Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France.
Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
Cell Rep Med. 2023 Feb 21;4(2):100919. doi: 10.1016/j.xcrm.2023.100919. Epub 2023 Jan 26.
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.
X 连锁慢性肉芽肿病（CGD）与吞噬作用缺陷、危及生命的感染和炎症并发症有关。我们在四名患者中进行了基于慢病毒的基因治疗临床试验（NCT02757911）。两名患者表现出稳定的嵌合和临床获益，而另外两名患者则逐渐失去了基因校正细胞。单细胞转录组分析显示 CGD 患者的造血干细胞（HSCs）频率明显较低，尤其是在两名嵌合不良的患者中。这两名患者的 HSC 状态发生了深刻变化，干扰素评分高，髓样祖细胞频率升高。我们使用弹性网络逻辑回归来鉴定一组 51 个干扰素基因和转录因子，这些基因和转录因子可预测 HSC 嵌合的失败。在一名患者中，异常的 HSC 状态伴随着 CEBPβ表达的升高，导致 HSC 衰竭，异种移植模型中的低再殖证明了这一点。针对 HSC 的保护治疗，加上针对基因表达的靶向筛选，可能会改善 CGD 的临床结果。
