Non-viral in situ gene editing effectively and safely rescues congenital ichthyosis-causing mutations in human skin

Autosomal recessive congenital ichthyosis (ARCI) comprises a heterogeneous group of rare, severe genodermatoses that profoundly reduce patients’ quality of life and for which no curative therapies are currently available. In this study, we demonstrate clinically relevant in situ correction of the most prevalent ARCI-associated mutation, TGM1 c.877-2A>G, a pathogenic splice-site variant, using human disease models. Transient modulation of the skin barrier followed by topical delivery of the cytosine base editor eTD encapsulated in lipid nanoparticles resulted in restoration of approximately 30% of wild-type transglutaminase 1 activity in treated skin tissue. Repeated dosing was well tolerated and revealed an excellent safety profile, with no evidence of systemic exposure to either the lipid nanoparticles or the genetic payload, as confirmed by highly sensitive analyses including desorption electrospray ionization (DESI) metabolic imaging. Together, these data provide a comprehensive preclinical framework supporting the feasibility of in situ gene correction for genodermatoses and highlight its potential to enable curative, next-generation therapies for severe inherited skin disorders.