Optimizing Direct Delivery of Nucleic Acid Therapeutics

优化核酸治疗的直接递送

• 批准号: 9986109
• 负责人: Kuldeepsinh Rana
• 金额: $ 9.94万
• 依托单位: FHC, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2019-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986109
• 关键词: 3-Dimensional; Animal Model; Animals; Autopsy; Brain; Brain region; Caliber; Cannulas; Cell Therapy; Cells; Central Nervous System Diseases; Ceramics; Clinical; Clinical Trials; Complex; Corpus striatum structure; Development; Devices; Dimensions; Distal; Double-Blind Method; Effectiveness; Engineering; Equipment Design; Failure; Hemorrhage; Human; Huntington Disease; Infection; Infusion procedures; Injections; Intervention; Intracranial Hemorrhages; Latex; Length; Life; Liquid substance; Magnetic Resonance Imaging; Medicine; Memory; Methods; Microinjections; Microspheres; Modeling; Modification; Monkeys; Mucopolysaccharidosis III; Operative Surgical Procedures; Outcome; Parkinson Disease; Patients; Penetration; Phase; Plastics; Positioning Attribute; Preparation; Procedures; Rattus; Reflux; Risk; Rodent; Savings; Sepharose; Shapes; Site; Structure; Suspensions; System; Technology; Testing; Therapeutic; Time; Transgenes; Translating; Trauma; Treatment Failure; Up-Regulation; Viral Vector; Virus; Work; base; brain tissue; brain volume; design; gene therapy; image guided; improved; in vivo evaluation; innovation; instrument; nervous system disorder; nitinol; nonhuman primate; nucleic acid delivery; nucleic acid-based therapeutics; preservation; prevent; protein expression; prototype; real-time images; stem cell therapy; success; tissue trauma; titanium nickelide; tool

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).

项目摘要 核酸疗法在啮齿动物和非人类隐私模型中显示出希望 中枢神经系统疾病，迄今为止，所有双盲临床试验都失败了。一个可能的解释 故障是靶向大脑区域中的治疗分布不佳。例如，验证后 接受帕金森氏病的患者接受了AAV-NTN的核范围内注射 证明蛋白质表达非常有限。在这项研究中，只有10-16％的转化是 使用标准注射方法可观察到的后验尸，最多15％ 法规。尽管这项研究的结果令人失望，但有充分的证据表明 这种基因治疗方法是有效的，并且能够高效。 非人类灵长类研究和人类试验之间的主要区别是 猴子会受到广泛的感染分布，而人类的感染却急剧 由于大脑量更大而减少。根据由 Ceregene（AAV-NTN），Sanofi-Genzyme（AAV-HAADC）和Neurologix（AAV-GAD），我们 包含这些临床试验的失败部分是由于治疗不足 送货。如今，理论分布到纹状体等大脑区域需要 每个半球使用大型套管的多个轨迹。执行连续输注 沿多个轨迹使用直套管会延长手术时间并增加风险 出血和组织创伤。需要一个新系统来提高效率和 核酸治疗在大脑中的有效性。 我们建议开发能够 达到普通中枢神经系统疾病靶标的广泛的核酸治疗覆盖率。这 设备将使用病毒载体替代物在大鼠中进行测试。拟议的交付技术是 非特异性，可以应用于多种CNS条件的处理 正在研究核酸治疗，包括亨廷顿氏病（Ionis-HTT）， 帕金森氏病（VY-AADC）和Sanfilippo综合征（LYS-SAF302）。