Erythrokeratodermia variabilis (EKV), previously known as Mendes da Costa syndrome, is characterized by migratory red patches coupled together with either fixed localized or generalized keratotic plaques. Protheragen offers an extensive range of preclinical development services that drive and support the development of targeted therapies and diagnostics for EKV, using the latest technologies and disease-specific models.
Introduction to Erythrokeratodermia Variabilis
Erythrokeratodermia Variabilis (EKV) is a rare hereditary skin condition primarily defined by transient erythematous patches and fixed hyperkeratotic plaques, linked to mutations in the genes GJB3 and GJB4 or less commonly GJA1 alleles that encode for connexin proteins responsible for communication among epidermal cells. Recent studies emphasize the condition is reported to have autosomal dominant inheritance and high penetrance with variable expressivity encompassing localized hyperkeratosis or generalized migratory erythema. Newer epidemiologic data suggest no obvious gender association; however, prevalence remains low due to overlap with other keratinization disorders such as ichthyosis.
Fig.1 Schematic diagram of connexin 31 (GJB3) and connexin 30.3 (GJB4) showing structural motifs and all reported mutations associated with erythrokeratodermia variabilis et progressiva. (Dai, Wang and Lin, 2020)
Pathogenesis of Erythrokeratodermia Variabilis
Erythrokeratodermia Variabilis is caused by pathogenic mutations in the connexin genes (GJB3, GJB4, and GJA1) that disrupt gap junction function and epidermal homeostasis. Pathogenic mutations in the connexin gene result in aberrant differentiation in keratinocytes contributing to an impaired barrier formation and disrupted calcium signaling. Effects such as dominant-negative, or haploinsufficiency lead to disruption of connexin complex stability resulting in an cyclic pattern of inflammation, hyperproliferation, and migratory erythematous changes. Faulty Wnt/β-catenin and Notch pathway functions can typically underlie the hyperkeratosis and epidermal remodeling.
Therapeutics Development for Erythrokeratodermia Variabilis
Novel therapeutics for EKV could be advancing precision targeted medicines targeting the core genetic defects in connexin proteins, while inducing inflammatory or epidermal defects. Current therapeutic approaches are focusing on restoring gap junction activity, through modifying keratinocyte differentiation as well as innovative genetic repair techniques (directly targeting the causal defect).
Small Molecule Therapies
Recently, novel small molecules have been designed for the stabilization of connexin hemichannels or potential compensation for normal channel dysfunction. Small molecules such as derivatives of doxycycline functions in preclinical system indirectly enhancing trafficking of connexin-26 (GJB3) and in some case delaying cytoplasmic aggregation of mutant keratinocytes.
Gene-Targeted Approaches
Recent expansion of prime editing technology allows localized mapping and precise repair of missense GJB4 mutations in patient-derived keratinocytes to restore connexin-30.3 functionality in vitro and result in increased gap-junction intercellular communication (GJIC). Expanded preclinical research with siRNA targeting mutant GJA1 alleles has demonstrated reduction in aberrant calcium signaling.
Cell-Based Therapies
Additional progress with iPSCs from patients with CRISPR-corrected GJB3 mutations in iPSCs that were differentiated into functional keratinocytes, with >80% connexin-26 expression levels observed in bioengineered skin equivalents. Xenografts with the grafts restored epidermal integrity in murine models, showing reduction in scaling at 12 hours post-transplantation.
Our Services
Protheragen offers a full range of services to accelerate therapies targeting erythrokeratodermia variabilis. Experts including scientists, dermatologists, and geneticists integrate state-of-the-art technologies to advance therapies, all of positions therapeutic development forwards with focused therapeutic development and disease model development services.
Therapeutic Development for Erythrokeratodermia Variabilis
At Protheragen, we will consider end-to-end services across small molecule, gene therapy, cell therapy, and/or biologics platforms, addressing connexin dysfunction, inflammation and hyperproliferation.
Disease Models Development for Erythrokeratodermia Variabilis
Protheragen offers an end to end for preclinical models for developing erythrokeratodermia variabilis research including the advanced models development for 2D cell models, 3D skin models and animal models development all intending to replicate disease-specific pathologies and accelerate therapeutics development.
| 2D Cell Models & 3D Skin Models |
| Protheragen’s preclinical research services are tailored to erythrokeratodermia variabilis with the intent to enable the development of effective therapies. We perform in vitro studies using 2D cell models and 3D skin models for erythrokeratodermia variabilis at the cellular and molecular levels. |
| Optional Models |
- GJB3-mutant keratinocyte monolayers
- GJB4-KO epidermal organoids
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- 3D EKV "skin-on-a-chip" with migratory erythema induction
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| Animal models |
| Preclinical in vivo animal studies are also an integral component of our services. We employ, for example, genetically engineering models to assess the safety and effectiveness of new potential therapies. These models are selected for their relevance to the disease erythrokeratodermia variabilis. |
| Optional Models |
- GJB3 knock-in mice with cyclic erythema
- GJB1-overexpression zebrafish
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- Connexin-30.3 conditional knockout rats
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| Optional Species |
Mice, Rats, Non-human primates, Others |
With the integration of all modern preclinical research services, Protheragen aims to improve the treatment of rare skin diseases, such as EKV. We provide all-inclusive services starting from identifying a biological target and modeling the disease to sophisticated drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Dai, S., H. Wang, and Z. Lin. "Novel and Recurrent Mutations in Gjb3 and Gjb4 Cause Erythrokeratodermia Variabilis Et Progressiva." Indian J Dermatol Venereol Leprol 86.1 (2020): 87-90.
- Wu, J. P., H. S. Ge, and C. Yang. "Erythrokeratodermia Variabilis with Hypertrichosis on the Lesions." Chin Med J (Engl) 133.4 (2020): 501-02. Print.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
