A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna
A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna
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DOI：
10.1016/j.ymthe.2019.11.012
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发表时间：
2020-02-05
影响因子：
12.4
通讯作者：
Gray-Edwards, Heather L.
中科院分区：
文献类型：
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作者：
Taghian, Toloo;Marosfoi, Miklos G.;Gray-Edwards, Heather L.
向中枢神经系统的整体基因递送对于治疗影响整个中枢神经系统的神经系统疾病具有重要的治疗意义。由于与中枢神经系统直接接触，脑脊液（CSF）是中枢神经系统基因传递的一种有吸引力的途径。需要一种安全有效的途径来实现中枢神经系统的全球基因分布，并且通过枕骨下穿刺通过小脑延髓池 (CM) 进行基因管理，导致基因在大脑和脊髓中广泛分布。然而，由于患者存在严重且可能致命的并发症的风险，将该技术转化为临床实践具有挑战性。在此，我们报告了通过血管内微导管改造向 CM 提供基因治疗递送方法的开发，该微导管可以在荧光镜引导下安全地在鞘内导航。我们使用自我互补的腺相关病毒 9 (scAAV9)-GFP 载体检查了该方法在绵羊中的安全性、重现性和分布/转导。该技术用于通过 AAV 基因治疗治疗两名泰萨克斯病患者（30 个月和 7 个月）。输注期间或治疗后未观察到不良反应。这种输送技术是直接输注到 CM 的安全且微创的替代方案，可实现 AAV 基因转移到 CNS 的广泛分布。
Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.