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A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.
Neumayer, Gernot; Torkelson, Jessica L; Li, Shengdi; McCarthy, Kelly; Zhen, Hanson H; Vangipuram, Madhuri; Mader, Marius M; Gebeyehu, Gulilat; Jaouni, Taysir M; Jacków-Malinowska, Joanna; Rami, Avina; Hansen, Corey; Guo, Zongyou; Gaddam, Sadhana; Tate, Keri M; Pappalardo, Alberto; Li, Lingjie; Chow, Grace M; Roy, Kevin R; Nguyen, Thuylinh Michelle; Tanabe, Koji; McGrath, Patrick S; Cramer, Amber; Bruckner, Anna; Bilousova, Ganna; Roop, Dennis; Tang, Jean Y; Christiano, Angela; Steinmetz, Lars M; Wernig, Marius; Oro, Anthony E.
Afiliação
  • Neumayer G; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Torkelson JL; Department of Pathology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Li S; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • McCarthy K; Center for Definitive and Curative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Zhen HH; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.
  • Vangipuram M; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Mader MM; Center for Definitive and Curative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Gebeyehu G; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Jaouni TM; Center for Definitive and Curative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Jacków-Malinowska J; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Rami A; Department of Pathology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Hansen C; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Guo Z; Department of Pathology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Gaddam S; Thermo Fisher Scientific, Life Sciences Solutions Group, Cell Biology, Research and Development, Frederick, MD, USA.
  • Tate KM; Thermo Fisher Scientific, Life Sciences Solutions Group, Cell Biology, Research and Development, Frederick, MD, USA.
  • Pappalardo A; Department of Dermatology, Columbia University, New York, NY, USA.
  • Li L; St. John's Institute of Dermatology, King's College London, London, UK.
  • Chow GM; Department of Dermatology, Columbia University, New York, NY, USA.
  • Roy KR; Department of Dermatology, Columbia University, New York, NY, USA.
  • Nguyen TM; Department of Dermatology, Columbia University, New York, NY, USA.
  • Tanabe K; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • McGrath PS; Center for Definitive and Curative Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
  • Cramer A; Department of Dermatology, Columbia University, New York, NY, USA.
  • Bruckner A; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Bilousova G; Department of Dermatology-Program in Epithelial Biology, Stanford University, School of Medicine, Stanford, CA, USA.
  • Roop D; Department of Genetics, Stanford University, School of Medicine, Stanford, CA, USA.
  • Tang JY; Stanford Genome Technology Center, Stanford University, School of Medicine, Stanford, CA, USA.
  • Christiano A; Department of Genetics, Stanford University, School of Medicine, Stanford, CA, USA.
  • Steinmetz LM; Stanford Genome Technology Center, Stanford University, School of Medicine, Stanford, CA, USA.
  • Wernig M; I Peace Inc., Palo Alto, CA, USA.
  • Oro AE; Department of Dermatology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
Nat Commun ; 15(1): 5834, 2024 Jul 11.
Article em En | MEDLINE | ID: mdl-38992003
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epidermólise Bolhosa Distrófica / Colágeno Tipo VII / Células-Tronco Pluripotentes Induzidas / Terapia Baseada em Transplante de Células e Tecidos Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epidermólise Bolhosa Distrófica / Colágeno Tipo VII / Células-Tronco Pluripotentes Induzidas / Terapia Baseada em Transplante de Células e Tecidos Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article