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 虽然核酸疗法在啮齿动物和非人灵长类动物模型中显示出了希望 到目前为止，所有的双盲临床试验都失败了。一种可能的解释是 失败是指治疗在目标脑区的分布不佳。例如，尸检 脑实质内注射AAV-NTN治疗帕金森病的研究 显示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 使用标准注射方法进行尸检，最高可达15%- 监管。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，而且能够非常有效。 非人灵长类动物研究和人体试验之间的主要区别是 猴子会受到广泛的感染，而人类的感染则非常严重。 由于更大的大脑体积而减少。基于以下研究的结果： Ceregene(AAV-NTN)、Sanofi-Genzyme(AAV-hAADC)和Neurologix(AAV-GAD)，WE 得出的结论是，这些临床试验的失败部分是由于治疗不当 送货。今天，将治疗药物分配到大脑区域，如纹状体，需要 使用大口径插管的每个半球有多个弹道。进行连续输液 沿多个轨迹使用直管延长了手术时间，增加了风险。 出血和组织创伤。需要一种新的系统来提高效率和 脑内核酸治疗给药的有效性。 我们建议开发一种与MR兼容的立体定向递送装置，能够 实现常见中枢神经系统疾病靶点的广泛核酸治疗覆盖。这个 该装置将使用病毒载体替代品在老鼠身上进行测试。建议的交付技术是 非特异性，可应用于治疗多种中枢神经系统疾病 正在研究核酸疗法，包括亨廷顿病(Ionis-HTT)， 帕金森氏病(VY-AADC)和Sanfilippo综合征(Lys-SAF302)。