RARE DISEASE
Netherton syndrome
Netherton syndrome
Netherton syndrome
Synonyms: Bamboo hair syndrome, Comèl-Netherton syndrome, NS
Synonyms: Bamboo hair syndrome, Comèl-Netherton syndrome, NS
Synonyms: Bamboo hair syndrome, Comèl-Netherton syndrome, NS
Drug discovery
12
drugs
With orphan designations
Overview
Netherton syndrome is a rare autosomal recessive disorder caused by SPINK5 mutations, leading to lymphoepithelial Kazal-type-related inhibitor (LEKTI) deficiency. It presents with the triad of congenital ichthyosiform erythroderma, trichorrhexis invaginata ("bamboo hair"), and immune dysregulation. Neonates often exhibit erythroderma, collodion membrane, and failure to thrive, with risks of sepsis, hypernatremic dehydration, and dermopathic enteropathy. Chronic manifestations include pruritic ichthyosis linearis circumflexa, atopic diathesis, and recurrent infections. Management requires multidisciplinary care to address dermatologic, immunologic, and nutritional complications [1][2][7][12].
Categories: rare genetic diseases, rare immunological diseases, rare skin diseases
Research Papers
279 drug discovery papers about Netherton syndrome, with 3 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
279 drug discovery papers about Netherton syndrome, with 3 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-01 | What treatment strategies are described in case reports for managing skin manifestations in patients with Netherton syndrome?
Case reports describe a range of treatment strategies for managing skin manifestations in Netherton syndrome, including topical agents and systemic therapies such as biologics and immunoglobulins, although evidence is limited and variable in efficacy.
2026-05-18 | Squamous Cell Carcinoma of the External Auditory Canal in a Patient with Netherton Syndrome.
Netherton syndrome is a rare autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities, atopic diathesis, and a broad spectrum of immunologic dysfunction. Although cutaneous malignancies are uncommon, affected individuals may develop early-onset tumors that can pose diagnostic and therapeutic challenges. We report the case of a 33-year-old woman with Netherton syndrome who presented with persistent left otorrhea and a granulomatous mass in the external auditory canal. Imaging demonstrated a soft-tissue lesion with focal bony erosion and suspected dural involvement, accompanied by fluorodeoxyglucose uptake in a cervical lymph node. Biopsy confirmed squamous cell carcinoma (SCC), staged as T4N1M0. The patient underwent superselective intra-arterial cisplatin infusion combined with radiotherapy, resulting in complete remission of both the primary lesion and nodal metastasis, with no evidence of recurrence over 4 years. Including this case, 9 patients with Netherton syndrome and cutaneous malignancies have been reported, with tumors frequently arising at a young age and showing variable HPV status. Interpretation of SCC antigen may be complicated by elevations associated with atopic dermatitis. This case highlights the elevated risk of cutaneous malignancies in Netherton syndrome and underscores the need for long-term surveillance and multidisciplinary care.
2026-01-01 | Incomplete Netherton Syndrome treated successfully with Isotretinoin
Netherton syndrome is a rare autosomal recessive ichthyosis caused by serine peptidase inhibitor Kazal 5 mutation, characterized by congenital ichthyosis, trichorrhexis invaginata, atopy, high serum immunoglobulin E levels, and hyper eosinophilia. The demonstration of bamboo hair by microscopy is used as a method to diagnose Netherton syndrome. We report a rare patient with Netherton syndrome confirmed by genetic analysis and protein expression studies who had normal hair and was successfully treated with low dose isotretinoin, without any adverse events.
2026-01-01 | Use of Janus Kinase Inhibitors in the Treatment of Genodermatoses: A Systematic Review
Introduction Genodermatoses are rare inherited skin disorders with limited treatment options. Emerging evidence suggests Janus kinase (JAK) inhibitors may offer therapeutic benefits by modulating underlying immune and inflammatory pathways. This study aims to systematically review the efficacy and safety of JAK inhibitors in treating genodermatoses, including epidermolysis bullosa (EB), Netherton syndrome, and Hailey‐Hailey disease. Methods A comprehensive literature search identified case reports and series evaluating JAK inhibitor therapy in genodermatoses. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal Tools for Case Reports, demonstrating high methodological quality across included studies. Results Twenty studies involving patients with EB subtypes (especially dystrophic EB), Netherton syndrome, and other inherited dermatoses reported clinical improvement following treatment with JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib. Outcomes included reduction in pruritus, skin inflammation, and lesion severity, with notable improvements in quality‐of‐life measures. Treatment regimens varied (e.g., tofacitinib 5 mg twice daily, baricitinib 2 mg once daily, and upadacitinib 15 mg once daily) with follow‐up ranging from weeks to months. Laboratory monitoring showed stable profiles without significant adverse events. Reports of adverse events were rare or absent across studies, indicating favorable safety profiles. Conclusions JAK inhibitors represent a promising therapeutic avenue for genodermatoses characterized by immune dysregulation and chronic inflammation. While preliminary data are encouraging, further controlled studies are warranted to establish long‐term efficacy and safety. These findings support expanded clinical investigation of JAK inhibition in managing inherited skin disorders.
2025-11-11 | LEKTI-Grafted Sunflower Trypsin Inhibitor: A Potential Therapeutic for Skin Diseases.
Kallikrein 5 (KLK5) is a serine protease expressed in the outer skin layers, where it regulates the barrier function by cleaving desmosomal proteins. Elevated KLK5 causes excessive proteolysis, leading to corneocyte overdesquamation and barrier compromise. Increased KLK5 activity has been linked to atopic dermatitis (AD), a chronic inflammatory disease affecting up to 20% of children, highlighting the need for therapies that restore barrier integrity. While many serine protease inhibitors have been developed, most lack KLK5 selectivity. To address this, novel analogues of the sunflower trypsin inhibitor were designed and evaluated. Lead 7 emerged as a potent (IC50 = 14 ± 4 nM; Ki = 11 nM) selective KLK5 inhibitor. In keratinocytes from a Netherton syndrome patient, lead 7 significantly reduced the KLK5 activity and improved epithelial barrier integrity, as shown by transepithelial electrical resistance. These findings suggest lead 7 as a potential therapy for AD and other conditions with elevated KLK5 activity.
antibodies
2026-09-03 | Paired blood-skin transcriptomic profiling during dupilumab treatment of SPINK5-FLG-mutated Netherton syndrome
Netherton syndrome (NS) is a rare congenital barrier disorder caused by pathogenic variation in SPINK5, resulting in severe epidermal dysfunction and immune dysregulation. Although dupilumab is increasingly used in NS, molecular data describing treatment-associated tissue responses remain limited, particularly in genetically complex presentations. We investigated treatment-associated molecular trajectories during IL-4Rα blockade in two siblings with NS carrying heterozygous compound SPINK5 (c.2468dup & c.2243 A > G) and FLG (p.Arg501*) variants. Longitudinal whole-exome sequencing and paired bulk RNA sequencing of peripheral blood and lesional skin were performed before and after six months of dupilumab therapy. Transcriptomic changes were evaluated using effect-size– and rank-based approaches and contextualized through integration with publicly available NS reference datasets. Across both compartments, post-treatment transcriptional profiles exhibit coordinated shifts toward healthy-control–like expression states. Blood transcriptomes show reduced inflammatory, metabolic, and proliferative signatures alongside modulation of FURIN and increase expression of PAPPA, LPAR5, CELSR1, and ARHGEF19. Skin transcriptomes transition from neurosensory and follicular programs toward lipid metabolic organization, keratinocyte differentiation, and cornified-envelope–associated pathways. Cross-compartment integration highlights shared treatment-associated transcripts, including ADAM23, and candidate markers of immune–epithelial recalibration. Together, this exploratory dual-compartment longitudinal analysis provides rare molecular insight into biologic treatment response in a genetically complex NS context and establishes a foundational reference for future genotype-informed and biomarker-oriented studies. Netherton syndrome is a rare inherited skin disorder that causes severe inflammation and a weakened protective skin barrier. Although dupilumab is increasingly being used to treat this condition, its effects on the underlying biological mechanisms are not yet fully understood. To investigate this, we studied two siblings with Netherton syndrome and analyzed blood and skin samples collected before treatment and after six months of therapy. We found that dupilumab was associated with reduced inflammatory activity and gene expression patterns that became more similar to those seen in healthy individuals. These findings suggest that dupilumab may help restore both immune balance and skin barrier function, providing new insight into its mechanism of action and supporting the development of more personalized treatment strategies for people with Netherton syndrome. Bajo-Santos et al. longitudinally profile blood and skin transcriptomes before and after dupilumab treatment in two siblings with genetically complex Netherton syndrome. They observe that IL-4Rα blockade shifts molecular signatures toward healthy-like states, reducing inflammation and promoting epidermal differentiation and barrier-repair pathways.
