Paired blood skin transcriptomic profiling during Dupilumab treatment of SPINK5-FLG Netherton Syndrome
Netherton syndrome is a rare autosomal recessive disorder caused by pathogenic variants in SPINK5, leading to LEKTI deficiency, barrier dysfunction, and chronic Th2 inflammation. Dupilumab, an IL-4Ra antagonist blocking IL-4 and IL-13 signaling, has shown promising clinical benefit in NS, but its molecular effects remain poorly defined. This study aimed to characterize the transcriptomic changes induced by dupilumab in NS and to identify molecular pathways underlying clinical improvement.  Methods: Two siblings with NS harboring SPINK5 c.2468dup and FLG p.Arg501* variants received dupilumab for six months. Clinical, hematologic, and transcriptomic assessments were performed before and after treatment. Whole-exome sequencing and RNA-seq were conducted on blood and paired skin biopsies. Differential expression and pathway enrichments were analyzed.  Results: Blood RNA-seq revealed 18,205 DEGs, with post-treatment expression profiles clustering toward healthy controls. Dupilumab suppression of inflammatory, hypermetabolic, and proliferative programs being FURIN identied as a clear mediator. Upregulation of PAPPA, LPAR5, CELSR1, and ARHGEF19 indicated activation of WNT/ß-catenin and planar-cell-polarity pathways. Skin transcriptomes demonstrated restoration of lipid metabolism, keratinocyte differentiation, and cornified-envelope formation with repression of neurosensory. Cross-compartment integration identified RIN3 and MT-ATP6P1 reappearance as indicators of recovered endocytic and mitochondrial homeostasis, ADAM23 as a convergent blood–skin repair marker, and PROB1, PRKC-AS1, and PARM1 as signatures restored toward healthy transcriptional states. RHOBTB3 was identified as a potential biomarker for  Conclusions: Dupilumab produces broad systemic and cutaneous transcriptomic normalization in NS, extending beyond Th2 suppression to restore protease balance, lipid metabolism, differentiation, and polarity networks. IL-4Ra blockade may function as a molecular disease-modifying therapy, and integrated blood–skin transcriptomics may help identify biomarkers of treatment response.
Netherton syndrome is a rare autosomal recessive disorder caused by pathogenic variants in SPINK5, leading to LEKTI deficiency, barrier dysfunction, and chronic Th2 inflammation. Dupilumab, an IL-4Ra antagonist blocking IL-4 and IL-13 signaling, has shown promising clinical benefit in NS, but its molecular effects remain poorly defined. This study aimed to characterize the transcriptomic changes induced by dupilumab in NS and to identify molecular pathways underlying clinical improvement.  Methods: Two siblings with NS harboring SPINK5 c.2468dup and FLG p.Arg501* variants received dupilumab for six months. Clinical, hematologic, and transcriptomic assessments were performed before and after treatment. Whole-exome sequencing and RNA-seq were conducted on blood and paired skin biopsies. Differential expression and pathway enrichments were analyzed.  Results: Blood RNA-seq revealed 18,205 DEGs, with post-treatment expression profiles clustering toward healthy controls. Dupilumab suppression of inflammatory, hypermetabolic, and proliferative programs being FURIN identied as a clear mediator. Upregulation of PAPPA, LPAR5, CELSR1, and ARHGEF19 indicated activation of WNT/ß-catenin and planar-cell-polarity pathways. Skin transcriptomes demonstrated restoration of lipid metabolism, keratinocyte differentiation, and cornified-envelope formation with repression of neurosensory. Cross-compartment integration identified RIN3 and MT-ATP6P1 reappearance as indicators of recovered endocytic and mitochondrial homeostasis, ADAM23 as a convergent blood–skin repair marker, and PROB1, PRKC-AS1, and PARM1 as signatures restored toward healthy transcriptional states. RHOBTB3 was identified as a potential biomarker for  Conclusions: Dupilumab produces broad systemic and cutaneous transcriptomic normalization in NS, extending beyond Th2 suppression to restore protease balance, lipid metabolism, differentiation, and polarity networks. IL-4Ra blockade may function as a molecular disease-modifying therapy, and integrated blood–skin transcriptomics may help identify biomarkers of treatment response.