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

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 () and Anthony E. Oro
Additional contact information
Gernot Neumayer: School of Medicine
Jessica L. Torkelson: School of Medicine
Shengdi Li: Genome Biology Unit
Kelly McCarthy: School of Medicine
Hanson H. Zhen: School of Medicine
Madhuri Vangipuram: School of Medicine
Marius M. Mader: School of Medicine
Gulilat Gebeyehu: Research and Development
Taysir M. Jaouni: Research and Development
Joanna Jacków-Malinowska: Columbia University
Avina Rami: Columbia University
Corey Hansen: Columbia University
Zongyou Guo: Columbia University
Sadhana Gaddam: School of Medicine
Keri M. Tate: School of Medicine
Alberto Pappalardo: Columbia University
Lingjie Li: School of Medicine
Grace M. Chow: School of Medicine
Kevin R. Roy: School of Medicine
Thuylinh Michelle Nguyen: School of Medicine
Koji Tanabe: I Peace Inc.
Patrick S. McGrath: University of Colorado School of Medicine, Anschutz Medical Campus
Amber Cramer: School of Medicine
Anna Bruckner: University of Colorado School of Medicine, Anschutz Medical Campus
Ganna Bilousova: University of Colorado School of Medicine, Anschutz Medical Campus
Dennis Roop: University of Colorado School of Medicine, Anschutz Medical Campus
Jean Y. Tang: School of Medicine
Angela Christiano: Columbia University
Lars M. Steinmetz: Genome Biology Unit
Marius Wernig: School of Medicine
Anthony E. Oro: School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49400-z

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