Targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells in vivo using the engineered AVID adenovirus vector platform.
Targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells in vivo using the engineered AVID adenovirus vector platform.
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使用工程化的 AVID 腺病毒载体平台，将基因靶向、安全、高效地递送至体内人类造血干细胞和祖细胞。
DOI：
10.1016/j.ymthe.2023.10.023
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Shayakhmetov,DmitryM
中科院分区：
文献类型：
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作者：
Yao,Jia;Atasheva,Svetlana;Wagner,Nicole;DiPaolo,NelsonC;Stewart,PhoebeL;Shayakhmetov,DmitryM
靶向递送和在体内各种细胞类型中特定细胞类型表达基因编辑蛋白是迄今为止开发的所有病毒和非病毒递送平台面临的主要挑战。在这里，我们描述了人工血管内递送载体(AVDS)的开发和分析，这是一种基于腺病毒的工程化基因递送平台，在静脉注射载体后，它可以高度靶向、安全和高效地将基因递送到活体中的人造血干细胞和祖细胞(HSPC)。由于一系列精细的结构修改，静脉注射Avids没有引发细胞因子风暴、肝毒性或血小板减少症。将人CD34+细胞移植到人源化小鼠体内，一次静脉注射可导致骨髓中CD34+CD38CD45RA−−HSPC亚群转导达20%。重要的是，针对CD34+CD38−CD45RA−CD90−CD49f+亚群的活体转导，高度浓缩的人造血干细胞(HSCs)高达19%，这意味着与谱系承诺的CD34阴性细胞群体相比，对HSC富集型基因的选择性提高了1,900倍。由于Avid平台允许基因编辑技术受调控的、细胞类型特异性的表达以及免疫调节蛋白的表达，以确保体内纠正的HSC的持久性，因此以HSC为靶点的Avid平台可以在单一静脉给药后通过对人类HSC进行活体纠正来开发治疗方法。
Targeted delivery and cell-type-specific expression of gene-editing proteins in various cell typesin vivorepresent major challenges for all viral and non-viral delivery platforms developed to date. Here, we describe the development and analysis of artificial vectors for intravascular delivery (AVIDs), an engineered adenovirus-based gene delivery platform that allows for highly targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells (HSPCs)in vivoafter intravenous vector administration. Due to a set of refined structural modifications, intravenous administration of AVIDs did not trigger cytokine storm, hepatotoxicity, or thrombocytopenia. Single intravenous administration of AVIDs to humanized mice, grafted with human CD34+cells, led to up to 20% transduction of CD34+CD38−CD45RA−HSPC subsets in the bone marrow. Importantly, targetedin vivotransduction of CD34+CD38−CD45RA−CD90−CD49f+subsets, highly enriched for human hematopoietic stem cells (HSCs), reached up to 19%, which represented a 1,900-fold selectivity in gene delivery to HSC-enriched over lineage-committed CD34-negative cell populations. Because the AVID platform allows for regulated, cell-type-specific expression of gene-editing technologies as well as expression of immunomodulatory proteins to ensure persistence of corrected HSCsin vivo, the HSC-targeted AVID platform may enable development of curative therapies throughin vivogene correction in human HSCs after a single intravenous administration.