2026-07-06 | The role of dupilumab in skin microbiome shifts in the Netherton genodermatosis: a case report and review of literature.
Skin dysbiosis plays a crucial role in inflammatory skin diseases, particularly in genodermatoses such as Netherton syndrome (NS). This case report aimed to investigate changes in the skin microbiome of a patient with Netherton syndrome before and during dupilumab therapy, with the goal of expanding the limited evidence currently available on this topic. We report the case of a 35-year-old woman diagnosed with NS at birth, who, prior to dupilumab therapy, presented with atopic dermatitis (AD), ichthyosis linearis circumflexa, and severe pruritus. Dupilumab therapy was initiated, and skin swabs were collected from lesional sites at three different time points: at baseline, after 1 month, and after 1 year of continuous dupilumab therapy. At baseline, a microbiome analysis revealed low microbial diversity with a predominance of Pantoea and Pseudomonas species. After 1 year, a significant increase in microbial diversity, with a predominance of Staphylococcus species and an increase in Malassezia species, was observed. Clinically, the patient experienced remission in parallel with these microbiome shifts. Post-treatment, the skin microbiome showed increased microbial diversity and re-establishment of beneficial commensals, more closely resembling healthy skin. The findings of this case report underscore the role of dupilumab in restoring a healthy skin microbiome along with symptomatological and clinical improvement in the genodermatosis Netherton syndrome.
2026-05-08 | Management of Netherton syndrome and hereditary angioedema with concurrent biologic therapy: a case report
Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, leading to impaired skin barrier function and severe atopic manifestations. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare autosomal dominant disorder characterised by recurrent bradykinin-mediated angioedema. Their coexistence has not previously been reported, and evidence on combined biologic therapy is lacking. We report a 30-year-old woman with confirmed NS and long-standing HAE-C1-INH presenting with severe pruritus, xerosis, widespread eczema, elevated IgE, eosinophilia, and trichorrhexis invaginata. Dupilumab was initiated to target T helper (Th)2-mediated inflammation. Due to persistent angioedema attacks despite prior prophylaxis, lanadelumab was introduced. Dupilumab improved eczema severity, hyperkeratosis, and hair abnormalities over 13 months. Lanadelumab reduced angioedema attacks by 88.50%, allowing dose spacing while maintaining disease control. No adverse effects or drug interactions were observed. This is the first reported case of NS and HAE-C1-INH successfully treated with dual biologic therapy. Targeting distinct immunological pathways simultaneously may represent an effective and safe strategy for complex rare disease phenotypes.
2026-01-30 | SPINK5 Variants Drive Clinical Variability in Netherton Syndrome Through Th2/Th17 Skewing and Influence Therapeutic Outcomes.
Netherton syndrome (NS) is a rare genetic disorder resulting from biallelic mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI). Although currently classified as a hyper-IgE syndrome, several manifestations contradict this categorization. Data on genotype-phenotype correlations remain limited, and pediatric outcomes of biologic therapies are inconsistent. This study investigated the clinical, immunological features, genotype-phenotype correlations, and pediatric outcomes of various systemic and biologic therapies in detail. Clinical, immunological, and treatment data from 8 patients were collected in a mixed retrospective-prospective design. Variants were categorized based on the affected bioreactive fragments (FR1-FR5) of the LEKTI protein. Among 6 SPINK5 variants, including 2 novel ones, 4 FR1-related variants were linked to severe phenotypes, whereas 2 FR5-related variants were associated with milder disease. The onset of skin features was significantly earlier in patients with allergic manifestations than in those without. Although no intrinsic developmental defects in T or B cells were identified, skin barrier disruption was associated with immune activation and skewing toward Th2/Th17 responses. Notably, increased programmed cell death protein-1 expression, expansion of CD4+IL-17+ T cells, and reduced frequencies of IFN-γ-producing CD4+ T cells correlated with clinical disease severity. In scaly erythroderma, secukinumab was most effective for scaling, whereas dupilumab was more effective for pruritus. The efficacy of dupilumab and infliximab was temporary, with rebound skin lesions observed during follow-up. Immunoglobulin therapy supported growth but revealed variable skin benefits. The described findings support the concept of indirect immune dysregulation in NS due to a defective skin barrier, emphasizing the need for therapies that extend beyond single cytokine or receptor blockade.
2026-01-05 | Netherton Syndrome: A Systematic Review of the Challenges of Diagnosis and Treatment.
Netherton syndrome is an autosomal recessive genodermatosis caused by biallelic mutations in the SPINK5 gene, a gene that codes for lymphoepithelial Kazal-type-related inhibitor 1 (LEKT1) protein. This disorder is characterized by erythroderma, ichthyosis, hair shaft abnormalities, and immune dysregulation. While there is increasing research and recognition of Netherton syndrome, much remains unknown, with limited knowledge of the history, manifestations, and responses to therapies. The purpose of this study was to review case reports of Netherton's to draw conclusions from patient demographics, symptoms, treatment, and outcomes. A systematic review of 30 case reports and clinical studies on Netherton syndrome was conducted, including only patient-level clinical data of studies in English. Data were extracted via full-text review, organized into comparative tables, and analyzed for common patterns in symptoms, diagnostic techniques, and treatments. Biologic therapies consistently reduced Netherton syndrome effects with improvements in symptoms and infection rates. No cases of complete remission have been reported from the cases examined. With no standardized treatment in place, larger studies are needed. While biologic therapies have offered improvement of symptoms for patients with Netherton syndrome, remission is still not achievable. Treatment outcomes are variable and require an individualized technique in patient care. Genetic testing is the most valuable for diagnosis, but it is not always accessible. Lack of standardized therapy exhibits a need for larger studies to be conducted in order to improve patient care.
gene therapies
2023-11-22 | Netherton Syndrome: Unraveling the Molecular Underpinnings of a Rare Epidermal Disorder
Netherton Syndrome (NS) is a rare and complex autosomal recessive genetic disorder that primarily affects the skin and hair, resulting in a spectrum of dermatological manifestations with profound clinical implications. This article aims to provide a comprehensive overview of NS, shedding light on its etiopathogenesis, clinical presentation, diagnostic modalities, and management strategies. A thorough exploration of the molecular intricacies underlying this condition reveals a captivating interplay of genetics, immunology, and epidermal biology. This syndrome, which arises from mutations in the SPINK5 gene encoding the serine protease inhibitor Kazal-type 5 (LEKTI), manifests with a triad of distinctive features: ichthyosis linearis circumflexa, atopic diathesis, and trichorrhexis invaginata. Notably, NS poses significant diagnostic challenges, and an early and accurate diagnosis is paramount for optimizing therapeutic outcomes. Advances in understanding the disease's pathophysiology have paved the way for innovative treatment modalities, ranging from topical emollients to emerging targeted therapies. This article also explores the ongoing research endeavors and the prospects of gene therapy in the management of NS. Netherton Syndrome remains an intriguing puzzle, with implications extending beyond dermatology, into the realms of immunology, genetics, and personalized medicine.
2022-11-01 | Establishment of a mouse model of Netherton syndrome based on CRISPR/Cas9 technology.
Netherton syndrome is a rare but severe autosomal recessive disorder with dominant impaired skin barrier function, caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, which encodes LEKTI (lymphoepithelial Kazal-type-related inhibitor). To establish a murine model of Netherton syndrome based on CRISPR/Cas9 gene editing technology. Spink5-sgRNA was designed to target exon 3 of the mouse Spink5 gene. Cas9 mRNA and sgRNA were microinjected into the zygotes of C57BL/6J mice. Spink5 homozygous knockout mice were born from a heterozygous intercross, and the phenotype of these mice was compared with wild-type regarding gross morphology, histopathology and immunofluorescent detection of LEKTI. Following microinjection of zygotes using the CRISPR/Cas9 system, sequencing demonstrated a 22-bp deletion at exon 3 of the mouse Spink5 gene. Histological investigation revealed complete detachment of the stratum corneum from the underlying granular layer and an absence of LEKTI in skin from Spink5 homozygous knockout mice. The 22-bp deleted Spink5 transgenic mouse model demonstrates the clinical phenotype and genotype of human Netherton syndrome, representing a useful tool for future gene correction and skin barrier/inflammation studies.
