Optimizing Direct Delivery of Nucleic Acid Therapeutics

项目摘要 虽然核酸治疗剂已经在啮齿动物和非人灵长类动物模型中显示出前景， CNS疾病，迄今为止所有双盲临床试验均失败。一种可能的解释是 失败是在目标脑区域中的不良治疗分布。比如说， 接受脑实质内注射AAV-NTN的帕金森病患者的研究 表现出非常有限的蛋白质表达。在这项研究中，只有10-16%的转基因是 使用标准注射方法观察尸检，最多注射15%的TH， 调控尽管这项研究的结果令人失望，但有强有力的证据表明， 这种基因治疗方法是有效的，并且能够非常有效。 非人类灵长类动物研究和人类试验之间的主要区别是， 猴子受到广泛的感染，而人类的感染则急剧增加。 由于大脑体积大得多而减少。根据研究结果， Ceregene（AAV-NTN）、Sanofi-Genzyme（AAV-hAADC）和Neurologix（AAV-GAD），我们 我的结论是，这些临床试验的失败部分是由于治疗不足， 交付.今天，将治疗剂分配到诸如纹状体的大脑区域需要 使用大规格套管每个半球多个轨迹。进行连续输注 沿沿着多个轨迹使用直插管延长了手术时间并增加了风险 出血和组织创伤需要一个新的系统来提高效率， 在脑中核酸治疗递送的有效性。 我们建议开发一种MR兼容的立体定向输送装置， 实现了对常见CNS疾病靶点的广泛核酸治疗覆盖。的 将使用病毒载体替代品在大鼠中测试器械。拟议的交付技术是 非特异性的，可以应用于治疗广泛的CNS疾病， 正在研究核酸疗法，包括亨廷顿氏病（IONIS-HTT）， 帕金森氏病（VY-AADC）和圣菲利波综合征（LYS-SAF 302）。

Project Summary While nucleic acid therapeutics have shown promise in rodent and nonhuman primate models of CNS diseases, all double blind clinical trials to date have failed. One likely explanation for this failure is poor therapeutic distribution in targeted brain regions. For example, post-mortem studies of patients with Parkinson's Disease receiving intraparenchymal injections of AAV-NTN demonstrated very limited protein expression. In this study, only 10-16% of the transgene was observable post-mortem using a standard injection approach with a maximum of 15% of TH up- regulation. Although the results of this study were disappointing, there is strong evidence that this gene therapy approach is valid and is capable of being highly effective. A primary difference between non-human primate studies and human trials has been that the monkeys receive a wide distribution of infection, while infection in humans is dramatically reduced due to the much larger brain volumes. Based on the results of the studies conducted by Ceregene (AAV-NTN), Sanofi-Genzyme (AAV-hAADC), and Neurologix (AAV-GAD), we conclude that the failure of these clinical trials was due in part to inadequate therapeutic delivery. Today, distribution of therapeutic to a brain region such as the striatum requires multiple trajectories per hemisphere using a large gauge cannula. Performing serial infusions using a straight cannula along multiple trajectories extends surgical time and increases the risk of hemorrhage and tissue trauma. A new system is needed to improve the efficiency and effectiveness of nucleic acid therapeutic delivery in the brain. We propose development of an MR-compatible stereotactic delivery device capable of achieving widespread nucleic acid therapeutic coverage of common CNS disease targets. The device will be tested in rats using a viral vector substitute. The proposed delivery technology is nonspecific and could be applied to the treatment of a wide range of CNS conditions where nucleic acid therapeutics are being investigated, including Huntington’s Disease (IONIS-HTT), Parkinson's Disease (VY-AADC), and Sanfilippo syndrome (LYS-SAF302).