Translational AAV Delivery Platform to the Brain

大脑转化 AAV 传递平台

• 批准号: 8084288
• 负责人: Krystof S Bankiewicz
• 金额: $ 57.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084288
• 关键词: Address; Axonal Transport; Behavior; Brain; Brain Stem; Brain region; Cannulas; Cellular Tropism; Clinic; Clinical; Clinical Trials; Communities; Corpus striatum structure; Development; Disease; Employee Strikes; FDA approved; Gene Delivery; Gene Transduction Agent; Gray unit of radiation dose; Human; Image; Immune response; Infusion procedures; Investments; Island; Magnetic Resonance Imaging; Monitor; Movement; Multiple Sclerosis; Nature; Neurologic; Neurons; Neurosurgeon; Oligodendroglia; Patients; Performance; Primates; Procedures; Property; Protocols documentation; Relative (related person); Research Personnel; Resources; Safety; Scientist; Serotyping; Specificity; Structure; System; Techniques; Technology; Thalamic structure; Therapeutic; Therapeutic Agents; Tracer; Viral Vector; adeno-associated viral vector; anterograde transport; base; clinically relevant; design; empowered; gene therapy; gray matter; improved; in vivo; millimeter; nervous system disorder; neurosurgery; nonhuman primate; programs; putamen; response; transgene expression; vector; white matter

DESCRIPTION (provided by applicant): To advance neurological gene therapy applications into the clinic there is an urgent need to improve our understanding of gene delivery vectors, with particular emphasis on distribution and safety after direct brain delivery. While AAV2 currently dominates clinical development, alternative AAV serotypes may be better suited for some applications. The recent game-changing development of image-guided delivery techniques provides opportunity to accurately compare different vectors after direct brain delivery. Accordingly we aim to investigate the distribution and immune responses of 5 AAV serotypes (AAV1, 2, 5, 8 and 9) after confined delivery to grey or white matter structures in the non-human primate (NHP) brain. This in-depth assessment of AAV vectors will provide investigators with scientific rational for selecting a specific vector for a particular neurological application. PUBLIC HEALTH RELEVANCE: Neurological gene delivery is emerging as a viable therapeutic platform with over 200 patients having been treated in clinical trials to date. However, lack of a reliable delivery system has been a major barrier that we have only recently overcome with the development of a complete system for direct image guided brain infusions. This standardized delivery system now enables us to fully investigate alternative gene delivery approaches and will ultimately provide other investigators with the ability to select the best approach for treating a specific neurological disorder.

描述（由申请人提供）：为了将神经基因治疗应用推向临床，迫切需要提高我们对基因递送载体的理解，特别强调直接脑递送后的分布和安全性。虽然 AAV2 目前主导临床开发，但替代 AAV 血清型可能更适合某些应用。图像引导递送技术的最新发展改变了游戏规则，为直接大脑递送后准确比较不同的载体提供了机会。因此，我们的目标是研究 5 种 AAV 血清型（AAV1、2、5、8 和 9）在限制递送至非人灵长类动物 (NHP) 大脑灰质或白质结构后的分布和免疫反应。这种对 AAV 载体的深入评估将为研究人员为特定神经学应用选择特定载体提供科学依据。 公共健康相关性：神经基因传递正在成为一种可行的治疗平台，迄今为止已有 200 多名患者在临床试验中接受了治疗。然而，缺乏可靠的输送系统一直是我们最近通过开发直接图像引导脑输注的完整系统才克服的主要障碍。这种标准化的递送系统现在使我们能够全面研究替代基因递送方法，并最终使其他研究人员能够选择治疗特定神经系统疾病的最佳方法。