Laboratory of Molecular Biology
Gene Therapy of Genodermatoses; Head: Dr. Daniela Ortner-Tobider
Our research group is using designer nucleases to develop gene therapies for inherited keratinopathies. Currently, the focus is on heterozygous mutations in KRT9 causing palmoplantar keratoderma (PPK).
Keratins are the most abundant proteins in the epidermis and essential for skin integrity. The molecules polymerise yia their central rod-shaped domains into filaments forming a cytoskeleton that spans the entire cytoplasm and provides cell stability. Mutant keratins integrate into the cytoskeleton and reduce its resilience towards stress. In palmar or plantar skin, this causes hyperkeratosis in patients with PPK (restricted to palms and soles).
Until recently, inherited diseases were seen as incurable. With the invention of designer nuclease technology, that allows specific targeting and traceless repair of genetic mutations, effective treatments for genetic disorders such as genodermatoses becomes feasible.
Our gene therapy approach for keratinopathies aims to delete expression of the dominant-negative mutant keratin allele while leaving the wild-type allele intact. The latter is sufficient to form stable filaments and restore skin resilience. To this end, we are using CRISPR/Cas9 to target and delete the mutant keratin genes in keratinocytes isolated from patients. Correctly targeted keratinocytes are expanded and further investigated. The goal is to identify keratinocyte clones which build resilient keratin filaments, lack any off-target effects from the nuclease treatment, and are capable of forming and sustaining regeneration of a functional epidermis over a life time when grafted onto the skin.
Team: Univ.-Prof. Dr. med. Matthias Schmuth, Thomas Trafoier, Dr. med., PhD student