Advances in understanding of Netherton syndrome and therapeutic implications

ABSTRACT

Introduction: Netherton syndrome (NS) is a rare and severe ichthyosis characterized by superficial scaling, skin inflammation, a specific hair shaft defect, severe atopic manifestations and multisystemic complications. It is an orphan disease with currently no satisfactory treatment. NS is caused by loss-of-function mutations in SPINK5 encoding the serine protease inhibitor LEKTI. NS patients present with ichthyosiform erythroderma or ichthyosis linearis circumflexa and show considerable clinical variability.

Areas covered: Uncontrolled serine protease activity leads to a profound skin barrier defect and the release of pro-inflammatory and pro-allergic mediators by keratinocytes and immune cells. Improved understanding of NS pathogenesis has led to the successful use of repurposed biologics such as intravenous immunoglobulins and anti-IL-17A blockers. Between April 1, 2020 and November 18, 2020, authors searched for NS-relevant information in the following databases: MEDLINE, DrugBank, ClinicalTrials.gov, and patent datasets accessed through lens.org.

Expert opinion: Specific KLK5 and/or KLK7 inhibitors represent the most promising disease-modifying treatments. They are currently being developed by several companies. Comprehension of the determinants of NS variability, flares and modification over time will be the foundation for precision medicine. While improved knowledge of the inflammatory and allergic pathways involved is still needed, clinical trials using repurposed biologics have already begun.

KEYWORDS:

• Netherton syndrome
• ichthyosis
• LEKTI
• Spink5
• hyper-IgE
• kallikrein-related peptidase
• biologics therapy
• PAR-2
• IL-17A

Article highlights

• Netherton syndrome is a rare and severe genetic skin disease with very high unmet medical need.

• It is characterized by a clinical triad of ichthyosiform erythroderma, a specific hair shaft abnormality (trichorrhexis invaginata, or bamboo hair), atopic manifestations and multisystemic complications.

• Ichthyosiform erythroderma often evolves into ichthyosis linearis circumflexa which is highly specific, but not constant.

• All NS patients have bi-allelic loss-of-function mutations in the SPINK5 gene encoding the lymphoepithelial Kazal-Type-related protease inhibitor (LEKTI).

• Loss of inhibition of kallikrein-related peptidases (KLK) 5, 7 and 14 plays a crucial role in NS pathogenesis, with KLK5 being central for the initiation of the proteolytic process.

• A profound skin barrier defect is a major, but not exclusive, determinant of skin inflammation and allergy, in which keratinocytes and immune cells actively participate.

• Immunophenotyping of peripheral blood cells shows Th17 skewing with debated features of immune deficiency.

• Case studies using intravenous immunoglobulins and diverse biologics including monoclonal antibodies targeting TNF-α, IL-17A, IL4-Rα, or IL-12/IL-23 have shown clinical benefits, but involved only a limited number of patients.

• Improved understanding of NS pathogenesis has allowed to develop specific therapeutic approaches aiming at blocking KLK5 and/or KLK7, or at using biologics targeting secondary but determinant inflammatory and/or allergic events.

• Clinical trials have begun and should allow to assess the potential use of these drugs to alleviate the disease burden.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Jesus Maria Lopez-Gay Orts (Curie Institute, Paris, France) for help with scientific drawings.

Declaration of interest

E Petrova receives funding from the ANR project TARGET-NS-19-CE17-0017-02 to A Hovnanian. E Petrova received funding by INSERM for a research service project sponsored by UCB Pharma. A Hovnanian is a consultant for Amagma, Boehringer-Ingelheim, BridgeBio, Genentech, Kamari and LifeMax.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by State funding from the Agence Nationale de la Recherche under ‘Investissements d’avenir’ program (ANR-10-IAHU-01).