2022-03-01 | The Potential of CRISPR-Guided Therapies in the Dermatology Clinic
Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist. Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist.
2022-01-17 | Highly branched poly(β-amino ester)s for gene delivery in hereditary skin diseases.
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
2021-06-15 | Netherton Syndrome: Case Report and Review of the Literature
Netherton syndrome (NS) is a rare genodermatosis with an autosomal recessive pattern of inheritance caused by pathogenic variants in the SPINK5 gene. It is characterized by a triad consisting of atopic diathesis, ichthyosis linearis circumflexa, and hair shaft abnormalities. Ichthyosis linearis circumflexa can be confused with atopic dermatitis leading to a delayed diagnosis. Furthermore, difficulty in making the differential diagnosis with other atopiform, erythrodermic, and ichthyosiform entities that exhibit hair shaft abnormalities represent a challenge. Trichoscopy is an accessible and noninvasive auxiliary diagnostic tool in these cases; the hair shaft abnormalities found in NS are bamboo, golf tee, and matchstick hairs. Identification of a pathogenic variant in the SPINK5 gene through genetic testing is necessary to confirm the diagnosis. Multiple treatment options are available including topical therapy with emollients, corticosteroids, calcineurin inhibitors, antiseptics, and narrowband UVB phototherapy. Systemic treatments comprehend intravenous immunoglobulins, and advances in the understanding of the pathophysiology of NS have led to more directed therapies with biologics such as infliximab, ixekizumab, secukinumab, ustekinumab, and dupilumab. Treatments currently under investigation include inhibitors of kallikrein 5, cathelicidins, drugs activating the transcription factor nuclear factor erythroid-derived 2-like 2, and gene therapy using autologous keratinocytes induced with a lentiviral vector encoding SPINK5.
proteins
2026-01-01 | Relapses and Remissions of Netherton Syndrome in a Preadolescent Child- Letter to Editor
Dear Editor, A 9-year-old male child presented to the dermatology outpatient department with intensely pruritic dermatosis, along with sparse eyebrow hair. The mother reported that he developed scalp lesions at birth and subsequently disseminated intermittent eczematous plaques. Physical examination revealed erythematous and squamous plaques with double-edged desquamation showing polycyclic and serpiginous borders on the abdomen and left thigh [Figures 1,2]. Also, a lack of the external portion of the eyebrows was noted with few short and brittle hair predominantly in the occipital region [Figure 3]. On dermoscopy, polarised mode, 10x magnification of serpiginous borders of the abdominal plaque, incomplete double edged scales were evident [Figure 4]. Trichoscopy of the eyebrows showed bamboo hairs, golf tee and matchstick hairs; trichorrhexis invaginata was observed predominantly in the occipital region [Figure 5]. Laboratory findings were remarkable for peripheral eosinophilia and increased immunoglobulin E levels. The patient was given topical mild-potency corticosteroids, oral antihistamines.Figure 1: On clinical examination multiple red, scaly, annular to polycyclic plaques with incomplete advancing double edged scale were seen on the left thighFigure 2: On clinical examination multiple red, scaly, annular to polycyclic plaques with incomplete advancing double edged scale were seen on the abdomenFigure 3: On clinical examination of the face, sparse lateral one thirds of bilateral eyebrows were seenFigure 4: On dermoscopy, polarised mode, 10x magnification incomplete double edged scales were evident.Figure 5: On Trichoscopy of eyebrow hair, polarised mode,10x magnification, findings of Trichorrehxis invaginata was notedWith an incidence of one instance per 200,000 births, Netherton syndrome (NS) is an uncommon and potentially fatal autosomal recessive genodermatosis.[1,2] One of the hallmarks of NS is icthyosis linearis circumflexa (ILC), first reported in 1949 and is characterized by itchy, polycyclic erythematous patches with a double-edged circinate or serpiginous scale.[3] The bamboo hair (trichorrhexis invaginata), a pathognomonic hair abnormality of NS that was first identified by Netherton in 1958, is another characteristic.[4] It consists of an invagination of the hair shaft that gives the hair a “ball in cup” appearance.[5] Finally, atopic diathesis and the first two observations fit the well-known trio that was originally identified.[6] NS is a complex condition that can be difficult to diagnose due to its similarities with other skin disorders, such as atopic dermatitis. Fortunately, trichoscopy has emerged as a valuable diagnostic tool in these cases. This noninvasive technique allows clinicians to examine hair and skin features in greater detail, facilitating a more accurate diagnosis. In our case, trichoscopy helped in diagnosing Netherton syndrome by the trichoscopic presence of trichorrhexis invaginata. Declaration of patient consent The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s)/guardian(s) of the patient. In the form, the parent(s)/guardian(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child/children will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2025-10-23 | Immunological phenotype and skin modeling of Netherton syndrome.
Netherton syndrome (NTS) is a syndromic ichthyosis characterized by scaling, erythroderma, and proneness towards allergies and infections. It is caused by mutations in the SPINK5 gene, encoding the lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), which regulates the activity of kallikreins in the skin. Treatment options are limited, insufficient, time-consuming and a financial burden for the patients. In the last years, genotype-phenotype correlations in NTS and immunological phenotypes have been delineated. Psoriasiform patterns have been described. Moreover, the literature reports on biological therapies as novel therapeutic options in NTS. Previously, recombinant human LEKTI domain 8+9 (rhLEKTI 8+9) was identified as a potent kallikrein inhibitor, implying that these subunits are suitable for a topical protein substitution therapy. We aimed to characterize NTS in more detail to discuss further personalized therapeutic options by phenotyping a large cohort of NTS patients and performing serum analyses. Moreover, we worked on preliminary steps for a protein replacement therapy by investigating recombinant expressed rhLEKTI8+9 and establishing 3D epidermal equivalents for therapeutic evaluation.
2024-11-05 | Dual Challenges: Case Comparison of Children with Ichthyosis and Acute Leukemia
The coexistence of severe chronic diseases and acute leukemia can be a diagnostic and treatment challenge It requires a complex medical approach that includes not only precise diagnosis and treatment of both diseases, but also management of their mutual interactions. The presented cases show the possible impact of various genetic mutations of ichtyosis - related genes on the therapeutic process in acute lymphoblastic leukemia (ALL). The cases we compare have different genetic origins of ichthyosis: the first boy has a germline mutation of the SPINK5 gene (p.Cys510*)- Netherton syndrome, while the second has a mutation of the STS gene (p.Ala364Pro)- X-linked recessive ichthyosis (RXLI). It is worth emphasizing that in the second boy it is the first such mutation of the STS gene in the literature. The boys were diagnoses with leukemia at different ages (15 years vs. 2.5 years). The final diagnoses were: for the first boy - ALL, common type, L1 (45, XY, t(5; 18) (q35 ;q21), del(12)(pI3), -13 ,der(21 )add(21) (q22)[ 18]/46, XY, ETV6/RUNX1 fusion) and for the second boy - B-ALL, common type (karyotype 46,XY, JAK2 p.Arg683Gly, IL17RC p.Ala303Thr, NUP214 p.Arg815Gln).The first patient underwent therapy according to ALL IC-BFM 2009 HRG protocol (initial WBC 4.420/ul, CNS 3, 15th day MRD 11%, 33th day MRD neg) while the second boy was treated according to the ALL IC 2009 IRG protocol (initial WBC- 22.970/ul, CNS 1, 15th day MRD neg, 33th day MRD neg). The course of the diseases differed - the first suffered many notable complications during chemotherapy, mainly due to infections such as EBV, sinusitis, or multiple skin infections. Complications were worsened by chemotherapy including Mtx (dermatitis WHO grade IV), glucocorticoid-induced diabetes, hepatotoxicity, syndrome of inappropriate antidiuretic hormone secretion (SIADH). The second boy, on the other hand, developed complications typical for chemotherapy: severe thrombopenia requiring FFP and platelet transfusions, frequent upper respiratory tract infections, secondary immunodeficiency and glucocorticoid-induced Cushing's syndrome. The reason for the increased number of recorded infectious complications in the first boy was probably related to the Netherton syndrome (significant skin and mucosal barrier disruption, T and B lymphocyte maturation disorder, reduced cytotoxicity, defective thymic differentiation). The severity of skin lesions in both cases could also play a significant role. Both boys are currently in complete remission for 7 and 6 year. In available literature, only a few cases of X-linked ichtyosis complicated with ALL were reported, with no detailed genetic analysis. There might be no direct interplay between the mentioned mutations, however, some postulate that increased chromosome fragility of lymphocytes in ichtyosis may lead to higher incidence of leukemia in affected population. The similar pathogenesis is proposed in Netherton syndrome. Clot formation abnormalities were are more frequent in X-linked ichtyosis with higher predisposition to haemorrhagic complications. The described cases offer an important addition to the accumulated knowledge on the purported correlations between ichtyosis and leukemia and highlight the need for deeper molecular studies in patients with ichtyosis.
