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  • A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.

A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.

Nature communications (2024-07-12)
Gernot Neumayer, Jessica L Torkelson, Shengdi Li, Kelly McCarthy, Hanson H Zhen, Madhuri Vangipuram, Marius M Mader, Gulilat Gebeyehu, Taysir M Jaouni, Joanna Jacków-Malinowska, Avina Rami, Corey Hansen, Zongyou Guo, Sadhana Gaddam, Keri M Tate, Alberto Pappalardo, Lingjie Li, Grace M Chow, Kevin R Roy, Thuylinh Michelle Nguyen, Koji Tanabe, Patrick S McGrath, Amber Cramer, Anna Bruckner, Ganna Bilousova, Dennis Roop, Jean Y Tang, Angela Christiano, Lars M Steinmetz, Marius Wernig, Anthony E Oro
PMID38992003
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.