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Netherton Syndrome (NS)
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Netherton Syndrome (NS)

Netherton syndrome is an uncommon autosomatic genodermatosis with a diagnosis deriving from a defect in the SPINK5 gene, which results in deficient expression of LEKTI protein, dysfunctional epidermal barrier, and chronic inflammation. Protheragen offers full service Netherton syndrome preclinical drug development and therapy development services to accelerate translational developments.

Overview of Netherton Syndrome

Netherton syndrome has features including congenital ichthyosiform erythroderma, bamboo hair (trichorrhexis invaginata), and severe atopic diathesis. In SPINK5 mutations, the LEKTI-mediated inhibition of some epidermal proteases (kallikrein 5/7) becomes uncoupled, leading to excessive proteolytic activity and barrier destruction, resulting in chronic inflammation. While affecting approximately 1 in 200,000 people globally, more recent studies show immune dysregulation (Th2/IL-17 skewing) and alteration of the microbiome as major contributors of the disease.

Immune cells, mediators and receptors involved in NS and their biological inhibitorsFig.1 Immune cells, mediators and receptors involved in NS and their biological inhibitors; red and white targets showing drug sites of action. (Pontone et al., 2022)

Diagnostic Development for Netherton Syndrome

Genetic and Molecular Diagnostics

The diagnosis of Netherton syndrome is done primarily by sequencing the SPINK5 gene and targeted next generation sequencing (NGS) facilitates rapid identification of pathogenic variants. Keratinocyte models validated functionally by CRISPR editing tested for LEKTI expression and proteolytic activity to validate pathogenicity of the variant. Some advanced methods such as RNA-seq of skin swabs are capable of non-invasively detecting SPINK5 splicing and expression.

Biomarker-Driven Diagnostics

Innovative fluorogenic peptide substrate assays have identified the reduction of LEKTI protein and increased kallikrein 5/7 activity as primary diagnostic markers. TSLP and IL-17 levels in serum or stratum corneum are important for monitoring the disease and can indicate changes with treatment, correlating with the level of disease. Genetic, proteomic, and immune profile multiplexed platforms are integrating towards advanced precision diagnosis.

Therapeutics Development for Netherton Syndrome

Therapies for Netherton syndrome aim for LEKTI restoration via gene therapy (AAV-SPINK5), protease inhibitors, and biologics such as dupilumab (anti-IL-4Rα) for immunomodulation, mostly in clinical trials or preclinical phases. New approaches are focused on decreasing inflammation and recurrent infections by targeting the foundation of the epidermal barrier and inhibiting kallikrein along with altering the microbiome.

Table.1 Therapeutic Development of Netherton Syndrome.

Therapeutic Strategy Key Agents/Interventions Key Findings/Mechanism Development Stage
Phototherapy NB-UVB Suppresses protease activity via immunomodulation. Approved
IV Immunoglobulins (IVIG) IVIG 500 mg/kg/month Immunomodulation; reduces erythema and pruritus Phase II
Biologics Dupilumab (anti-IL-4Rα) Blocks Th2 signaling; improves pruritus and scaling. Phase II
Gene Therapy AAV-SPINK5 delivery Restores LEKTI expression in keratinocytes. Preclinical
Phage Therapy Bacteriophage cocktails Targets antibiotic-resistant infections. Preclinical

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen offers comprehensive and integrated preclinical services to innovate Netherton syndrome, supporting therapeutic development, diagnostics development, and disease models to accelerate therapeutic translation. With advanced platforms, we ensure an undisrupted changeover from discovery to IND-enabling studies.

  • Patient-Derived NS Keratinocytes
  • SPINK5 Knockout HaCaT Cells
  • 3D Reconstructed Human Epidermis (RHE)
  • KLK5 Transgenic Mice
  • SPINK5 Conditional Knockout Mice

Protheragen uses advanced multi in vitro and in vivo platforms to accelerate Netherton syndrome's preclinical translation. With integrated services such as drug safety evaluation and DMPK, therapeutic strategies involving LEKTI restoration, kallikrein inhibition, and Th2/IL-17 immune modulation can be swiftly prioritized for deeper investigation.

Partner with us to Netherton syndrome research into viable therapeutic innovations. For inquiries regarding our comprehensive services, please contact us.

References

  • Kostova, P., et al. "Netherton Syndrome-a Therapeutic Challenge in Childhood." Clin Case Rep 12.4 (2024): e8770.
  • Pontone, M., et al. "Biological Treatments for Pediatric Netherton Syndrome." Front Pediatr 10 (2022): 1074243.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.

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