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Published on: July 11, 2013
Development of a pathogenesis-based therapy for peeling skin syndrome type 1
F Valentin1,2, H Wiegmann1, T Tarinski1
1Department of Dermatology, University Hospital Münster, Münster, 48149, Germany.
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.
Insights
Peeling skin syndrome type 1 (PSS1) is a severe genetic skin disorder. This study developed a liposomal delivery system to deliver corneodesmosin (CDSN) protein, showing promise for a new PSS1 therapy.
Area of Science:
- Dermatology
- Genetics
- Biotechnology
Background:
- Peeling skin syndrome type 1 (PSS1) is a rare, severe autosomal recessive congenital ichthyosis.
- Characterized by erythroderma, pruritus, and generalized skin peeling due to CDSN gene mutations.
- Current therapies for PSS1 are inadequate, significantly impacting patient quality of life.
Purpose of the Study:
- To develop the initial phase of a protein replacement therapy for CDSN deficiency in PSS1.
- To restore CDSN function and enhance cell-cell cohesion in the epidermis.
- To investigate a novel therapeutic strategy for PSS1.
Main Methods:
- Recombinant expression of human corneodesmosin (CDSN) in E. coli.
- Development of a liposome-based carrier system with cationic lipopeptide for keratinocyte delivery.
- Characterization of liposomal system and investigation of its interaction with keratinocytes and epidermal equivalents.
Main Results:
- Liposomes effectively accumulated at keratinocyte membranes.
- CDSN-deficient epidermal equivalents treated with liposomal CDSN showed CDSN presence in the stratum granulosum.
- Improved epidermal integrity was observed in treated CDSN-deficient epidermal equivalents.
Conclusions:
- This study provides the first preclinical in vitro evidence for a targeted protein replacement therapy for PSS1.
- The developed liposomal CDSN delivery system shows potential for treating CDSN deficiency.
- Further research may lead to effective therapeutic options for PSS1 patients.
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