Annular Epidermolytic Ichthyosis (AEI) is an uncommon genetic skin disorder emerged with cyclic erythematous plaques, blistering, and hyperkeratosis, resulting from mutations in KRT1 or KRT10 genes. Protheragen provides end-to-end preclinical development services tailored to the unique demands of AEI, from target validation to therapeutic development.
Introduction to Annular Epidermolytic Ichthyosis
Annular epidermolytic ichthyosis is one of a rare sub-types of epidermolytic ichthyosis and is an autosomal dominant mutation either in the KRT1 or KRT10 genes leading to the disruption of keratin filament formation. Recent estimates note an incidence rate of <1 in 1,000,000, with subsequent reports involving sporadic cases and isolated de novo variants. Advancements in genetic diagnostic methodology has had a major impact on distinguishing AEI versus other ichthyosis sub-types, however, AEI is fairly heterogeneous at the molecular level which complicates the phenotype-genotype correlations.
Pathogenesis of Annular Epidermolytic Ichthyosis
AEI is caused by the autosomal dominant mutations either in either the KRT1 or KRT10 gene, which encodes keratin 1 and keratin 10 proteins which are key components of the structural integrity of the epidermis. The mutations lead to disruption of keratin intermediate filament formation in the suprabasal layers of the epidermis, leading to the cytoskeletal instability and increased fragility of keratinocytes. This loss of integrity again leads to the typical blistering and hyperkeratosis associated with AEI.
Fig.1 Hyperkeratosis, epidermal acanthosis with granular layer degeneration and vacoular alteration in keratinocytes. (Jha
et al., 2015)
Diagnostic Development for Annular Epidermolytic Ichthyosis
- Genetic Diagnostics: Genetic diagnostics play an important role in fast and accurate diagnosis of AEI. Using next-generation sequencing (NGS) panels that have been designed to target hotspot regions of the KRT1 and KRT10 genes allows laboratories to rapidly detect pathogenic mutations causing the disorder.
- Biomarker Development: In addition to genetic testing, the analysis of non-invasive biomarkers improves diagnostic accuracy for AEI. Elevated activity of serine proteases, kallikrein-5 (KLK5) or kallikrein-7 (KLK7) found in blister fluid, can provide clinicians with a non-invasive biomarker to assess disease severity and progression.
Therapeutics Development for Annular Epidermolytic Ichthyosis
Small Molecule Therapies
Research is underway to develop small molecules that stabilize keratin structures to ameliorate the disrupted keratin networks caused by the mutation in KRT1 or KRT10 genes. For example, the retinoid, adapalene, is used to modulate keratinocyte proliferation and differentiation which leads to improvements in hyperkeratosis and blistering.
Gene Therapy
By utilizing gene editing technology, researchers are able to accurately repair the pathogenic mutation in the KRT1 or KRT10 genes in patient-derived keratinocytes, thus restoring normal keratin expression and function. Furthermore, AAV vectors have been used to deliver a healthy keratin gene into the patient's skin cells to provide sustained therapeutic effect.
RNA-Based Therapies
Selective silencing of mutations can be achieved using allele-specific siRNA or antisense oligonucleotides (ASOs) to block mutant KRT1 or KRT10 mRNA and reduce the production of harmful mutant proteins while preserving the expression of wild-type proteins. This process helps to reduce toxic protein aggregation within the cell ultimately reducing skin symptoms.
Our Services
Protheragen is a full-service provider committed to advancing therapies for annular epidermolytic ichthyosis. Our team of scientists, dermatologists, and geneticists leverage cutting-edge technologies to drive progress in AEI, with a focus on therapeutic development, diagnostics development as well as disease model development services to support your projects.
- KRT10-Mutant Keratinocytes
- Allele-Specific siRNA Knockdown Cells
- AEC Patient-Derived Skin Grafts
- KRT1E478K/+ or KRT1I479T/+ Mice
- KRT10V143M/+ Mice
- Conditional Keratin Mutant Mice
Protheragen offers complete preclinical research services to advance AEI therapeutics from discovery through development. With our nimble core facilities and experienced team, we are able to conduct comprehensive in vitro and in vivo studies using validated models to assess the safety and efficacy of your drug candidates. Our goal is to ensure that your lead candidates are built on rigorous scientific evidence, given the importance of their potential uses.
Partner with Protheragen to speed up your AEI preclinical research and provide functional solutions that will improve therapeutic innovations. If you have any interest in our services, please contact us.
References
- Jha, A., et al. "Annular Epidermolytic Ichthyosis: A Rare Phenotypic Variant of Bullous Congenital Ichthyosiform Erythroderma." Indian J Dermatol Venereol Leprol 81.2 (2015): 194-7.
- Liang, B., et al. "Annular Epidermolytic Ichthyosis with Palmoplantar Keratosis: A Unique Phenotype Associated with Interfamilial Phenotypic Heterogeneity." Eur J Dermatol 30.3 (2020): 294-99.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
