Research & Innovation
Publications
Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models
PMU Authors
Johannes Bischof, Ulrich Koller
All Authors
Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Bruning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Jennifer Kirwan, Ulrich Koller, Achim D. Gruber, Wolfgang Baumer, Sarah Hedtrich
Journal association
CELL STEM CELL
Abstract
Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients' quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of similar to 30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.
Keywords
STEM-CELLS, TRANSGLUTAMINASE, MICE LACKING, DELIVERY, STRATUM-CORNEUM, EFFICIENT, PHOTODYNAMIC THERAPY, VIVO, Ablative fractional laser, Bathing suit ichthyosis