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

In Cell reports. Medicine

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.

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

2023-Jan-19

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