Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

Humans Genetic Therapy / adverse effects Granulomatous Disease, Chronic / diagnosis Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells / metabolism Inflammation / metabolism Interferons / metabolism
chronic granulomatous disease chronic inflammation exhaustion gene therapy hematopoietic stem cells inborn errors of immunity machine learning single-cell RNA-seq

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
21 02 2023
Historique:
received: 06 07 2022
revised: 20 10 2022
accepted: 06 01 2023
pubmed: 28 1 2023
medline: 25 2 2023
entrez: 27 1 2023
Statut: ppublish

Résumé

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 CEBPβ 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.

Identifiants

DOI: 10.1016/j.xcrm.2023.100919 PMID: 36706754 PMC: PMC9975109
pubmed: 36706754
pii: S2666-3791(23)00004-6
doi: 10.1016/j.xcrm.2023.100919
pmc: PMC9975109
pii:
doi:

Substances chimiques

Interferons 9008-11-1

Types de publication

Clinical Trial Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

100919

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests S.S., L.M., A.C., A.D., A. Guilloux, A.R., M.C., and E.S. have submitted a patent related to the use of the predictive markers for assessing HSC exhaustion induced by chronic inflammation (EP22305722.5 filed on May 16, 2022).

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Auteurs

Steicy Sobrino (S)

Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Alessandra 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.

Michaela Semeraro (M)

Clinical Investigation Center CIC 1419, Necker-Enfants Malades Hospital, GH Paris Centre, Université Paris Cité, AP-HP, Paris, France.

Loredana Martignetti (L)

Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Akira Cortal (A)

Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Adeline Denis (A)

Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Chloé 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.

Capucine 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 Héréditaires (CEREDIH), Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Jacinta 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 Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Elisa 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.

Laure Joseph (L)

Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Cécile 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.

Aurélie 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.

Tayebeh Soheili (T)

Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Corinne Cordier (C)

Plateforme de Cytométrie en Flux, Structure Fédérative de Recherche Necker, INSERM US24-CNRS UAR3633, Paris, France.

Olivier Lortholary (O)

Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France.

François Lefrere (F)

Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Department of Adult Hematology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Frédéric Rieux-Laucat (F)

Immunogenetics of Pediatric Autoimmune Diseases Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

Jean-Laurent 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.

Sylvain 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.

Nathalie Boddaert (N)

Département de Radiologie Pédiatrique, INSERM UMR 1163 and UMR 1299, Imagine Institute, AP-HP, Necker-Enfants Malades Hospital, Paris, France.

Adrian J Thrasher (AJ)

UCL Great Ormond Street Institute of Child Health, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Fabien 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.

Sophie Taque (S)

CHU de Rennes, Département de Pédiatrie, Rennes, France.

Felipe 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.

Ambroise Marcais (A)

Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France.

Agathe Guilloux (A)

Mathematics and Modelization Laboratory, CNRS, Université Paris-Saclay, Université d'Evry, Evry, France.

Chantal 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.

Anne Galy (A)

Genethon, Evry-Courcouronnes, France; Université Paris-Saclay, University Evry, Inserm, Genethon (UMR_S951), Evry-Courcouronnes, France.

Antonio 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.

Stephane Blanche (S)

Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.

Marina 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.

Emmanuelle Six (E)

Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Génie génétique › Thérapie génétique › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Granulomatose septique chronique › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › Procédures de chirurgie opératoire › Transplantation › Transplantation cellulaire › Transplantation de cellules souches › Transplantation de cellules souches hématopoïétiques › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système hématopoïétique › Cellules de la moelle osseuse › Cellules souches hématopoïétiques › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Severe hematopoietic stem cell inflammation...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interférons › Severe hematopoietic stem cell inflammation...