Ectodermal Dysplasia-Skin Fragility Syndrome (ED-SFS) Ectodermal Dysplasia-Skin Fragility Syndrome (ED-SFS) is an uncommon, autosomal recessive syndrome characterized by skin fragility, nail dystrophy, and abnormal hair development linked to mutations in genes encoding desmosomal or hemidesmosomal proteins. Protheragen offers comprehensive preclinical drug and therapy development services for ED-SFS, bridging research to clinical translation.
Introduction to ED-SFS
Dysplasia-Skin Fragility Syndrome (ED-SFS) is a serious genodermatosis caused by biallelic mutations in structural adhesion proteins, such as linking cytoskeletal networks to epidermal integrity. Recently, studies have shown that pathogenic variants in PLEC (plectin) are the most common cause of ED-SFS associated with the impairment of cytoskeletal-keratin interactions, leading to blistering, erosions, and mucosal involvement.
Pathogenesis of ED-SFS
- Structural Adhesion Defects: ED-SFS is diagnosed in patients with biallelic variants in genes like PLEC, PKP1, or DSP which code for desmosomal or hemidesmosomal proteins, leading to dysregulation of essential binding between keratin intermediate filaments and membrane of the cell. This results in poor epidermal integrity which presents as skin fragility and blistering as well as erosions of mucosal surfaces due to mechanical forces causing cell detachment.
- Cytoskeletal Dysregulation and Cellular Stress: Absence of function in plectin (PLEC) or plakophilin-1 (PKP1) causes destabilization of cytoskeletal scaffolding, which results in abnormal keratinocyte differentiation and inadequate apoptosis. Moreover, other effects such as increased oxidative stress signalling and activation of inflammasome like NLRP3 further increases the already injured tissue, which results in chronic wounding and abnormal follicles of hair.
Fig.1 Schematic of mutations in PKP1 in ectodermal dysplasia-skin fragility syndrome. (Hsu
et al., 2016)
Therapeutics Development for ED-SFS
Therapeutic approaches for the ectodermal dysplasia-skin fragility syndrome aim to restore skin integrity and repair the underlying molecular defects.
Table.1 Current Therapeutic Development for ED-SFS.
| Therapy Category |
Drug/Intervention |
Target |
Mechanism of Action |
Development Stage |
| Gene Therapy |
AAV9-PKP1 Gene Therapy |
PKP1 Gene |
AAV-mediated transfer of functional PKP1 to restore desmosomal plakophilin-1 expression |
Preclinical |
| Protein Replacement |
Recombinant Plakophilin-1 (rPKP1) |
Desmosomal Adhesion Complexes |
Topical application of recombinant PKP1 for keratinocyte adhesion stabilization |
Preclinical |
| Small Molecule |
Diacerein (IL-1β Inhibitor) |
IL-1β/Pro-inflammatory Cytokines |
Reduces skin inflammation and promotes epithelial healing |
Phase II Clinical Trial |
| Monoclonal Antibody |
Secukinumab (Anti-IL-17A) |
IL-17A Cytokine |
Neutralization of IL-17A to reduce autoimmune-mediated destruction of skin |
Preclinical |
| Cell-Based Therapy |
Autologous Keratinocyte Transplants |
Epidermal Stem Cells |
Transplantation of gene-corrected keratinocytes for functional skin regeneration |
Early Clinical Trials |
| Exosome Therapy |
MSC-derived Exosomes |
TGF-β/SMAD Signaling |
Modulation of the extracellular matrix remodeling and reduction of fibrosis |
Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen provides full service to advance therapeutics for rare genetic diseases like ED-SFS. Our team of experts, including scientists, dermatologists, and geneticists, is committed to therapeutic development and disease model development services to advance research in every phase of research project.
Therapeutic Development Platforms for ED-SFS
Disease Models Development for ED-SFS
Protheragen offers custom 2D cell models and 3D skin models to study relevant molecular pathologies in ED-SFS, including desmosomal complex defects and cytoskeletal dysregulation. Our animal models replicate hallmark manifestations of ED-SFS including skin fragility, blistering, mucosal erosions and hair follicle abnormalities providing rigorous demonstration of therapeutics to restore desmosome function, mitigate oxidative stress signalling and modulate inflammatory pathways.
- Patient-Derived Primary Keratinocytes
- HaCaT Keratinocyte Lines
- iPSC-Derived Keratinocyte Monolayers
- iPSC-Derived Mucocutaneous Organoids
- Conditional PLEC Knockout Mice
- Hypomorphic PKP1 Mice (PKP1G125R/G125R)
- Xenograft Blistering Models
- Gene-Edited Zebrafish (plecb−/−)
As a one-stop preclinical research services provider, Protheragen is dedicated to advancing therapeutics for esoteric conditions of the skin, such as ED-SFS. Our unique model allows for seamless integration of solutions from target discovery and disease modeling, and in-depth drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Chandra Konda, S., et al. "Ectodermal Dysplasia-Skin Fragility Syndrome - Identification of a Novel Plakophilin1 (Pkp1) Gene Variant through Whole Exome Sequencing." Indian J Dermatol Venereol Leprol (2024): 1-5.
- Hsu, C. K., et al. "Ectodermal Dysplasia-Skin Fragility Syndrome Resulting from a New Atypical Homozygous Cryptic Acceptor Splice Site Mutation in Pkp1." J Dermatol Sci 84.2 (2016): 210-12.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
