Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Steicy Sobrino; Alessandra Magnani; Michaela Semeraro; Loredana Martignetti; Akira Cortal; Adeline Denis; Chloé Couzin; Capucine Picard; Jacinta Bustamante; Elisa Magrin; Laure Joseph; Cécile Roudaut; Aurélie Gabrion; Tayebeh Soheili; Corinne Cordier; Olivier Lortholary; François Lefrere; Frédéric Rieux-Laucat; Jean-Laurent Casanova; Sylvain Bodard; Nathalie Boddaert; Adrian J Thrasher; Fabien Touzot; Sophie Taque; Felipe Suarez; Ambroise Marcais; Agathe Guilloux; Chantal Lagresle-Peyrou; Anne Galy; Antonio Rausell; Stephane Blanche; Marina Cavazzana; Emmanuelle Six

doi:10.1016/j.xcrm.2023.100919

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Cell Rep Med. 2023 Feb 21;4(2):100919. doi: 10.1016/j.xcrm.2023.100919. Epub 2023 Jan 26.

Authors

Steicy Sobrino¹, Alessandra Magnani², Michaela Semeraro³, Loredana Martignetti⁴, Akira Cortal⁴, Adeline Denis¹, Chloé Couzin², Capucine Picard⁵, Jacinta Bustamante⁶, Elisa Magrin², Laure Joseph⁷, Cécile Roudaut², Aurélie Gabrion², Tayebeh Soheili¹, Corinne Cordier⁸, Olivier Lortholary⁹, François Lefrere¹⁰, Frédéric Rieux-Laucat¹¹, Jean-Laurent Casanova¹², Sylvain Bodard¹³, Nathalie Boddaert¹⁴, Adrian J Thrasher¹⁵, Fabien Touzot², Sophie Taque¹⁶, Felipe Suarez¹⁷, Ambroise Marcais⁹, Agathe Guilloux¹⁸, Chantal Lagresle-Peyrou¹⁹, Anne Galy²⁰, Antonio Rausell²¹, Stephane Blanche²², Marina Cavazzana²³, Emmanuelle Six¹

Affiliations

¹ Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
² Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
³ Clinical Investigation Center CIC 1419, Necker-Enfants Malades Hospital, GH Paris Centre, Université Paris Cité, AP-HP, Paris, France.
⁴ Clinical Bioinformatics Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
⁵ 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.
⁶ 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.
⁷ Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
⁸ Plateforme de Cytométrie en Flux, Structure Fédérative de Recherche Necker, INSERM US24-CNRS UAR3633, Paris, France.
⁹ Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cité, Imagine Institute, Paris, France.
¹⁰ Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Department of Adult Hematology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
¹¹ Immunogenetics of Pediatric Autoimmune Diseases Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
¹² 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.
¹³ 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.
¹⁴ Département de Radiologie Pédiatrique, INSERM UMR 1163 and UMR 1299, Imagine Institute, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
¹⁵ UCL Great Ormond Street Institute of Child Health, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
¹⁶ CHU de Rennes, Département de Pédiatrie, Rennes, France.
¹⁷ 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.
¹⁸ Mathematics and Modelization Laboratory, CNRS, Université Paris-Saclay, Université d'Evry, Evry, France.
¹⁹ 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.
²⁰ Genethon, Evry-Courcouronnes, France; Université Paris-Saclay, University Evry, Inserm, Genethon (UMR_S951), Evry-Courcouronnes, France.
²¹ 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.
²² Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
²³ 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.

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 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.

Keywords: chronic granulomatous disease; chronic inflammation; exhaustion; gene therapy; hematopoietic stem cells; inborn errors of immunity; machine learning; single-cell RNA-seq.

Publication types

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

MeSH terms

Genetic Therapy / adverse effects
Granulomatous Disease, Chronic* / diagnosis
Granulomatous Disease, Chronic* / genetics
Granulomatous Disease, Chronic* / therapy
Hematopoietic Stem Cell Transplantation*
Hematopoietic Stem Cells / metabolism
Humans
Inflammation / metabolism
Interferons / metabolism

Substances

Interferons