Sobrino, S;
Magnani, A;
Semeraro, M;
Martignetti, L;
Cortal, A;
Denis, A;
Couzin, C;
... Six, E; + view all
(2023)
Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.
Cell Reports Medicine
, 4
(2)
, Article 100919. 10.1016/j.xcrm.2023.100919.
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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.
| Type: | Article |
|---|---|
| Title: | Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xcrm.2023.100919 |
| Publisher version: | https://doi.org/10.1016/j.xcrm.2023.100919 |
| Language: | English |
| Additional information: | © 2023 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | chronic granulomatous disease, chronic inflammation, exhaustion, gene therapy, hematopoietic stem cells, inborn errors of immunity, machine learning, single-cell RNA-seq |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166108 |
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