Haemophilia B Curative FIX Production from a Low Dose UCOE-based Lentiviral Vector Following Hepatic Pre-natal Delivery
Haemophilia B Curative FIX Production from a Low Dose UCOE-based Lentiviral Vector Following Hepatic Pre-natal Delivery
复制标题
DOI：
10.2174/1566523216666161102150101
复制
发表时间：
2016-01-01
影响因子：
3.6
通讯作者：
Antoniou, Michael N.
中科院分区：
文献类型：
--
作者：
Kao, Vincent Yu-cheng;Ferreira, Sonia;Antoniou, Michael N.
来自人HNRPA 2B 1-CBX 3管家基因座（A2 UCOE）的普遍存在的染色质开放元件能够提供稳定的和细胞间可重现的转基因表达水平，而不管靶细胞基因组整合位点如何，其在体外和体内在成体、胚胎和诱导多能干细胞及其分化后代中证明了功效。在这里，我们评估了基于A2 UCOE的慢病毒载体在小鼠产前分娩后稳定表达的能力。我们的研究结果表明，稳定的出生后A2 UCOE-eGFP和A2 UCOE-luciferase慢病毒载体存在于肝脏和造血系统中，伴随着持续的表达，证明了胎儿肝脏和造血干细胞的有效转导。此外，我们发现A2 UCOE-FIX慢病毒载体产生的血浆FIX蛋白量与从SFFV-FIX构建体获得的相当。此外，A2 UCOE-FIX载体显示，在每个肝细胞的低（0.19）平均载体拷贝数下，它可以提供稳定水平的血浆FIX产生，这将转化严重的血友病B（
The ubiquitous chromatin opening element from the human HNRPA2B1-CBX3 housekeeping gene locus (A2UCOE) is able to provide stable and cell-to-cell reproducible levels of transgene expression regardless of target cell genome integration site with efficacy demonstrated in adult, embryonic and induced pluripotent stem cells and their differentiated progeny in vitro and in vivo. Here we evaluate the ability of A2UCOE-based lentiviral vectors to confer stable expression following pre-natal delivery in mice. Our results show stable post-natal A2UCOE-eGFP and A2UCOE-luciferase lentiviral vector presence in both the liver and haematopoietic system with concomitant persistence of expression demonstrating efficient transduction of both fetal liver and haematopoietic stem cells. In addition, we find that an A2UCOE-FIX lentiviral vector produces comparable amounts of plasma FIX protein to that obtained from a SFFV-FIX construct. Furthermore, the A2UCOE-FIX vector shows that at a low (0.19) average vector copy number per liver cell, it can provide stable levels of plasma FIX production, which would convert severe haemophilia B (