2022-07-19 | New developments in the molecular treatment of ichthyosis: review of the literature.
Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.
2022-06-02 | Phage Display Selected Cyclic Peptide Inhibitors of Kallikrein-Related Peptidases 5 and 7 and Their In Vivo Delivery to the Skin.
Kallikrein-related peptidases 5 (KLK5) and 7 (KLK7) are serine proteases with homeostatic functions in the epidermis that play a critical role in Netherton syndrome (NS), a rare yet life-threatening genetic disorder that currently lacks specific treatment. Previous research suggests that controlling KLKs could lead to the development of NS therapies, but existing synthetic inhibitors have limitations. Herein, we used phage display to screen libraries comprising more than 100 billion different cyclic peptides and found selective, high-affinity inhibitors of KLK5 (Ki = 2.2 ± 0.1 nM) and KLK7 (Ki = 16 ± 4 nM). By eliminating protease-prone sites and conjugating the inhibitors to an albumin-binding peptide, we enhanced the inhibitor stability and prolonged the elimination half-life to around 5 h in mice. In tissue sections taken from mice, a fluorescently labeled peptide was detected in the epidermis, suggesting that the inhibitors can reach the KLKs upon systemic delivery and should be suited to control deregulated protease activity in NS.
other
2026-05-06 | Bioengineering Game Changing Technology: a horizon scan of genetically engineered technologies
As the field of bioengineering continues to evolve rapidly, staying informed about promising technologies is essential for effectively applying new advancements to medical research and healthcare. This study used a novel, exploratory search method to generate a large number of results relevant to bioengineering. These terms were then first screened, cleaned, then grouped into clusters and visualised using VOSviewer, and finally those identified in VOSviewer as being particularly high frequency or new were further analysed by searching for applications in bibliographic databases and clinicaltrials.gov.Six keywords were identified using the novel methodology. The three most frequent were “CRISPR”, “microRNA” and “Saccharomyces cerevisiae”. Applications of these included using gene editing to alter the invasiveness of bladder cancer microtumours, using gene therapies to locally delivery microRNA (miRNA) to treat epilepsy, and S. cerevisiae being used to create therapeutics for immune support in Parkinson’s disease.The three keywords defined as newest were “Staphylococcus epidermidis”, “arginine” and “Herpesviridae”. Applications of these included an engineered S. epidermidis strain for the treatment of Netherton syndrome, engineering CAR-T cells to make their own arginine to attack cancer cells, and genetically altered herpes simplex virus to treat bladder cancer. This horizon scan used a new method to identify technologies with the potential to provide new solutions to unmet needs within genetic engineering. Some technologies could have important roles in addressing important national issues, such as antimicrobial resistance, and help to give patients access to more personalised medical care. This study demonstrates the utility of a novel horizon-scanning method to identify transformative genetic engineering technologies. These findings could inform policy, funding, and research priorities, ultimately improving patient access to innovative healthcare solutions.
2024-10-30 | Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome.
Netherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency. Vaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls. None of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls. Vaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.
2024-01-17 | Unique Usages of Dehydrated Human Amnion Chorion Membrane Allografts in Dermatology.
Dehydrated human amnion chorion membrane (dHACM) allografts are synthetic skin substitutes derived from placental tissue. dHACM allografts are used for replacing lost or damaged dermal tissue, as they contain many of the components found within the extracellular matrix that are beneficial in wound healing. Common uses of dHACM allografts include the healing of diabetic and non-diabetic foot and leg ulcers, decubitus ulcers, and wounds following debridement. While these grafts have been proven to be beneficial in other disciplines of medicine, their potential for use in the field of dermatology is emerging. Current clinical cases and research have shown dHACM allografts to be beneficial in repairing damaged tissue due to dermatologic conditions. They could play a role in the treatment of conditions causing chronic wounds, including dermal scarring or loss, and the repair of fragile skin. Examples of dHACM allograft use in dermatology include cases of pyoderma gangrenosum, Netherton syndrome, and wound healing with Mohs micrographic surgery. This literature review explores the efficacy of using dHACM allografts for the treatment of healing wounds within the field of dermatology. J Drugs Dermatol. 2023;22(12):1228-1231. doi:10.36849/JDD.7115.
2022-09-01 | Controlling skin microbiome as a new bacteriotherapy for inflammatory skin diseases
The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.
2022-08-29 | Multiscale modelling of desquamation in the interfollicular epidermis
Maintenance of epidermal thickness is critical to the barrier function of the skin. Decreased tissue thickness, specifically in the stratum corneum (the outermost layer of the tissue), causes discomfort and inflammation, and is related to several severe diseases of the tissue. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell proliferation in the epidermis occurs in the basal layer and causes constant upwards movement in the tissue. Cell loss occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Desquamation is thought to occur through a gradual reduction in adhesion between cells, due to the cleaving of adhesion proteins by enzymes, in the stratum corneum. In this paper we will investigate combining a (mass action) subcellular model of desquamation with a three dimensional (cell centre based) multicellular model of the interfollicular epidermis to better understand maintenance of epidermal thickness. These investigations show that hypothesised biological models for the degradation of cell-cell adhesion from the literature are able to provide a consistent rate of cell loss in the multicellular model. This loss balances proliferation, and hence maintains a homeostatic tissue thickness. Moreover, we find that multiple proliferative cell populations in the basal layer can be represented by a single proliferative cell population, simplifying investigations with this model. The model is used to investigate a disorder (Netherton Syndrome) which disrupts desquamation. The model shows how biochemical changes can cause disruptions to the tissue, resulting in a reduced tissue thickness and consequently diminishing the protective role of the tissue. A hypothetical treatment result is also investigated. [ABR]
small molecules
2026-06-01 | What treatment strategies are described in case reports for managing skin manifestations in patients with Netherton syndrome?
Case reports describe a range of treatment strategies for managing skin manifestations in Netherton syndrome, including topical agents and systemic therapies such as biologics and immunoglobulins, although evidence is limited and variable in efficacy.
2026-05-18 | Squamous Cell Carcinoma of the External Auditory Canal in a Patient with Netherton Syndrome.
Netherton syndrome is a rare autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities, atopic diathesis, and a broad spectrum of immunologic dysfunction. Although cutaneous malignancies are uncommon, affected individuals may develop early-onset tumors that can pose diagnostic and therapeutic challenges. We report the case of a 33-year-old woman with Netherton syndrome who presented with persistent left otorrhea and a granulomatous mass in the external auditory canal. Imaging demonstrated a soft-tissue lesion with focal bony erosion and suspected dural involvement, accompanied by fluorodeoxyglucose uptake in a cervical lymph node. Biopsy confirmed squamous cell carcinoma (SCC), staged as T4N1M0. The patient underwent superselective intra-arterial cisplatin infusion combined with radiotherapy, resulting in complete remission of both the primary lesion and nodal metastasis, with no evidence of recurrence over 4 years. Including this case, 9 patients with Netherton syndrome and cutaneous malignancies have been reported, with tumors frequently arising at a young age and showing variable HPV status. Interpretation of SCC antigen may be complicated by elevations associated with atopic dermatitis. This case highlights the elevated risk of cutaneous malignancies in Netherton syndrome and underscores the need for long-term surveillance and multidisciplinary care.
2026-01-01 | Incomplete Netherton Syndrome treated successfully with Isotretinoin
Netherton syndrome is a rare autosomal recessive ichthyosis caused by serine peptidase inhibitor Kazal 5 mutation, characterized by congenital ichthyosis, trichorrhexis invaginata, atopy, high serum immunoglobulin E levels, and hyper eosinophilia. The demonstration of bamboo hair by microscopy is used as a method to diagnose Netherton syndrome. We report a rare patient with Netherton syndrome confirmed by genetic analysis and protein expression studies who had normal hair and was successfully treated with low dose isotretinoin, without any adverse events.
