Journal Article

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa

Nazaroff, Jaron, Chiou, Albert S., So, Jodi Y., Tang, Jean Y., Fulchand, Shivali, Harris, Nicki, Iwummadu, Chinonso V., Gorell, Emily S., Bailey, Irene, Siprashvili, Zurab, Marinkovich, M. Peter, McCarthy, Daniel

2022

Overview

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. Methods Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm 2 ) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. Results Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4–8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing ( p  < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. Conclusions Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. Trial registration ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Antibodies / Autografts / Autoimmunity / Biomedical materials / Blistering diseases / Care and treatment / Cell death / Clinical outcomes / Clinical trials / Collagen / Collagen (type VII) / Dystrophic epidermolysis bullosa / Epidermolysis bullosa / Gene therapy / Genetic aspects / Genetic diseases / Genodermatoses / Genodermatosis / Health aspects / Human Genetics / Infections / Keratinocytes / Medical research / Medicine / Medicine & Public Health / Metastasis / Methods / Pain / Pharmacology/Toxicology / Rare diseases / Rare skin diseases / Recessive dystrophic epidermolysis bullosa / Squamous cell carcinoma / Testing / Wound healing / Wounds and injuries