Awarded a two-year, $145,447 grant from Pachyonychia Congenita Project.
Pachyonychia congenita (PC) is a rare genetic skin condition that causes thick, painful skin on the hands and feet, making walking and daily activities difficult. This project aims to closely study PC skin at a very detailed level to understand which cells and biological pathways are not working properly and how this differs between patients. By identifying these problem pathways, we can match them to existing medicines that may reduce pain and skin thickening more effectively. The results will help move PC treatment toward more personalized, targeted therapies that can significantly improve patients’ quality of life.
Project Title: Elucidation of key molecular pathways in Pachyonychia Congenita at spatial single-cell resolution to guide precision-targeted therapies
Principal Investigator (PI) Name: Alain Hovnanian, MD, PhD
PI Affiliations: INSERM, Imagine Institute for Genetic Diseases, Necker Hospital for Sick Children, Paris University
Abstract
Pachyonychia Congenita (PC) is a rare, debilitating genetic skin disorder caused by pathogenic variants in keratin genes (KRT6A, KRT6B, KRT6C, KRT16, or KRT17). Patients suffer from painful palmoplantar keratoderma and related cutaneous manifestations that severely impair quality of life. Despite promising case reports using EGFR inhibitors and statins, there are currently no approved, consistently effective therapies, largely due to an incomplete understanding of PC pathogenesis at the molecular and cellular levels.
Building on the success of our previously funded multi-omics Project 1, which generated the most comprehensive proteomic and phosphoproteomic dataset to date from full-thickness PC skin biopsies, this proposal (Project 2) aims to elucidate key molecular pathways in PC at single-cell spatial resolution. We will integrate deep visual (spatial) proteomics with high-resolution spatial and single-cell transcriptomics to map dysregulated pathways directly within their native tissue context. This approach is critical, as RNA expression alone does not reliably reflect protein abundance or signaling activity.
Our specific aims are to: (i) identify cell-type–specific molecular dysregulations in lesional PC skin, with a focus on keratinocytes and immune infiltrates; (ii) define gene-specific spatial molecular signatures associated with distinct PC genotypes to enable precision medicine approaches; and (iii) repurpose existing drugs by computationally matching disease signatures to compounds capable of normalizing aberrant pathways. Candidate therapies will be validated using patient-derived keratinocytes and established cellular and preclinical models.
Preliminary data reveal profound alterations in lipid metabolism and overactivation of EGFR-associated signaling pathways, providing a strong mechanistic rationale for targeted therapeutic intervention. By combining cutting-edge spatial proteomics with functional validation, this project will deliver an unprecedented molecular framework for PC, enabling rational drug selection and paving the way toward personalized, more effective treatments for patients living with this painful disorder.
