsatisfactory. OBJECTIVES We wanted to develop the first steps toward a specific protein replacement therapy for CDSN deficiency. The aim is to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to stratum corneum (SC). METHODS Human CDSN was recombinantly expressed in E. 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 characterised 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. CONCLUSION The study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients suffering from PSS1.