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

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2024-11-11 DOI:10.1016/j.stem.2024.10.012

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, Vijay G. Sankaran

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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.

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将调控 GATA1 表达作为钻石-黑方贫血症的通用基因疗法

利用造血干细胞和祖细胞的基因疗法正在改变血液病、免疫病和代谢性疾病患者的治疗格局，但对于骨髓衰竭综合征钻石-贝克范贫血症（DBA）患者的基因疗法尚未成功开发。30 多种基因突变会导致核糖体功能受损，并导致红细胞主调节因子 GATA1 翻译效率低下，从而引起 DBA，这为适用于所有 DBA 患者（无论其潜在基因型如何）的治疗干预提供了潜在途径。在此，我们报告了临床级慢病毒基因疗法的开发情况，该疗法可实现红细胞系限制性表达 GATA1。我们的研究表明，这种载体能够增强 DBA 模型和不同患者样本的红细胞生成，而不会影响造血干细胞的功能，也不会表现出任何恶性前克隆扩增的迹象。这些临床前安全性和有效性数据为通过调控 GATA1 的表达来治疗 DBA 的首次人体通用基因治疗试验提供了强有力的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.