A Scalable and CGMP-compatible Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jul 11

PMID 38992003

Authors

Gernot Neumayer

Jessica L Torkelson

Shengdi Li

Kelly McCarthy

Hanson H Zhen

Madhuri Vangipuram

Marius M Mader

Gulilat Gebeyehu

Taysir M Jaouni

Joanna Jackow-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

Soon will be listed here.

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.

Citing Articles

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Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Koutsoukos S, Bilousova G Dermatol Ther (Heidelb). 2024; 14(9):2379-2392.

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Bischof J, Hierl M, Koller U Int J Mol Sci. 2024; 25(4).

PMID: 38396920 PMC: 10889532. DOI: 10.3390/ijms25042243.

Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects.

Hou P, Del Agua N, Lwin S, Hsu C, McGrath J Ther Clin Risk Manag. 2023; 19:455-473.

PMID: 37337559 PMC: 10277004. DOI: 10.2147/TCRM.S386923.

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