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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.
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.
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.
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.
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.
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
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