2026-01-01 | Use of Janus Kinase Inhibitors in the Treatment of Genodermatoses: A Systematic Review
Introduction Genodermatoses are rare inherited skin disorders with limited treatment options. Emerging evidence suggests Janus kinase (JAK) inhibitors may offer therapeutic benefits by modulating underlying immune and inflammatory pathways. This study aims to systematically review the efficacy and safety of JAK inhibitors in treating genodermatoses, including epidermolysis bullosa (EB), Netherton syndrome, and Hailey‐Hailey disease. Methods A comprehensive literature search identified case reports and series evaluating JAK inhibitor therapy in genodermatoses. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal Tools for Case Reports, demonstrating high methodological quality across included studies. Results Twenty studies involving patients with EB subtypes (especially dystrophic EB), Netherton syndrome, and other inherited dermatoses reported clinical improvement following treatment with JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib. Outcomes included reduction in pruritus, skin inflammation, and lesion severity, with notable improvements in quality‐of‐life measures. Treatment regimens varied (e.g., tofacitinib 5 mg twice daily, baricitinib 2 mg once daily, and upadacitinib 15 mg once daily) with follow‐up ranging from weeks to months. Laboratory monitoring showed stable profiles without significant adverse events. Reports of adverse events were rare or absent across studies, indicating favorable safety profiles. Conclusions JAK inhibitors represent a promising therapeutic avenue for genodermatoses characterized by immune dysregulation and chronic inflammation. While preliminary data are encouraging, further controlled studies are warranted to establish long‐term efficacy and safety. These findings support expanded clinical investigation of JAK inhibition in managing inherited skin disorders.
2025-11-11 | LEKTI-Grafted Sunflower Trypsin Inhibitor: A Potential Therapeutic for Skin Diseases.
Kallikrein 5 (KLK5) is a serine protease expressed in the outer skin layers, where it regulates the barrier function by cleaving desmosomal proteins. Elevated KLK5 causes excessive proteolysis, leading to corneocyte overdesquamation and barrier compromise. Increased KLK5 activity has been linked to atopic dermatitis (AD), a chronic inflammatory disease affecting up to 20% of children, highlighting the need for therapies that restore barrier integrity. While many serine protease inhibitors have been developed, most lack KLK5 selectivity. To address this, novel analogues of the sunflower trypsin inhibitor were designed and evaluated. Lead 7 emerged as a potent (IC50 = 14 ± 4 nM; Ki = 11 nM) selective KLK5 inhibitor. In keratinocytes from a Netherton syndrome patient, lead 7 significantly reduced the KLK5 activity and improved epithelial barrier integrity, as shown by transepithelial electrical resistance. These findings suggest lead 7 as a potential therapy for AD and other conditions with elevated KLK5 activity.
antibodies
2026-09-03 | Paired blood-skin transcriptomic profiling during dupilumab treatment of SPINK5-FLG-mutated Netherton syndrome
Netherton syndrome (NS) is a rare congenital barrier disorder caused by pathogenic variation in SPINK5, resulting in severe epidermal dysfunction and immune dysregulation. Although dupilumab is increasingly used in NS, molecular data describing treatment-associated tissue responses remain limited, particularly in genetically complex presentations. We investigated treatment-associated molecular trajectories during IL-4Rα blockade in two siblings with NS carrying heterozygous compound SPINK5 (c.2468dup & c.2243 A > G) and FLG (p.Arg501*) variants. Longitudinal whole-exome sequencing and paired bulk RNA sequencing of peripheral blood and lesional skin were performed before and after six months of dupilumab therapy. Transcriptomic changes were evaluated using effect-size– and rank-based approaches and contextualized through integration with publicly available NS reference datasets. Across both compartments, post-treatment transcriptional profiles exhibit coordinated shifts toward healthy-control–like expression states. Blood transcriptomes show reduced inflammatory, metabolic, and proliferative signatures alongside modulation of FURIN and increase expression of PAPPA, LPAR5, CELSR1, and ARHGEF19. Skin transcriptomes transition from neurosensory and follicular programs toward lipid metabolic organization, keratinocyte differentiation, and cornified-envelope–associated pathways. Cross-compartment integration highlights shared treatment-associated transcripts, including ADAM23, and candidate markers of immune–epithelial recalibration. Together, this exploratory dual-compartment longitudinal analysis provides rare molecular insight into biologic treatment response in a genetically complex NS context and establishes a foundational reference for future genotype-informed and biomarker-oriented studies. Netherton syndrome is a rare inherited skin disorder that causes severe inflammation and a weakened protective skin barrier. Although dupilumab is increasingly being used to treat this condition, its effects on the underlying biological mechanisms are not yet fully understood. To investigate this, we studied two siblings with Netherton syndrome and analyzed blood and skin samples collected before treatment and after six months of therapy. We found that dupilumab was associated with reduced inflammatory activity and gene expression patterns that became more similar to those seen in healthy individuals. These findings suggest that dupilumab may help restore both immune balance and skin barrier function, providing new insight into its mechanism of action and supporting the development of more personalized treatment strategies for people with Netherton syndrome. Bajo-Santos et al. longitudinally profile blood and skin transcriptomes before and after dupilumab treatment in two siblings with genetically complex Netherton syndrome. They observe that IL-4Rα blockade shifts molecular signatures toward healthy-like states, reducing inflammation and promoting epidermal differentiation and barrier-repair pathways.
2026-07-06 | The role of dupilumab in skin microbiome shifts in the Netherton genodermatosis: a case report and review of literature.
Skin dysbiosis plays a crucial role in inflammatory skin diseases, particularly in genodermatoses such as Netherton syndrome (NS). This case report aimed to investigate changes in the skin microbiome of a patient with Netherton syndrome before and during dupilumab therapy, with the goal of expanding the limited evidence currently available on this topic. We report the case of a 35-year-old woman diagnosed with NS at birth, who, prior to dupilumab therapy, presented with atopic dermatitis (AD), ichthyosis linearis circumflexa, and severe pruritus. Dupilumab therapy was initiated, and skin swabs were collected from lesional sites at three different time points: at baseline, after 1 month, and after 1 year of continuous dupilumab therapy. At baseline, a microbiome analysis revealed low microbial diversity with a predominance of Pantoea and Pseudomonas species. After 1 year, a significant increase in microbial diversity, with a predominance of Staphylococcus species and an increase in Malassezia species, was observed. Clinically, the patient experienced remission in parallel with these microbiome shifts. Post-treatment, the skin microbiome showed increased microbial diversity and re-establishment of beneficial commensals, more closely resembling healthy skin. The findings of this case report underscore the role of dupilumab in restoring a healthy skin microbiome along with symptomatological and clinical improvement in the genodermatosis Netherton syndrome.
2026-05-08 | Management of Netherton syndrome and hereditary angioedema with concurrent biologic therapy: a case report
Netherton syndrome (NS) is a rare autosomal recessive disorder caused by SPINK5 mutations, leading to impaired skin barrier function and severe atopic manifestations. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare autosomal dominant disorder characterised by recurrent bradykinin-mediated angioedema. Their coexistence has not previously been reported, and evidence on combined biologic therapy is lacking. We report a 30-year-old woman with confirmed NS and long-standing HAE-C1-INH presenting with severe pruritus, xerosis, widespread eczema, elevated IgE, eosinophilia, and trichorrhexis invaginata. Dupilumab was initiated to target T helper (Th)2-mediated inflammation. Due to persistent angioedema attacks despite prior prophylaxis, lanadelumab was introduced. Dupilumab improved eczema severity, hyperkeratosis, and hair abnormalities over 13 months. Lanadelumab reduced angioedema attacks by 88.50%, allowing dose spacing while maintaining disease control. No adverse effects or drug interactions were observed. This is the first reported case of NS and HAE-C1-INH successfully treated with dual biologic therapy. Targeting distinct immunological pathways simultaneously may represent an effective and safe strategy for complex rare disease phenotypes.
2026-01-30 | SPINK5 Variants Drive Clinical Variability in Netherton Syndrome Through Th2/Th17 Skewing and Influence Therapeutic Outcomes.
