Neurological disorders pose a challenge for targeted therapy due to restricted access of therapeutic agents to the central nervous system (CNS). Current methods are limited by procedure-related risks, invasiveness, and insufficient CNS biodistribution. A novel percutaneous transvenous technology, currently in clinical trials for communicating hydrocephalus, offers a minimally invasive approach by providing endovascular access to the cerebrospinal fluid-filled cerebellopontine angle (CPA) cistern. We hypothesized that drug delivery to the CPA cistern could yield widespread CNS distribution. Using an ovine model, we compared the biodistribution of scAAV9-CB-GFP following CPA cistern infusion with previously reported cisterna magna (CM) administration. Targeting both the CPA cistern and CM in sheep, we employed a lumbar spine-inserted microcatheter under fluoroscopy. CPA delivery of AAV9 demonstrated biodistribution and transduction in the cerebral cortices, striatum, thalamus, midbrain, cerebellum, and spinal cord, with minor liver distribution comparable to CM. The favorable safety profile in humans with hydrocephalus suggests that percutaneous endovascular injection into the CPA could offer a clinically safer and minimally invasive delivery system for CNS gene and cell-based therapies.

中文翻译：

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小脑桥脑角池的微创血管内入路可实现 scAAV9-CB-GFP 的广泛 CNS 生物分布


由于治疗药物进入中枢神经系统 （CNS） 的机会有限，神经系统疾病对靶向治疗构成挑战。目前的方法受到手术相关风险、侵入性和 CNS 生物分布不足的限制。一种新型经皮经静脉技术，目前正在进行交通脑积水的临床试验，通过提供进入充满脑脊液的桥小脑角 （CPA） 池的血管内通路，提供了一种微创方法。我们假设将药物输送到 CPA 蓄水池可以产生广泛的 CNS 分布。使用绵羊模型，我们比较了 CPA 水箱输注与先前报道的大池 （CM） 给药后 scAAV9-CB-GFP 的生物分布。针对绵羊的 CPA 池和 CM，我们在透视下采用了腰椎插入微导管。AAV9 的 CPA 递送在大脑皮层、纹状体、丘脑、中脑、小脑和脊髓中显示出生物分布和转导，肝脏分布较小，与 CM 相当。脑积水患者的良好安全性表明，经皮血管内注射到 CPA 中可以为 CNS 基因和基于细胞的疗法提供临床更安全的微创输送系统。