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Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.
Sobrino, Steicy; Magnani, Alessandra; Semeraro, Michaela; Martignetti, Loredana; Cortal, Akira; Denis, Adeline; Couzin, Chloé; Picard, Capucine; Bustamante, Jacinta; Magrin, Elisa; Joseph, Laure; Roudaut, Cécile; Gabrion, Aurélie; Soheili, Tayebeh; Cordier, Corinne; Lortholary, Olivier; Lefrere, François; Rieux-Laucat, Frédéric; Casanova, Jean-Laurent; Bodard, Sylvain; Boddaert, Nathalie; Thrasher, Adrian J; Touzot, Fabien; Taque, Sophie; Suarez, Felipe; Marcais, Ambroise; Guilloux, Agathe; Lagresle-Peyrou, Chantal; Galy, Anne; Rausell, Antonio; Blanche, Stephane; Cavazzana, Marina; Six, Emmanuelle.
Afiliação
  • Sobrino S; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Magnani A; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Semeraro M; Clinical Investigation Center CIC 1419, Necker-Enfants Malades Hospital, GH Paris Centre, Université Paris Cité, AP-HP, Paris, France.
  • Martignetti L; Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Cortal A; Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Denis A; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Couzin C; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Picard C; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Paris, France; Lymphocyte Activation and Susceptibility to EBV Infection Laboratory, INSERM UMR 1163, Imagine Institute, Paris, France; Centre de Références des Déficits Immunitaires Héréditai
  • Bustamante J; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Paris, France; Human Genetics of Infectious Diseases Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; St. Giles Laboratory of Human Genetics of Infectious
  • Magrin E; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Joseph L; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
  • Roudaut C; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Gabrion A; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Soheili T; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Cordier C; Plateforme de Cytométrie en Flux, Structure Fédérative de Recherche Necker, INSERM US24-CNRS UAR3633, Paris, France.
  • Lortholary O; Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France.
  • Lefrere F; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Department of Adult Hematology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
  • Rieux-Laucat F; Immunogenetics of Pediatric Autoimmune Diseases Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
  • Casanova JL; Human Genetics of Infectious Diseases Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • Bodard S; Department of Adult Radiology, Necker Enfants-Malades Hospital, AP-HP, Université Paris Cité, Paris, France; Laboratoire d'Imagerie Biomédicale, LIB, Sorbonne Université, CNRS, INSERM, Paris, France.
  • Boddaert N; Département de Radiologie Pédiatrique, INSERM UMR 1163 and UMR 1299, Imagine Institute, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
  • Thrasher AJ; UCL Great Ormond Street Institute of Child Health, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • Touzot F; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Taque S; CHU de Rennes, Département de Pédiatrie, Rennes, France.
  • Suarez F; Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France; Imagine Institute, Université Paris Cité, Paris, France.
  • Marcais A; Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France.
  • Guilloux A; Mathematics and Modelization Laboratory, CNRS, Université Paris-Saclay, Université d'Evry, Evry, France.
  • Lagresle-Peyrou C; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
  • Galy A; Genethon, Evry-Courcouronnes, France; Université Paris-Saclay, University Evry, Inserm, Genethon (UMR_S951), Evry-Courcouronnes, France.
  • Rausell A; Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; Service de Médecine Génomique des Maladies Rares, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
  • Blanche S; Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
  • Cavazzana M; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France; Imagine Institute, Université Paris Cité, Paris, France. Electronic address: m.cavazzana@aphp.fr.
  • Six E; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
Cell Rep Med ; 4(2): 100919, 2023 02 21.
Article em En | MEDLINE | ID: mdl-36706754
ABSTRACT
X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPß expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transplante de Células-Tronco Hematopoéticas / Doença Granulomatosa Crônica Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transplante de Células-Tronco Hematopoéticas / Doença Granulomatosa Crônica Idioma: En Ano de publicação: 2023 Tipo de documento: Article