Netherton syndrome (NS) is a rare genetic disorder resulting from biallelic mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI). Although currently classified as a hyper-IgE syndrome, several manifestations contradict this categorization. Data on genotype-phenotype correlations remain limited, and pediatric outcomes of biologic therapies are inconsistent. This study investigated the clinical, immunological features, genotype-phenotype correlations, and pediatric outcomes of various systemic and biologic therapies in detail. Clinical, immunological, and treatment data from 8 patients were collected in a mixed retrospective-prospective design. Variants were categorized based on the affected bioreactive fragments (FR1-FR5) of the LEKTI protein. Among 6 SPINK5 variants, including 2 novel ones, 4 FR1-related variants were linked to severe phenotypes, whereas 2 FR5-related variants were associated with milder disease. The onset of skin features was significantly earlier in patients with allergic manifestations than in those without. Although no intrinsic developmental defects in T or B cells were identified, skin barrier disruption was associated with immune activation and skewing toward Th2/Th17 responses. Notably, increased programmed cell death protein-1 expression, expansion of CD4+IL-17+ T cells, and reduced frequencies of IFN-γ-producing CD4+ T cells correlated with clinical disease severity. In scaly erythroderma, secukinumab was most effective for scaling, whereas dupilumab was more effective for pruritus. The efficacy of dupilumab and infliximab was temporary, with rebound skin lesions observed during follow-up. Immunoglobulin therapy supported growth but revealed variable skin benefits. The described findings support the concept of indirect immune dysregulation in NS due to a defective skin barrier, emphasizing the need for therapies that extend beyond single cytokine or receptor blockade.
2026-01-05 | Netherton Syndrome: A Systematic Review of the Challenges of Diagnosis and Treatment.
Netherton syndrome is an autosomal recessive genodermatosis caused by biallelic mutations in the SPINK5 gene, a gene that codes for lymphoepithelial Kazal-type-related inhibitor 1 (LEKT1) protein. This disorder is characterized by erythroderma, ichthyosis, hair shaft abnormalities, and immune dysregulation. While there is increasing research and recognition of Netherton syndrome, much remains unknown, with limited knowledge of the history, manifestations, and responses to therapies. The purpose of this study was to review case reports of Netherton's to draw conclusions from patient demographics, symptoms, treatment, and outcomes. A systematic review of 30 case reports and clinical studies on Netherton syndrome was conducted, including only patient-level clinical data of studies in English. Data were extracted via full-text review, organized into comparative tables, and analyzed for common patterns in symptoms, diagnostic techniques, and treatments. Biologic therapies consistently reduced Netherton syndrome effects with improvements in symptoms and infection rates. No cases of complete remission have been reported from the cases examined. With no standardized treatment in place, larger studies are needed. While biologic therapies have offered improvement of symptoms for patients with Netherton syndrome, remission is still not achievable. Treatment outcomes are variable and require an individualized technique in patient care. Genetic testing is the most valuable for diagnosis, but it is not always accessible. Lack of standardized therapy exhibits a need for larger studies to be conducted in order to improve patient care.
gene therapies
2023-11-22 | Netherton Syndrome: Unraveling the Molecular Underpinnings of a Rare Epidermal Disorder
Netherton Syndrome (NS) is a rare and complex autosomal recessive genetic disorder that primarily affects the skin and hair, resulting in a spectrum of dermatological manifestations with profound clinical implications. This article aims to provide a comprehensive overview of NS, shedding light on its etiopathogenesis, clinical presentation, diagnostic modalities, and management strategies. A thorough exploration of the molecular intricacies underlying this condition reveals a captivating interplay of genetics, immunology, and epidermal biology. This syndrome, which arises from mutations in the SPINK5 gene encoding the serine protease inhibitor Kazal-type 5 (LEKTI), manifests with a triad of distinctive features: ichthyosis linearis circumflexa, atopic diathesis, and trichorrhexis invaginata. Notably, NS poses significant diagnostic challenges, and an early and accurate diagnosis is paramount for optimizing therapeutic outcomes. Advances in understanding the disease's pathophysiology have paved the way for innovative treatment modalities, ranging from topical emollients to emerging targeted therapies. This article also explores the ongoing research endeavors and the prospects of gene therapy in the management of NS. Netherton Syndrome remains an intriguing puzzle, with implications extending beyond dermatology, into the realms of immunology, genetics, and personalized medicine.
2022-11-01 | Establishment of a mouse model of Netherton syndrome based on CRISPR/Cas9 technology.
Netherton syndrome is a rare but severe autosomal recessive disorder with dominant impaired skin barrier function, caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, which encodes LEKTI (lymphoepithelial Kazal-type-related inhibitor). To establish a murine model of Netherton syndrome based on CRISPR/Cas9 gene editing technology. Spink5-sgRNA was designed to target exon 3 of the mouse Spink5 gene. Cas9 mRNA and sgRNA were microinjected into the zygotes of C57BL/6J mice. Spink5 homozygous knockout mice were born from a heterozygous intercross, and the phenotype of these mice was compared with wild-type regarding gross morphology, histopathology and immunofluorescent detection of LEKTI. Following microinjection of zygotes using the CRISPR/Cas9 system, sequencing demonstrated a 22-bp deletion at exon 3 of the mouse Spink5 gene. Histological investigation revealed complete detachment of the stratum corneum from the underlying granular layer and an absence of LEKTI in skin from Spink5 homozygous knockout mice. The 22-bp deleted Spink5 transgenic mouse model demonstrates the clinical phenotype and genotype of human Netherton syndrome, representing a useful tool for future gene correction and skin barrier/inflammation studies.
2022-03-01 | The Potential of CRISPR-Guided Therapies in the Dermatology Clinic
Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist. Over the past decade, CRISPR has rapidly made its way from the bench to the bedside, providing a newfound therapeutic avenue to not only treat genetic diseases but also permanently cure them. Although there are several clinical trials in early stages, there are so far no CRISPR-based clinical trials for cutaneous disease. In this review, we describe multiple cutaneous diseases that represent ideal targets for CRISPR-based therapeutics owing to known single gene‒causing mutations. We also explore the potential of CRISPR nucleases to treat inflammatory disorders such as eczema and psoriasis, which are not classically categorized as genodermatoses. We describe the therapeutic solutions for these diseases that are guided by various CRISPR-associated (Cas) effector proteins, for example, using Cas9 to permanently edit the DNA of somatic cells, Cas3 to target foreign DNA to combat viral/bacterial skin infections, and Cas13 to edit mutated RNA transcripts in diseases where permanent DNA editing is untenable. Furthermore, we discuss various drug delivery modalities for CRISPR therapeutics, including transdermal patches and microneedles, which are uniquely suited for dermatological diseases. In summary, we highlight the potential of CRISPR-based therapeutics to revolutionize the treatment of cutaneous disease with a goal of being accessible to the practicing dermatologist.
2022-01-17 | Highly branched poly(β-amino ester)s for gene delivery in hereditary skin diseases.
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
2021-06-15 | Netherton Syndrome: Case Report and Review of the Literature
Netherton syndrome (NS) is a rare genodermatosis with an autosomal recessive pattern of inheritance caused by pathogenic variants in the SPINK5 gene. It is characterized by a triad consisting of atopic diathesis, ichthyosis linearis circumflexa, and hair shaft abnormalities. Ichthyosis linearis circumflexa can be confused with atopic dermatitis leading to a delayed diagnosis. Furthermore, difficulty in making the differential diagnosis with other atopiform, erythrodermic, and ichthyosiform entities that exhibit hair shaft abnormalities represent a challenge. Trichoscopy is an accessible and noninvasive auxiliary diagnostic tool in these cases; the hair shaft abnormalities found in NS are bamboo, golf tee, and matchstick hairs. Identification of a pathogenic variant in the SPINK5 gene through genetic testing is necessary to confirm the diagnosis. Multiple treatment options are available including topical therapy with emollients, corticosteroids, calcineurin inhibitors, antiseptics, and narrowband UVB phototherapy. Systemic treatments comprehend intravenous immunoglobulins, and advances in the understanding of the pathophysiology of NS have led to more directed therapies with biologics such as infliximab, ixekizumab, secukinumab, ustekinumab, and dupilumab. Treatments currently under investigation include inhibitors of kallikrein 5, cathelicidins, drugs activating the transcription factor nuclear factor erythroid-derived 2-like 2, and gene therapy using autologous keratinocytes induced with a lentiviral vector encoding SPINK5.
