ESTABLISHING AN IN VITRO MODEL FOR EPIDERMOLYTIC ICHTHYOSIS FOR DRUG TESTING

Abstract

Epidermolytic ichthyosis (EI) is a rare genetic skin fragility disorder that manifests at birth with skin blistering and erythroderma. As patients age, the blistering is gradually replaced by hyperkeratosis. EI patients, especially pediatric patients, experience a diminished quality of life. The disorder is caused by mutations in the keratin 1 (KRT1) and keratin 10 (KRT10) genes, resulting in the formation of unstable keratin intermediate filaments. These filaments are prone to collapse and aggregation, leading to cytolysis in suprabasal epidermal cells causing skin blistering. Despite extensive research, no curative therapy for EI has been developed to date. Current treatments are limited to symptom management. A middle-aged Qatari woman presented at the Dermatology Clinic in Al-Rumailah Hospital with severe EI. Sequencing revealed a missense mutation (c. 452 A>C, p.Q151P) in the KRT10 gene. This research aimed to develop an in vitro model for EI by introducing the patient’s mutation into keratinocytes. These transgenic cells can be used to better understand the molecular and cellular consequences of the pathogenic variant, and explore novel or repurposed drugs for the development of effective treatments for EI. Although stable line formation was not achieved, transient transfection of keratinocytes demonstrated spontaneous aggregation of the mutant keratin 10 and highlighted the cytotoxic effects of the patient's mutation, consistent with severe EI presentation in the patient. Future efforts will focus on refining the model to further investigate the molecular mechanisms of EI pathogenesis and develop novel therapeutic strategies through drug testing, with the hope of finding a cure for this devastating disease.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences