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

Author

Listed:
  • Gernot Neumayer

    (School of Medicine
    School of Medicine)

  • Jessica L. Torkelson

    (School of Medicine
    School of Medicine)

  • Shengdi Li

    (Genome Biology Unit)

  • Kelly McCarthy

    (School of Medicine
    School of Medicine)

  • Hanson H. Zhen

    (School of Medicine
    School of Medicine)

  • Madhuri Vangipuram

    (School of Medicine
    School of Medicine)

  • Marius M. Mader

    (School of Medicine
    School of Medicine)

  • Gulilat Gebeyehu

    (Research and Development)

  • Taysir M. Jaouni

    (Research and Development)

  • Joanna Jacków-Malinowska

    (Columbia University
    King’s College London)

  • 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
    School of Medicine)

  • Thuylinh Michelle Nguyen

    (School of Medicine
    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
    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
    School of Medicine)

  • Angela Christiano

    (Columbia University)

  • Lars M. Steinmetz

    (Genome Biology Unit
    School of Medicine
    School of Medicine)

  • Marius Wernig

    (School of Medicine
    School of Medicine
    School of Medicine)

  • Anthony E. Oro

    (School of Medicine
    School of Medicine)

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.

Suggested Citation

  • 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 Ra, 2024. "A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49400-z
    DOI: 10.1038/s41467-024-49400-z
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    References listed on IDEAS

    as
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