Nature Communications (Jul 2024)
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,
- Anthony E. Oro
Affiliations
- Gernot Neumayer
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine
- Jessica L. Torkelson
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Shengdi Li
- European Molecular Biology Laboratory, Genome Biology Unit
- Kelly McCarthy
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Hanson H. Zhen
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Madhuri Vangipuram
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine
- Marius M. Mader
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine
- Gulilat Gebeyehu
- Thermo Fisher Scientific, Life Sciences Solutions Group, Cell Biology, Research and Development
- Taysir M. Jaouni
- Thermo Fisher Scientific, Life Sciences Solutions Group, Cell Biology, Research and Development
- Joanna Jacków-Malinowska
- Department of Dermatology, Columbia University
- Avina Rami
- Department of Dermatology, Columbia University
- Corey Hansen
- Department of Dermatology, Columbia University
- Zongyou Guo
- Department of Dermatology, Columbia University
- Sadhana Gaddam
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Keri M. Tate
- Center for Definitive and Curative Medicine, Stanford University, School of Medicine
- Alberto Pappalardo
- Department of Dermatology, Columbia University
- Lingjie Li
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Grace M. Chow
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Kevin R. Roy
- Department of Genetics, Stanford University, School of Medicine
- Thuylinh Michelle Nguyen
- Department of Genetics, Stanford University, School of Medicine
- Koji Tanabe
- I Peace Inc.
- Patrick S. McGrath
- Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus
- Amber Cramer
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Anna Bruckner
- Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus
- Ganna Bilousova
- Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus
- Dennis Roop
- Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus
- Jean Y. Tang
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- Angela Christiano
- Department of Dermatology, Columbia University
- Lars M. Steinmetz
- European Molecular Biology Laboratory, Genome Biology Unit
- Marius Wernig
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine
- Anthony E. Oro
- Department of Dermatology—Program in Epithelial Biology, Stanford University, School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-49400-z
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
