Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome (EEC Syndrome) is a rare genetic disorder with limb defects, ectodermal dysplasia, and orofacial clefting that is primarily associated with mutations in the TP63 gene. Protheragen offers end-to-end preclinical development capabilities to support the development of therapies and diagnostics for EEC syndrome, leveraging the latest technologies and models that are specific to the disease.
Introduction to EEC Syndrome
EEC syndrome is associated with heterozygous mutations in the TP63 gene that is essential for the development of epithelia and limbs. The dominant inheritance pattern is variable gym expressivity that ranges from mild ectodermal defects to affected limbs with more severe defects, which has recently been supported in the literature. Emerging epidemiological data also registers a slight female predominance, though a precise global prevalence is unknown due to challenges in diagnosis and reporting.
Fig.1 Rescue of ΔNp63α-WT transcriptional activity by mutated-p63 allele-specific siRNAs. (Novelli
et al., 2021)
Pathogenesis of EEC Syndrome
EEC syndrome is the result of heterozygous mutations of the TP63 gene that affect the role of TP63 in limb morphogenesis, ectodermal differentiation, and epithelial development. These variants disrupt normal epithelial function and lead to gain-of-function or dominant-negative mutations that disrupt p63-mediated keratinocyte proliferation and apoptosis. Signs of dysregulation in cellular pathways also contribute to cleft lip/palate, ectodermal defects, and limb abnormalities.
Therapeutics Development for EEC Syndrome
Recent therapeutic developments targeting EEC syndrome are pushing therapeutic paradigms, with new treatment goals focusing on genetic repair, molecular stabilization, and regenerative medicine to address the ultimate causes of EEC.
Small Molecule Stabilizers
New compounds targeting the SAM domain of the p63 protein provide structural stabilization to counteract dominant-negative mutations related to ectodermal dysplasia. A primary effort in this arena has been with high throughput screens for approved pharmaceutical (drugs) like retinoids that regulate p63-dependent signaling pathways in order to enhance keratinocyte survival and decrease severity of clefting in animal models.
Gene Editing & Replacement Therapies
These preclinical therapeutic approaches are now being deemed possible due to advances in CRISPR/Cas9 systems whereby precise TP63 gene-modifying constructs can correct TP63 mutations in patient-derived keratinocytes, restoring differentiated functionality in vitro. Additionally, adeno-associated virus (AAV)-mediated delivery of wild-type TP63 has demonstrated in preclinical models a capacity to rescue limb patterning defects in murine embryos.
Stem Cell & Regenerative Strategies
Induced pluripotent stem cell (iPSC)-derived epithelial progenitors can be transplanted into TP63-mutant and other animal models to partly restore ectodermal tissue integrity, demonstrating that stem cell-based strategies can also be utilized as aforementioned to specific the defects characteristic in EEC syndrome. Additionally, bioprinted skin alternatives using gene-edited fibroblasts developed potential in treating chronic wounds in EEC individuals.
Our Services
Protheragen provides a wide range of services to advance therapies for EEC syndrome. Our contributing team of scientist, dermatologists, and geneticists use the latest technologies to lead the development of preclinical therapies related to this disorder, either through focused therapeutic development and disease model development services to assist your projects.
Therapeutic Development Platforms for EEC Syndrome
Protheragen utilizes a platform approach delivering integrated, end-to-end services across the small molecule, gene therapeutic, cell therapeutic, and biologic platforms to propose strategies for treatment and address T63- driven ectodermal dysplasia, limb anomalies (ectrodactyly), and craniofacial defects.
Disease Models Development for EEC Syndrome
Protheragen offers a comprehensive suite of preclinical models to advance EEC syndrome research, including cutting-edge 2D cell models, 3D skin models and animal models development all tailored to replicate disease-specific pathologies and accelerate therapeutic development.
| 2D Cell Models & 3D Skin Models |
| Protheragen's preclinical research services for EEC syndrome meet your needs for preclinical research that can serve as the groundwork for development of safe and effective therapies. We conduct in vitro research with 2D cell models and 3D skin models to study the molecular mechanisms involved in EEC syndrome. |
| Optional Models |
- TP63-mutant keratinocyte models
- TP63-mutant immortalized keratinocytes
|
- TP63-edited epidermal organoids
- EEC skin-hair follicle-on-a-chip
|
| Animal models |
| In vivo preclinical studies are also a vital part of our service offerings. These studies can utilize genetically engineering models to evaluate the safety and efficacy of potential therapeutic agents. These animal models are selected based on their suitability to the human condition of EEC syndrome. |
| Optional Models |
- Conditional Tp63 knockout mice
- TP63 point mutation knock-in mice
|
- TP63-mutant zebrafish
- TP63-fluorescent transgenic zebrafish
|
| Optional Species |
Mice, Rats, Non-human primates, Others |
As a preclinical research services provider that can provide a fully regulated service, Protheragen is committed to advancing the research and therapeutics for rare skin diseases like EEC syndrome. We can provide end-to-end services from discovery through disease modeling and regulatory based drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Novelli, F., et al. "P63 in Corneal and Epidermal Differentiation." Biochem Biophys Res Commun 610 (2022): 15-22.
- Orlandi, G., et al. "Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome. Prenatal Prospective Ultrasound Diagnosis." J Clin Ultrasound 51.8 (2023): 1348-55.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
