rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients

Roedl, Daniela; Oji, Vinzenz; Buters, Jeroen; Behrendt, Heidrun; Braun‐Falco, Markus

doi:10.1016/j.jdermsci.2010.12.004

Cited by 27 publications

(15 citation statements)

References 26 publications

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“…The currently utilized therapies for this life-threatening and disabling disease are only aimed at reducing the clinical symptoms (Saif and Al-Khenaizan, 2007;Renner et al, 2009). Nevertheless, in spite of the encouraging results (Di et al, 2010;Roedl et al, 2011), the ex-vivo gene transfer cannot be envisaged as an imminent therapeutic option. Local delivery through the horny layer, by means of topical application or non-invasive mini-gene transfer (Foldvari et al, 2006) of LEKTI bioactive fragments could attenuate unopposed KLKs activity and counteract the skin barrier impairment of NS patients.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Activation Cascade of the Netherton Syndrome–Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis

Fortugno

Bresciani

Paolini

et al. 2011

Journal of Investigative Dermatology

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Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is the defective protein of the ichthyosiform condition Netherton syndrome (NS). Strongly expressed in the most differentiated epidermal layers, LEKTI is a serine protease inhibitor synthesized as three different high-molecular-weight precursors, which are rapidly processed into shorter fragments and secreted extracellularly. LEKTI polypeptides interact with several proteases to regulate skin barrier homeostasis as well as inflammatory and/or immunoallergic responses. Here, by combining antibody mapping, N-terminal sequencing, and site-specific mutagenesis, we defined the amino-acid sequence of most of the LEKTI polypeptides physiologically generated in human epidermis. We also identified three processing intermediates not described so far. Hence, a proteolytic cascade model for LEKTI activation is proposed. We then pinpointed the most effective fragments against the desquamation-related kallikreins (KLKs) and we proved that LEKTI is involved in stratum corneum shedding as some of its polypeptides inhibit the KLK-mediated proteolysis of desmoglein-1. Finally, we quantified the individual LEKTI fragments in the uppermost epidermis, showing that the ratios between LEKTI polypeptides and active KLK5 are compatible with a fine-tuned inhibition. These findings are relevant both to the understanding of skin homeostasis regulation and to the design of novel therapeutic strategies for NS.

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Section: Discussionmentioning

confidence: 99%

Proteolytic Activation Cascade of the Netherton Syndrome–Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis

Fortugno

Bresciani

Paolini

et al. 2011

Journal of Investigative Dermatology

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“…Another group used an AAV2-mediated viral vector to restore LEKTI in NS keratinocytes. Expression of SPINK5 after transduction was increased to approximately 75% of wild-type KCs (Roedl et al 2011).…”

Section: Netherton Syndromementioning

confidence: 98%

Gene Therapy for Skin Diseases

Gorell

Ngôn

Lane

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…Roedl et al. employed an adenoviral‐based approach to restore the protease in patient cells through transfer of SPINK5 , while Di et al. generated a self‐inactivating lentiviral vector encoding SPINK5 to correct gene expression in vitro and also in skin graft models of humans and mice .…”

Section: Genome‐editing Tools and Gene Therapymentioning

confidence: 99%

Research on genodermatoses using novel genome‐editing tools

Lehmann

Seebode

Emmert

2017

J Deutsche Derma Gesell

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SummaryGenodermatoses comprise a clinically heterogeneous group of mostly devastating disorders affecting the skin. To date, treatment options have in general been limited to symptom relief. However, the recent technical evolution in genome editing has ushered in a new era in the development of causal therapies for rare monogenetic diseases such as genodermatoses. The present review revisits the advantages and drawbacks of engineered nuclease tools currently available: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases, and -the most innovative -clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) nuclease 9 (CRISPR/Cas9) system. A mechanistic overview of the different modes of action of these programmable nucleases as well as their significance for causal therapy of genodermatoses is presented. Remaining limitations and challenges such as efficient delivery and off-target activity are critically discussed, highlighting both the past and future of gene therapy in dermatology.

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rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients

Cited by 27 publications

References 26 publications

Proteolytic Activation Cascade of the Netherton Syndrome–Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis

Proteolytic Activation Cascade of the Netherton Syndrome–Defective Protein, LEKTI, in the Epidermis: Implications for Skin Homeostasis

Gene Therapy for Skin Diseases

Research on genodermatoses using novel genome‐editing tools

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