Dowling-Degos Disease (DDD) is an uncommon inherited cutaneous condition that involves progressive reticular hyperpigmentation, comedone-like lesions, and pitted scars, most often on flexural sites. At Protheragen, we provide end-to-end preclinical drug and therapy development services focused on DDD and will expedite the discovery of breakthroughs, from target validation through IND-enabling studies.
Overview of Dowling-Degos Disease
Dowling-Degos Disease (DDD) is an autosomal dominant genodermatosis first described in 1954. Recent studies suggest that pathogenic variants of the PSENEN gene are responsible for the pathogenicity of the disease by disrupting γ-secretase activity and thus leading to dysregulated keratinocyte differentiation. DDD commonly manifests in adolescence with slight female predominance, at times presenting with confounding disorders, namely, keratosis follicularis.
Fig.1 The protein model of human POGLUT1. (Wilson
et al., 2017)
Diagnostic Development for Dowling-Degos Disease
Genetic Testing
Next-generation sequencing (NGS) panels covering PSENEN, POFUT1, and POGLUT1 enable precise diagnosis, with a 70% detection rate in familial cases. Recent advancements include the integration of whole-exome sequencing (WES) to identify rare variants in non-coding regulatory regions, have led to an increase in diagnostic rates of approximately 15% in sporadic DDD cases.
Biomarker Identification
Proteomic analysis of epidermal exosomes has identified miR-203 and IL-6 as potential biomarkers for disease progression. Longitudinal cohort studies reveal that miR-203 levels correlate with lesional expansion rates, while expanded IL-6 are associated with follicular inflammation severity. Multi-omics integration furtheridentified ceramide [NP] depletion as a surrogate marker for epidermal barrier dysfunction.
Therapeutics Development for Dowling-Degos Disease
Dowling-Degos Disease therapeutics have focused on three main pathways of genetic correction, oxidative stress, and anti-inflammatory pathways, with therapeutic strategies along the spectrum of preclinical validation and early clinical phases.
Table.1 Therapeutic Development for Congenital Dowling-Degos Disease.
| Therapeutic Strategy |
Therapeutic Target |
Development Stage |
Key Findings/Mechanism |
| AAV-mediated PSENEN gene therapy |
PSENEN gene |
Preclinical |
Restored Notch signaling in 3D human skin models; reduced hyperpigmentation in preclinical studies. |
| γ-Secretase enhancers |
γ-Secretase complex |
Preclinical |
Small-molecule activators improved keratinocyte differentiation in patient-derived organoids. |
| Topical ROS scavengers |
ROS/NLRP3 inflammasome |
Preclinical |
Luteolin-loaded nanoparticles demonstrated efficacy in reducing oxidative stress and follicular pathology. |
| Repurposed topical ruxolitinib |
JAK1/2 kinases |
Phase I |
Early clinical observations indicated reduction in pigmentation and inflammation. |
| Gene therapy |
POFUT1 gene |
Preclinical |
Achieved efficient gene editing in iPSC-derived keratinocytes, normalizing Notch ligand activity. |
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 brands, a variety of services to accelerate the processes of developing therapies DDD. Our scientists, dermatologists, and geneticists apply current state-of-the-art technology to promote development, focusing on therapeutic development, diagnostics development as well as disease model development services to advance your proposals.
- KRT5-Mutant Primary Keratinocyte Monolayers
- Patient-Derived Reconstructed Human Epidermis
- PSENEN Conditional Knockout Mice
- Xenografted DDD Skin Equivalents
At Protheragen, focus on preclinical research so that effective drug and therapy candidates can emerge between discovery and development. Our new and modern facilities and scientific staff will execute suggested protocols for rigorous in vitro and in vivo studies to evaluate the safety and efficacy of potential therapeutics, ensuring the most productive constructs for your drug candidates.
Partner with us to accelerate your Dowling-Degos Disease research affect therapeutic innovations into viable solutions. If you are interested in our services, please contact us.
References
- Chen, Y., et al. "Novel Deletion of the Pofut1 Gene Associated with Multiple Seborrheic Keratosis Dowling-Degos Disease." J Dermatol 48.12 (2021): e591-e93.
- Wilson, N. J., et al. "Mutations in Poglut1 in Galli-Galli/Dowling-Degos Disease." Br J Dermatol 176.1 (2017): 270-74.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
