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

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.

DOI: 10.1016/j.xcrm.2023.100919, PMID: 36706754
Authors: 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