美国哈佛医学院波士顿儿童医院Vijay G. Sankaran和Richard A. Voit共同合作，近期取得重要工作进展。他们研究提出将调控GATA1表达作为Diamond-Blackfan贫血症的通用基因疗法。相关研究成果2024年11月11日在线发表于《细胞—干细胞》杂志上。

据介绍，使用造血干细胞和祖细胞的基因治疗正在改变血液、免疫和代谢疾病患者的治疗前景，但尚未成功开发用于骨髓衰竭综合征Diamond-Blackfan贫血（DBA）患者的治疗。超过30多种突变通过核糖体功能受损导致DBA，并导致红系主调节因子GATA1的翻译效率低下，为适用于所有DBA患者的治疗干预提供了一条潜在途径，而不管潜在的基因型如何。

研究人员报告了一种临床级慢病毒基因疗法的开发，该疗法实现了GATA1的红系谱系限制性表达。研究人员表明，该载体能够在DBA模型和各种患者样本中增强红细胞生成，而不会影响造血干细胞功能或显示任何癌前克隆扩增的迹象。这些临床前安全性和有效性数据为通过调节GATA1表达，进行DBA的首次人体通用基因治疗试验提供了强有力的支持。

附：英文原文

Title: Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia

Author: Richard A. Voit, Xiaotian Liao, Alexis Caulier, Mateusz Antoszewski, Blake Cohen, Myriam Armant, Henry Y. Lu, Travis J. Fleming, Elena Kamal, Lara Wahlster, Aoife M. Roche, John K. Everett, Angelina Petrichenko, Mei-Mei Huang, William Clarke, Kasiani C. Myers, Craig Forester, Antonio Perez-Atayde, Frederic D. Bushman, Danilo Pellin, Akiko Shimamura, David A. Williams, Vijay G. Sankaran

Issue&Volume: 2024-11-11

Abstract: Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.

DOI: 10.1016/j.stem.2024.10.012

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00374-6