Treating epidermolytic ichthyosis and ichthyosis with confetti with epidermal autografts cultured from revertant skin

Abstract

Background No efficient treatment has been established yet for epidermolytic ichthyosis (EI) caused by pathogenic variants in KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) show multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. Objective To assess the feasibility transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. Methods We performed a clinical trial of treatment with CEAs produced from each patient’s own revertant epidermal keratinocytes as a proof-of-concept study. This is a single-arm, open (masking not used), uncontrolled, single-assignment, treatment purpose study. The primary outcome was the rate of areas without the recurrence of ichthyosis lesions 4 weeks after the final transplant (%). The secondary outcome was the rate of areas without the recurrence of ichthyosis lesions 24 weeks after initial transplantation (%). Results We successfully produced CEAs from the genetically confirmed revertant skin of the two mosaic EI patients and one IWC patient and genetically confirmed that CEAs mainly consist of revertant wild-type cells by amplicon sequencing and droplet digital PCR analysis. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted to desquamated lesional sites of the patients. Four weeks after this transplantation, the rate of areas without the recurrence of ichthyosis lesions in the three cases was 39.52%, 100.0%, and 100.0% respectively, although the recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks after transplantation. Conclusion CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC. Trial registration jRCTb041190097