Preclinical evaluation of a modified HSV-1 vector encoding human TGM1 for the treatment of autosomal recessive congenital ichthyosis (ARCI).

Abstract Autosomal recessive congenital ichthyosis (ARCI) is a diverse group of cornification diseases associated with severe clinical complications and decreased quality of life. Germline mutations in the TGM1 gene, which encodes the enzyme transglutaminase 1 (TGM1), are the predominant cause of ARCI. These TGM1 mutations trigger the abnormal epidermal differentiation and impaired cutaneous barrier function observed in ARCI patients. Unfortunately, current ARCI therapies focus solely on symptomatic relief. Thus, there is a significant unmet need for therapeutic strategies aimed at correcting the TGM1 deficiency underlying ARCI. Here, we investigated the ability of KB105, a gene therapy vector encoding full-length human TGM1, to deliver functional human TGM1 to keratinocytes. In vitro, KB105 efficiently infected TGM1-deficient human keratinocytes, produced TGM1 protein, and rescued transglutaminase enzyme function. In vivo studies demonstrated that both single and repeated topical KB105 administration induced TGM1 protein expression in the target epidermal layer without triggering fibrosis, necrosis, or acute inflammation. Toxicity and biodistribution assessments upon repeat-dosing indicated that KB105 was well tolerated and restricted to the dose site. Overall, our results demonstrate that rescuing TGM1 deficiency in ARCI patients via topical KB105 application represents a promising strategy for safely and non-invasively treating this debilitating disease.