proteins
2026-01-01 | Relapses and Remissions of Netherton Syndrome in a Preadolescent Child- Letter to Editor
Dear Editor, A 9-year-old male child presented to the dermatology outpatient department with intensely pruritic dermatosis, along with sparse eyebrow hair. The mother reported that he developed scalp lesions at birth and subsequently disseminated intermittent eczematous plaques. Physical examination revealed erythematous and squamous plaques with double-edged desquamation showing polycyclic and serpiginous borders on the abdomen and left thigh [Figures 1,2]. Also, a lack of the external portion of the eyebrows was noted with few short and brittle hair predominantly in the occipital region [Figure 3]. On dermoscopy, polarised mode, 10x magnification of serpiginous borders of the abdominal plaque, incomplete double edged scales were evident [Figure 4]. Trichoscopy of the eyebrows showed bamboo hairs, golf tee and matchstick hairs; trichorrhexis invaginata was observed predominantly in the occipital region [Figure 5]. Laboratory findings were remarkable for peripheral eosinophilia and increased immunoglobulin E levels. The patient was given topical mild-potency corticosteroids, oral antihistamines.Figure 1: On clinical examination multiple red, scaly, annular to polycyclic plaques with incomplete advancing double edged scale were seen on the left thighFigure 2: On clinical examination multiple red, scaly, annular to polycyclic plaques with incomplete advancing double edged scale were seen on the abdomenFigure 3: On clinical examination of the face, sparse lateral one thirds of bilateral eyebrows were seenFigure 4: On dermoscopy, polarised mode, 10x magnification incomplete double edged scales were evident.Figure 5: On Trichoscopy of eyebrow hair, polarised mode,10x magnification, findings of Trichorrehxis invaginata was notedWith an incidence of one instance per 200,000 births, Netherton syndrome (NS) is an uncommon and potentially fatal autosomal recessive genodermatosis.[1,2] One of the hallmarks of NS is icthyosis linearis circumflexa (ILC), first reported in 1949 and is characterized by itchy, polycyclic erythematous patches with a double-edged circinate or serpiginous scale.[3] The bamboo hair (trichorrhexis invaginata), a pathognomonic hair abnormality of NS that was first identified by Netherton in 1958, is another characteristic.[4] It consists of an invagination of the hair shaft that gives the hair a “ball in cup” appearance.[5] Finally, atopic diathesis and the first two observations fit the well-known trio that was originally identified.[6] NS is a complex condition that can be difficult to diagnose due to its similarities with other skin disorders, such as atopic dermatitis. Fortunately, trichoscopy has emerged as a valuable diagnostic tool in these cases. This noninvasive technique allows clinicians to examine hair and skin features in greater detail, facilitating a more accurate diagnosis. In our case, trichoscopy helped in diagnosing Netherton syndrome by the trichoscopic presence of trichorrhexis invaginata. Declaration of patient consent The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s)/guardian(s) of the patient. In the form, the parent(s)/guardian(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child/children will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2025-10-23 | Immunological phenotype and skin modeling of Netherton syndrome.
Netherton syndrome (NTS) is a syndromic ichthyosis characterized by scaling, erythroderma, and proneness towards allergies and infections. It is caused by mutations in the SPINK5 gene, encoding the lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), which regulates the activity of kallikreins in the skin. Treatment options are limited, insufficient, time-consuming and a financial burden for the patients. In the last years, genotype-phenotype correlations in NTS and immunological phenotypes have been delineated. Psoriasiform patterns have been described. Moreover, the literature reports on biological therapies as novel therapeutic options in NTS. Previously, recombinant human LEKTI domain 8+9 (rhLEKTI 8+9) was identified as a potent kallikrein inhibitor, implying that these subunits are suitable for a topical protein substitution therapy. We aimed to characterize NTS in more detail to discuss further personalized therapeutic options by phenotyping a large cohort of NTS patients and performing serum analyses. Moreover, we worked on preliminary steps for a protein replacement therapy by investigating recombinant expressed rhLEKTI8+9 and establishing 3D epidermal equivalents for therapeutic evaluation.
2024-11-05 | Dual Challenges: Case Comparison of Children with Ichthyosis and Acute Leukemia
The coexistence of severe chronic diseases and acute leukemia can be a diagnostic and treatment challenge It requires a complex medical approach that includes not only precise diagnosis and treatment of both diseases, but also management of their mutual interactions. The presented cases show the possible impact of various genetic mutations of ichtyosis - related genes on the therapeutic process in acute lymphoblastic leukemia (ALL). The cases we compare have different genetic origins of ichthyosis: the first boy has a germline mutation of the SPINK5 gene (p.Cys510*)- Netherton syndrome, while the second has a mutation of the STS gene (p.Ala364Pro)- X-linked recessive ichthyosis (RXLI). It is worth emphasizing that in the second boy it is the first such mutation of the STS gene in the literature. The boys were diagnoses with leukemia at different ages (15 years vs. 2.5 years). The final diagnoses were: for the first boy - ALL, common type, L1 (45, XY, t(5; 18) (q35 ;q21), del(12)(pI3), -13 ,der(21 )add(21) (q22)[ 18]/46, XY, ETV6/RUNX1 fusion) and for the second boy - B-ALL, common type (karyotype 46,XY, JAK2 p.Arg683Gly, IL17RC p.Ala303Thr, NUP214 p.Arg815Gln).The first patient underwent therapy according to ALL IC-BFM 2009 HRG protocol (initial WBC 4.420/ul, CNS 3, 15th day MRD 11%, 33th day MRD neg) while the second boy was treated according to the ALL IC 2009 IRG protocol (initial WBC- 22.970/ul, CNS 1, 15th day MRD neg, 33th day MRD neg). The course of the diseases differed - the first suffered many notable complications during chemotherapy, mainly due to infections such as EBV, sinusitis, or multiple skin infections. Complications were worsened by chemotherapy including Mtx (dermatitis WHO grade IV), glucocorticoid-induced diabetes, hepatotoxicity, syndrome of inappropriate antidiuretic hormone secretion (SIADH). The second boy, on the other hand, developed complications typical for chemotherapy: severe thrombopenia requiring FFP and platelet transfusions, frequent upper respiratory tract infections, secondary immunodeficiency and glucocorticoid-induced Cushing's syndrome. The reason for the increased number of recorded infectious complications in the first boy was probably related to the Netherton syndrome (significant skin and mucosal barrier disruption, T and B lymphocyte maturation disorder, reduced cytotoxicity, defective thymic differentiation). The severity of skin lesions in both cases could also play a significant role. Both boys are currently in complete remission for 7 and 6 year. In available literature, only a few cases of X-linked ichtyosis complicated with ALL were reported, with no detailed genetic analysis. There might be no direct interplay between the mentioned mutations, however, some postulate that increased chromosome fragility of lymphocytes in ichtyosis may lead to higher incidence of leukemia in affected population. The similar pathogenesis is proposed in Netherton syndrome. Clot formation abnormalities were are more frequent in X-linked ichtyosis with higher predisposition to haemorrhagic complications. The described cases offer an important addition to the accumulated knowledge on the purported correlations between ichtyosis and leukemia and highlight the need for deeper molecular studies in patients with ichtyosis.
2022-07-19 | New developments in the molecular treatment of ichthyosis: review of the literature.
Ichthyosis covers a wide spectrum of diseases affecting the cornification of the skin. In recent years, new advances in understanding the pathophysiology of ichthyosis have been made. This knowledge, combined with constant development of pathogenesis-based therapies, such as protein replacement therapy and gene therapy, are rather promising for patients with inherited skin diseases. Several ongoing trials are investigating the potency of these new approaches and various studies have already been published. Furthermore, a lot of case series report that biological therapeutics are effective treatment options, mainly for Netherton syndrome and autosomal recessive congenital ichthyosis. It is expected that some of these new therapies will prove their efficacy and will be incorporated in the treatment of ichthyosis.
2022-06-02 | Phage Display Selected Cyclic Peptide Inhibitors of Kallikrein-Related Peptidases 5 and 7 and Their In Vivo Delivery to the Skin.
