Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates
Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates
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DOI：
10.1016/j.omtm.2018.12.001
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发表时间：
2019-06-14
影响因子：
4.7
通讯作者：
Bankiewicz, Krystof S.
中科院分区：
文献类型：
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作者：
Ohno, Kousaku;Samaranch, Lluis;Bankiewicz, Krystof S.
在这里，我们评估了MRI监测非人灵长类动物鞘内输注的实用性。加标钆特醇（一种基于钆的MRI造影剂）的腺相关病毒（AAV）能够实时可视化通过延髓池、腰椎、延髓和腰椎或脑室内输注输送的输注。分析了载体从脑脊液（CSF）中清除的动力学。我们的研究结果强调了MRI在优化输注液到CSF中的输送方面的价值。特别是，MRI显示输注液分布的差异模式取决于输送途径。Gadoteridol覆盖率分析表明，小脑延髓池输送是一种可靠有效的注射途径，可实现脑和脊髓中广泛的输注物分布，与腰椎注射联合使用时甚至更大。与此相反，侧脑室注射导致强大的皮质覆盖，但很少脊髓分布。单独腰椎注射导致MRI造影剂主要分布在脊髓中，几乎没有皮质覆盖，但这种输送途径不可靠。同样，媒介清除分析显示不同的传递途径之间存在差异。总体而言，我们的数据支持监测CSF注射的价值，以基于鞘内给药途径分析不同的钆特醇分布模式。
Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Our results highlight the value of MRI in optimizing the delivery of infusate into CSF. In particular, MRI revealed differential patterns of infusate distribution depending on the route of delivery. Gadoteridol coverage analysis showed that cerebellomedullary cistern delivery was a reliable and effective route of injection, achieving broad infusate distribution in the brain and spinal cord, and was even greater when combined with lumbar injection. In contrast, intracerebroventricular injection resulted in strong cortical coverage but little spinal distribution. Lumbar injection alone led to the distribution of MRI contrast agent mainly in the spinal cord with little cortical coverage, but this delivery route was unreliable. Similarly, vector clearance analysis showed differences between different routes of delivery. Overall, our data support the value of monitoring CSF injections to dissect different patterns of gadoteridol distribution based on the route of intrathecal administration.