Pachyonychia Congenita (PC)

Pachyonychia Congenita (PC) is a genodermatosis of a rare type, associated with dystrophic nail thickening, painful palmoplantar keratoderma and oral leukokeratosis. At Protheragen, we utilize state-of-the-art molecular insights and custom preclinical models of the disease to drive preclinical drug and therapy development services for pachyonychia congenita.

Introduction to Pachyonychia Congenita

Pachyonychia Congenita (PC) is a rare genetic condition (incidence ~1/50,000–1/100,000) stemming from pathogenic changes in genes that encode keratin proteins undergirding the skin structure, nails, and mucosal tissues like the cytoskeleton. Most recent work shows that the mutations KRT6A and KRT16 take up the vast part of the load, leading to dysfunctional keratin filament aggregation, altered epidermal differentiation, and persistent inflammation.

Pathogenesis of Pachyonychia Congenita

Pachyonychia congenita is caused by mutations in keratin genes (KRT6A, KRT6B, KRT16, KRT17) which disrupts the cytoskeletal architecture, leading to abnormal aggregation of keratin filaments in epidermal cells. This structural impairment, along with the mechanical stress, causes cell brittle weakening, hyperkeratosis, and blistering. At the same time, misfolded keratins cause ER stress, damage autophagy, and oxidative stress, which enhances the apoptosis of keratinocytes and drives chronic inflammation. Chronic inflammation, driven by TLR and NLRP3 pathways, leads to cytokine storm, e.g., IL-1β and amplifies tissue destruction while inflaming sensory neurons, explaining the intense nociception associated with palmoplantar lesions.

Fig.1 Features of pachyonychia congenita (PC) (McCarthy, de Brito and O'Toole, 2024)

Therapeutics Development for Pachyonychia Congenita

The development of therapeutics for pachyonychia congenita has focused on targeted molecular therapies and drug repurposing, with no positive outcomes from clinical trials and difficulties in pain control and the management systems of drug delivery. TRPV3 antagonists and combination therapies show promise but the absence of strong biomarkers, patient-facing trial designs, and optimized delivery systems stymies effective treatment progress.

Table.1 New Therapeutic Approaches for Pachyonychia Congenita.

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 a full-service approach model as a provider developing therapies for rare skin diseases like pachyonychia congenita. Our developed specialists like scientists and dermatologists, geneticists work on developing therapeutic and disease model to support for all stages of the research project.

Therapeutic Development Platforms for Pachyonychia Congenita

Disease Model Development for Pachyonychia Congenita

Protheragen has developed custom 2D cell models and 3D skin models featuring keratin aggregation along with endoplasmic reticulum (ER) stress and associated inflammatory tissue damage that recapitulate the molecular pathology of pachyonychia congenita. Protheragen's animal models for pachyonychia congenita have gained key features making them suitable for therapy testing focused on keratin stabilizing, anti-inflammatory, anti-pain, and cytoprotective strategies.

2D Cell Models & 3D Skin Models

• KRT6A Knockout HaCaT Cells
• Immortalized PC Keratinocytes
• 3D Reconstructed PC Epidermal Equivalents
• Organotypic Co-Cultures with Sensory Neurons

Animal Models Development

• Krt6a c.518T>C Knock-In Mice
• Inducible Epidermal-Specific Krt16 Conditional Knockout Mice
• Krt17 p.Arg94Cys Mutant Mice
• krt6aΔexon1 Zebrafish Mutants

Protheragen offers comprehensive preclinical solutions for pachyonychia congenita by employing a multi-pronged approach of innovative target identification, precise disease modeling, integrated drug safety evaluation, and DMPK services. Our platforms allow for therapeutic development from mechanistic insight to clinically validated candidates through our proprietary platforms.

References

• McCarthy, R. L., M. de Brito, and E. A. O'Toole. "Pachyonychia Congenita: Pathogenesis of Pain and Approaches to Treatment." Clin Exp Dermatol 49.12 (2024): 1510-17.
• O'Toole, E. A., et al. "Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches." J Invest Dermatol 144.4 (2024): 748-54.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.