Kallikrein-related peptidases 5 (KLK5) and 7 (KLK7) are serine proteases with homeostatic functions in the epidermis that play a critical role in Netherton syndrome (NS), a rare yet life-threatening genetic disorder that currently lacks specific treatment. Previous research suggests that controlling KLKs could lead to the development of NS therapies, but existing synthetic inhibitors have limitations. Herein, we used phage display to screen libraries comprising more than 100 billion different cyclic peptides and found selective, high-affinity inhibitors of KLK5 (Ki = 2.2 ± 0.1 nM) and KLK7 (Ki = 16 ± 4 nM). By eliminating protease-prone sites and conjugating the inhibitors to an albumin-binding peptide, we enhanced the inhibitor stability and prolonged the elimination half-life to around 5 h in mice. In tissue sections taken from mice, a fluorescently labeled peptide was detected in the epidermis, suggesting that the inhibitors can reach the KLKs upon systemic delivery and should be suited to control deregulated protease activity in NS.
other
2026-05-06 | Bioengineering Game Changing Technology: a horizon scan of genetically engineered technologies
As the field of bioengineering continues to evolve rapidly, staying informed about promising technologies is essential for effectively applying new advancements to medical research and healthcare. This study used a novel, exploratory search method to generate a large number of results relevant to bioengineering. These terms were then first screened, cleaned, then grouped into clusters and visualised using VOSviewer, and finally those identified in VOSviewer as being particularly high frequency or new were further analysed by searching for applications in bibliographic databases and clinicaltrials.gov.Six keywords were identified using the novel methodology. The three most frequent were “CRISPR”, “microRNA” and “Saccharomyces cerevisiae”. Applications of these included using gene editing to alter the invasiveness of bladder cancer microtumours, using gene therapies to locally delivery microRNA (miRNA) to treat epilepsy, and S. cerevisiae being used to create therapeutics for immune support in Parkinson’s disease.The three keywords defined as newest were “Staphylococcus epidermidis”, “arginine” and “Herpesviridae”. Applications of these included an engineered S. epidermidis strain for the treatment of Netherton syndrome, engineering CAR-T cells to make their own arginine to attack cancer cells, and genetically altered herpes simplex virus to treat bladder cancer. This horizon scan used a new method to identify technologies with the potential to provide new solutions to unmet needs within genetic engineering. Some technologies could have important roles in addressing important national issues, such as antimicrobial resistance, and help to give patients access to more personalised medical care. This study demonstrates the utility of a novel horizon-scanning method to identify transformative genetic engineering technologies. These findings could inform policy, funding, and research priorities, ultimately improving patient access to innovative healthcare solutions.
2024-10-30 | Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome.
Netherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency. Vaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls. None of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls. Vaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.
2024-01-17 | Unique Usages of Dehydrated Human Amnion Chorion Membrane Allografts in Dermatology.
Dehydrated human amnion chorion membrane (dHACM) allografts are synthetic skin substitutes derived from placental tissue. dHACM allografts are used for replacing lost or damaged dermal tissue, as they contain many of the components found within the extracellular matrix that are beneficial in wound healing. Common uses of dHACM allografts include the healing of diabetic and non-diabetic foot and leg ulcers, decubitus ulcers, and wounds following debridement. While these grafts have been proven to be beneficial in other disciplines of medicine, their potential for use in the field of dermatology is emerging. Current clinical cases and research have shown dHACM allografts to be beneficial in repairing damaged tissue due to dermatologic conditions. They could play a role in the treatment of conditions causing chronic wounds, including dermal scarring or loss, and the repair of fragile skin. Examples of dHACM allograft use in dermatology include cases of pyoderma gangrenosum, Netherton syndrome, and wound healing with Mohs micrographic surgery. This literature review explores the efficacy of using dHACM allografts for the treatment of healing wounds within the field of dermatology. J Drugs Dermatol. 2023;22(12):1228-1231. doi:10.36849/JDD.7115.
2022-09-01 | Controlling skin microbiome as a new bacteriotherapy for inflammatory skin diseases
The skin serves as the interface between the human body and the environment and interacts with the microbial community. The skin microbiota consists of microorganisms, such as bacteria, fungi, mites, and viruses, and they fluctuate depending on the microenvironment defined by anatomical location and physiological function. The balance of interactions between the host and microbiota plays a pivotal role in the orchestration of skin homeostasis; however, the disturbance of the balance due to an alteration in the microbial communities, namely, dysbiosis, leads to various skin disorders. Recent developments in sequencing technology have provided new insights into the structure and function of skin microbial communities. Based on high-throughput sequencing analysis, a growing body of evidence indicates that a new treatment using live bacteria, termed bacteriotherapy, is a feasible therapeutic option for cutaneous diseases caused by dysbiosis. In particular, the administration of specific bacterial strains has been investigated as an exclusionary treatment strategy against pathogens associated with chronic skin disorders, whereas the safety, efficacy, and sustainability of this therapeutic approach using isolated live bacteria need to be further explored. In this review, we summarize our current understanding of the skin microbiota, as well as therapeutic strategies using characterized strains of live bacteria for skin inflammatory diseases. The ecosystem formed by interactions between the host and skin microbial consortium is still largely unexplored; however, advances in our understanding of the function of the skin microbiota at the strain level will lead to the development of new therapeutic methods.
2022-08-29 | Multiscale modelling of desquamation in the interfollicular epidermis
Maintenance of epidermal thickness is critical to the barrier function of the skin. Decreased tissue thickness, specifically in the stratum corneum (the outermost layer of the tissue), causes discomfort and inflammation, and is related to several severe diseases of the tissue. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell proliferation in the epidermis occurs in the basal layer and causes constant upwards movement in the tissue. Cell loss occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Desquamation is thought to occur through a gradual reduction in adhesion between cells, due to the cleaving of adhesion proteins by enzymes, in the stratum corneum. In this paper we will investigate combining a (mass action) subcellular model of desquamation with a three dimensional (cell centre based) multicellular model of the interfollicular epidermis to better understand maintenance of epidermal thickness. These investigations show that hypothesised biological models for the degradation of cell-cell adhesion from the literature are able to provide a consistent rate of cell loss in the multicellular model. This loss balances proliferation, and hence maintains a homeostatic tissue thickness. Moreover, we find that multiple proliferative cell populations in the basal layer can be represented by a single proliferative cell population, simplifying investigations with this model. The model is used to investigate a disorder (Netherton Syndrome) which disrupts desquamation. The model shows how biochemical changes can cause disruptions to the tissue, resulting in a reduced tissue thickness and consequently diminishing the protective role of the tissue. A hypothetical treatment result is also investigated. [ABR]
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
12 orphan drug designations for Netherton syndrome.
12 orphan drug designations for Netherton syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
dupilumab | antibodies | FDA | Regeneron Pharmaceuticals, Inc. | |
dipalmitoyl hydroxyproline | small molecules | FDA | Quoin Pharmaceuticals, Ltd. | |
Dipalmitoyl hydroxyproline | small molecules | EMA | Quoin Therapeutics (Ireland) Limited | |
an engineered bacteria secreting a protease inhibitor that inhibit kallikrein 5 (KLK5) | other | FDA | — | ResVita Bio, Inc. |
Spesolimab-sbzo | antibodies | FDA | Boehringer Ingelheim Pharmaceuticals, Inc | |
a fusion protein comprised of genetically engineered human serine peptidase inhibitor and human immunoglobulin G1 Fc | proteins | FDA | Daiichi Sankyo, Inc. | |
(S)-2-isobutyrylamino-pentanedioic acid 5-amide 1-{[(2s,5s,8s,11r,12s,15s,18s,21r)-2,8-bis-((S)-sec-butyl)-21-hydroxy-5-(4-hydroxy-benzyl)-15-isobutyl-4,11-dimethyl-3,6,9,13,16,22-hexaoxo-10-oxa-1,4,7,14,17-pentaaza-bicyclo[16.3.1]docos-12-yl]-amide} | small molecules | EMA | — | Regintel Limited |
Kallikrein 7 and elastase 2 inhibitor | small molecules | FDA | — | LifeMax Laboratories, Inc. |
6-ethoxy-7-methoxy-2-(2-methylsulfanylphenyl)-3,1-bensoxazin-4-one | small molecules | FDA | Sixera Pharma AB | |
6-ethoxy-7-methoxy-2-(2-methylsulfanylphenyl)-3,1-benzoxazin-4-one | small molecules | EMA | Sixera Pharma AB | |
recombinant kallikrein inhibitor | proteins | FDA | — | Dermadis SA |
Recombinant kallikrein inhibitor | antibodies | EMA | Dermadis S.A.S. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.