{Reference Type}: Journal Article
{Title}: A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.
{Author}: Neumayer G;Torkelson JL;Li S;McCarthy K;Zhen HH;Vangipuram M;Mader MM;Gebeyehu G;Jaouni TM;Jacków-Malinowska J;Rami A;Hansen C;Guo Z;Gaddam S;Tate KM;Pappalardo A;Li L;Chow GM;Roy KR;Nguyen TM;Tanabe K;McGrath PS;Cramer A;Bruckner A;Bilousova G;Roop D;Tang JY;Christiano A;Steinmetz LM;Wernig M;Oro AE;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 Jul 11
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-49400-z
{Abstract}: 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.