Awarded a one-year, $99,960 grant from Pachyonychia Congenita Project.
Pachyonychia congenita (PC) is a genetic disease primarily characterized by abnormal nails as well as thickening of the skin of the palms, resulting in painful plantar skin that greatly impacts patients’ quality of life. There is no cure for PC and treatment is mainly supportive. The goal of this study is to investigate the factors that are abnormally expressed in the skin and blood of PC patients, with the aim of developing specific therapies that can normalize the expression of these factors and improve disease severity and patients’ quality of life.
Project Title: Systematic mapping of druggable pachyonychia congenita-associated targets
Principal Investigator (PI) Name: Eli Sprecher, MD, PhD
PI Affiliations: Division of Dermatology & Deputy Director General for R&D and Innovation, Tel-Aviv Medical Center, & Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Abstract
Pachyonychia congenita (PC) is a rare autosomal dominant disorder caused by pathogenic variants in the genes KRT6A, KRT6B, KRT6C, KRT16 or KRT17. PC main clinical features include painful palmoplantar keratoderma (PPK), nail dystrophy, follicular cysts, and involvement of mucous membranes leading to multiple potential complications and significantly affecting quality of life. Due to limited understanding of the molecular mechanisms underlying PC’s pathophysiology, treatment is currently mainly supportive and focused on providing short-term relief. However, in recent years, considerable efforts are being made at developing innovative therapies for PC. Initial efforts consisting in topical/local administration of small inhibitory RNAs-based technology or repurposed drugs have met with limited success thus far, probably due to technical challenges associated with drug delivery. Of note, the discovery of overactive epidermal growth factor receptor (EGFR) signaling in PC has led to the successful repurposing of EGFR inhibitors for the treatment of PC, pointing at systemic delivery as a more robust option for drug administration. Here we propose to systematically identify immunological (circulating) as well as non-immunological (epidermal and dermal) elements that may contribute to PC pathogenesis using a combination of in-depth single-cell transcriptomic profiling and spatial transcriptomics. These potential targets will then be validated using appropriate in vitro systems and wherever possible will be targeted by repurposed molecules. This will form the basis for future functional and clinical therapeutic studies.
