%0 Journal Article
%T A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.
%A Neumayer G
%A Torkelson JL
%A Li S
%A McCarthy K
%A Zhen HH
%A Vangipuram M
%A Mader MM
%A Gebeyehu G
%A Jaouni TM
%A Jacków-Malinowska J
%A Rami A
%A Hansen C
%A Guo Z
%A Gaddam S
%A Tate KM
%A Pappalardo A
%A Li L
%A Chow GM
%A Roy KR
%A Nguyen TM
%A Tanabe K
%A McGrath PS
%A Cramer A
%A Bruckner A
%A Bilousova G
%A Roop D
%A Tang JY
%A Christiano A
%A Steinmetz LM
%A Wernig M
%A Oro AE
%J Nat Commun
%V 15
%N 1
%D 2024 Jul 11
%M 38992003
%F 17.694
%R 10.1038/s41467-024-49400-z
%X We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.