Parameters of biliary hydrodynamic injection during endoscopic retrograde cholangio-pancreatography in pigs for applications in gene delivery.
Parameters of biliary hydrodynamic injection during endoscopic retrograde cholangio-pancreatography in pigs for applications in gene delivery.
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DOI：
10.1371/journal.pone.0249931
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Kumbhari V
中科院分区：
文献类型：
--
作者：
Huang Y;Kruse RL;Ding H;Itani MI;Morrison J;Wang ZZ;Selaru FM;Kumbhari V
胆道系统通常通过内窥镜逆行胰胆管造影术（ERCP）进入临床目的。我们之前在大型动物模型中开创了ERCP介导的流体动力学注射，作为单基因肝病的创新基因递送方法。然而，该手术存在主要与肝或胆道系统损伤相关的潜在安全性问题。在这里，我们试图进一步定义在人类大小的动物模型中耐受良好的胆汁流体动力学注射参数。在猪中进行ERCP，并使用新的协议进行流体动力学注射，以减少管壁应力。对每头猪进行多次重复注射，以加快试验并判断耐受性。对不同的注射参数（体积、流速）和注射口直径进行了试验。在整个手术过程中监测生命体征，并在术前和术后采集肝酶谱。猪耐受重复的胆汁流体动力学注射，仅偶尔、轻度、孤立的天冬氨酸转氨酶（AST）升高，在注射后1天内恢复至正常水平。所有其他肝脏检查结果均保持不变。未达到容量耐受性上限，这表明胆管树可以容易地将液体输送到血管间隙中。流速高达10 mL/sec也可耐受，对生命体征的干扰最小，无胆管解剖破裂。测量的胆内压高达150 mmHg，在高流速下在肝脏组织学中诱导充满液体的囊泡，模拟在小鼠尾静脉注射后在小鼠肝脏中观察到的组织学变化。总体而言，我们使用标准临床设备在人体大小的猪肝中进行的研究表明，患者可以安全耐受ERCP引导的流体动力学注射。未来的研究将询问更高的流速和压力是否介导更高的DNA递送效率。
The biliary system is routinely accessed for clinical purposes via endoscopic retrograde cholangiopancreatography (ERCP). We previously pioneered ERCP-mediated hydrodynamic injection in large animal models as an innovative gene delivery approach for monogenic liver diseases. However, the procedure poses potential safety concerns related mainly to liver or biliary tree injury. Here, we sought to further define biliary hydrodynamic injection parameters that are well-tolerated in a human-sized animal model. ERCP was performed in pigs, and hydrodynamic injection carried out using a novel protocol to reduce duct wall stress. Each pig was subjected to multiple repeated injections to expedite testing and judge tolerability. Different injection parameters (volume, flow rate) and injection port diameters were tested. Vital signs were monitored throughout the procedure, and liver enzyme panels were collected pre- and post-procedure. Pigs tolerated repeated biliary hydrodynamic injections with only occasional, mild, isolated elevation in aspartate aminotransferase (AST), which returned to normal levels within one day post-injection. All other liver tests remained unchanged. No upper limit of volume tolerance was reached, which suggests the biliary tree can readily transmit fluid into the vascular space. Flow rates up to 10 mL/sec were also tolerated with minimal disturbance to vital signs and no anatomic rupture of bile ducts. Measured intrabiliary pressure was up to 150 mmHg, and fluid-filled vesicles were induced in liver histology at high flow rates, mimicking the changes in histology observed in mouse liver after hydrodynamic tail vein injection. Overall, our investigations in a human-sized pig liver using standard clinical equipment suggest that ERCP-guided hydrodynamic injection will be safely tolerated in patients. Future investigations will interrogate if higher flow rates and pressure mediate higher DNA delivery efficiencies.
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影响因子：
3.5
作者：
Sendra L;Herrero MJ;Aliño SF
通讯作者：
Aliño SF
影响因子：
3.7
作者：
Kamimura K;Kanefuji T;Yokoo T;Abe H;Suda T;Kobayashi Y;Zhang G;Aoyagi Y;Liu D
通讯作者：
Liu D
影响因子：
4.2
作者：
Hyland, Kendra A.;Aronovich, Elena L.;McIvor, R. Scott
通讯作者：
McIvor, R. Scott
影响因子：
12.4
作者：
Kamimura, Kenya;Suda, Takeshi;Liu, Dexi
通讯作者：
Liu, Dexi
DOI：
10.1038/mt.2009.206
发表时间：
2010-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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作者：
通讯作者：
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