Substantial improvement of malnutrition by extensive skin replacement with revertant cultured epidermal autografts following mechanical epidermal stripping in recessive dystrophic epidermolysis bullosa

Summary: Abstract Body: Recessive dystrophic epidermolysis bullosa (RDEB) patients with biallelic defects in COL7A1 have little to no anchoring fibrils to hold the epidermis to the dermis, leading to recurrent erosions, malnutrition, and squamous cell carcinoma from APOBEC-induced somatic variations. A study of two RDEB patients, one severe and one intermediate, revealed the presence of revertant skin, measuring several cm2, in which somatic reversion of a pathogenic COL7A1 allele to wild-type occurred in keratinocytes. A comprehensive approach involving extensive mechanical epidermal stripping under general anesthesia and transplantation of revertant cultured epidermal autografts (CEAs) resulted in successful replacement of the COL7A1-deficient epidermis with revertant. Subsequent generation of CEA (sgCEA) from the revertant CEA-transplanted skin facilitated the expansion of revertant keratinocytes from a limited area to the entire body. Whole exome sequencing revealed no oncogenic variants in either CEA or sgCEA. A total of 78 and 35 CEAs and 27 and 15 sgCEAs, 10 x 8 cm in size, were transplanted at 17 and 18 years of age and at 16 years of age in severe and intermediate RDEB patients, respectively. This resulted in successful epidermal replacement in approximately 80% and 50% of the total skin, respectively, as confirmed by genetic analysis. The patients’ weight increased from 28.8 to 44.8 kg over a period of five years from the age of 17 and from 36.7 to 47.2 kg over a period of two years from the age of 16. In conclusion, the mechanical replacement of recurrently eroded epidermis with oncogenic variation-free revertant CEA resulted in substantial and sustained improvements of skin fragility, malnutrition, and quality of life in two RDEB patients, which may also reduce the future risk of carcinogenesis. Akiharu Kubo^{1, 2}, Hisato Suzuki³, Noriko Ono¹, Sonoko Saito¹, Satomi Aoki¹, Yoshio Nakamura¹, Takeru Funakoshi¹, Tomoyo Tanaka⁴, Masukazu Inoie⁴, Kenjiro Kosaki³, Masayuki Amagai¹ 1. Dermatology, Keio Univ., Tokyo, Japan. 2. Dermatology, Kobe Univ., Kobe, Japan. 3. Medical Genetics, Keio Univ., Tokyo, Japan. 4. Japan Tissue Engineering Co., Ltd., Gamagori, Japan. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics