1. A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa
- Author
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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
- Subjects
Science - 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.
- Published
- 2024
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