Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations.
Nanoparticle-mediated transgene expression of insulin-like growth factor 1 in the growth restricted guinea pig placenta increases placenta nutrient transporter expression and fetal glucose concentrations.
复制标题
纳米颗粒介导的胰岛素样生长因子 1 在生长受限的豚鼠胎盘中的转基因表达增加了胎盘营养转运蛋白的表达和胎儿葡萄糖浓度。
DOI：
10.1002/mrd.23644
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发表时间：
2022
影响因子：
2.5
通讯作者：
Jones,HelenN
中科院分区：
文献类型：
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作者：
Wilson,RebeccaL;Lampe,Kristin;Gupta,MukeshK;Duvall,CraigL;Jones,HelenN
胎儿生长受限（FGR）显着影响新生儿和围产儿的发病率和死亡率。目前，妊娠期 FGR 尚无有效的治疗方案。我们开发了一种针对胎盘的纳米颗粒基因疗法，以增加人胰岛素样生长因子 1 (hIGF1) 的表达，从而纠正胎儿的生长轨迹。使用 FGR 母体营养限制豚鼠模型，在妊娠中期在超声引导下胎盘内注射非病毒、基于聚合物的 hIGF1 纳米颗粒，该纳米颗粒含有带有 hIGF1 基因和胎盘特异性 Cyp19a1 启动子的质粒。治疗后 5 天，胎盘中确认了持续的 hIGF1 表达。虽然 hIGF1 增加不会改变胎儿体重，但胎儿循环葡萄糖浓度升高了 33%–67%。这与胎盘中葡萄糖和氨基酸转运蛋白的表达增加有关。此外，hIGF1纳米颗粒治疗增加了胎盘中胎儿毛细血管的体积密度，并缩短了母体和胎儿循环之间的血管间距离。总体而言，我们的研究结果表明，滋养层特异性 hIGF1 表达增加会导致葡萄糖转运蛋白表达发生变化，并在短时间内增加胎儿葡萄糖浓度，这凸显了这种治疗在纠正 FGR 并发的人类妊娠中胎盘营养转运受损方面的转化潜力。
Fetal growth restriction (FGR) significantly contributes to neonatal and perinatal morbidity and mortality. Currently, there are no effective treatment options for FGR during pregnancy. We have developed a nanoparticle gene therapy targeting the placenta to increase expression of humaninsulin‐like growth factor 1(hIGF1) to correct fetal growth trajectories. Using the maternal nutrient restriction guinea pig model of FGR, an ultrasound‐guided, intraplacental injection of nonviral, polymer‐basedhIGF1nanoparticle containing plasmid with thehIGF1gene and placenta‐specificCyp19a1promotor was administered at mid‐pregnancy. SustainedhIGF1expression was confirmed in the placenta 5 days after treatment. Whilst increasedhIGF1did not change fetal weight, circulating fetal glucose concentration were 33%–67% higher. This was associated with increased expression of glucose and amino acid transporters in the placenta. Additionally,hIGF1nanoparticle treatment increased the fetal capillary volume density in the placenta, and reduced interhaemal distance between maternal and fetal circulation. Overall, our findings, that trophoblast‐specific increased expression ofhIGF1results in changes to glucose transporter expression and increases fetal glucose concentrations within a short time period, highlights the translational potential this treatment could have in correcting impaired placental nutrient transport in human pregnancies complicated by FGR.