A Multipoint Injection Technology for Highly Efficient Convection-Enhanced Delivery of Gene-Based Therapeutics

用于基因治疗药物高效对流增强递送的多点注射技术

• 批准号: 10608114
• 负责人: TIMOTHY H LUCAS
• 金额: $ 59.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608114
• 关键词: Affect; Area; Autopsy; Benchmarking; Biomedical Engineering; Brain; Brain region; Cannulas; Catheters; Cell Nucleus; Central Nervous System Diseases; Cerebellar Nuclei; Cerebellum; Cerebrum; Chemicals; Clinical; Clinical Trials; Consumption; Contralateral; Contrast Media; Convection; Custom; Data; Dependovirus; Development; Devices; FDA approved; Future; Gadolinium; Gene Delivery; Gene Expression; Gene Transfer; Genes; Glioblastoma; Green Fluorescent Proteins; Histologic; Human; Huntington Disease; Image-Guided Surgery; Imaging technology; Infusion procedures; Injections; Magnetic Resonance Imaging; Methods; Molecular; Monitor; Nature; Neurological status; Neurology; Operative Surgical Procedures; Outcome; Parkinson Disease; Penetration; Performance; Positioning Attribute; Procedures; Prosencephalon; Protocols documentation; Radial; Radiology Specialty; Reporter; Risk; Risk Reduction; Safety; Signal Transduction; Site; Speed; Structure; System; Technology; Testing; Time; Tissues; Treatment Efficacy; Type 1 Spinocerebellar Ataxia; adeno-associated viral vector; clinical care; clinical translation; cost; delivery vehicle; gene therapy; improved; in vivo; innovation; mechanical properties; multidisciplinary; nervous system disorder; neurosurgery; nonhuman primate; novel; phantom model; pharmacologic; pressure; programs; prototype; putamen; risk minimization; technology validation; therapeutic gene; transduction efficiency; translational pipeline; vector

PROJECT SUMMARY/ABSTRACT The rapid development of novel molecular therapies for neurological disorders has led to a rapid progress in the translational pipeline: to date, there are multiple active clinical trials and one therapy has already been approved by FDA. Most commonly, gene therapies rely on Adeno Associated Virus (AAV) due to its safety, transduction efficiency, and long-term gene expression. In programs where AAV delivers cargo to restricted brain regions, it requires direct intracerebral injection. For instance, in Parkinson’s (PD) and Huntington’s disease (HD) a deep forebrain nucleus known as the putamen is often the target. However, complete coverage and efficient transduction of the entire putamen with AAV is challenging. Current delivery methods require multiple stereotactic injections through a single cannula. The serial nature of these injections is not only time consuming, but adds the risks of multiple brain penetrations and iterative displacement of the target. Furthermore, even in the most successful cases, the transduction efficiency of gene vectors delivered via single point injections is < 50%, which ultimately severely affects therapeutic efficacy. Beyond gene therapy, inadequate delivery is also critically affecting the efficacy of a number of other therapies relying on direct brain delivery, such as chemical and molecular platforms for treatment of glioblastoma. Inspired by this critical unmet need, we have developed a novel device for highly efficient intracerebral injections that minimizes risks. The Multipoint Injection Technology (MINT) consists in a central catheter integrating three moveable microcannulas connected to a central actuation mechanism for precise targeting and positioning, as well as maximization of volume coverage. Compared to current single cannula systems, MINT allows simultaneous injections from multiple microcannulas, thus eliminating the need for serial trajectories and potentially significantly reducing complexity, duration, and cost of the surgery. Furthermore, MINT is compatible with magnetic resonance imaging (MRI) and can be seamlessly integrated with the current surgical workflows based on MR-guidance and monitoring. Finally, the radial configuration and the multiple injections sites along each microcannula result in a more uniform distribution of the infusate in the tissue, thus maximizing the volume distribution and enabling targeting of different brain regions. In this project, we will advance this highly efficient intracerebral injection technology by validating it for MR-guided injections with benchtop tests and in vivo in non-human primates. Upon completion of this project, we expect to move the field forward by generating and validating a new delivery device that will significantly improve coverage, while reducing surgical time and number of transcortical trajectories. Overall this proposal will establish the future clinical potential of the multipoint injection device as a potentially transformative and enabling solution for highly efficient intracerebral delivery of gene-based, molecular, and pharmacological therapies and pave the way for fundamental innovations in the clinical care of neurological disorders.

项目摘要/摘要 新型分子疗法的神经系统疾病的快速发展导致了 翻译管道：迄今为止，有多项主动临床试验，并且已经批准了一种 由FDA。最常见的是，基因疗法由于其安全性而依赖于Adeno相关病毒（AAV） 效率和长期基因表达。在AAV将货物限制为限制大脑区域的计划中 需要直接脑内注射。例如，在帕金森氏（PD）和亨廷顿氏病（HD）中 前脑核通常是靶标。但是，完整的覆盖范围和高效 用AAV转导整个鬼盘是挑战。当前的交付方法需要多个 通过单个套管注射立体定向。这些注射的串行性质不仅是耗时的，而且 但增加了目标多种脑穿透和迭代位移的风险。此外，即使在 最成功的情况是，通过一次点注射传递的基因载体的转移效率为< 50％，最终严重影响治疗效率。除了基因疗法之外，分娩也不足 严重影响依赖脑部直接递送的许多其他疗法的效率，例如化学物质 和用于治疗胶质母细胞瘤的分子平台。受到这个关键的未满足需求的启发，我们已经发展了 一种用于高效脑内注射的新型装置，可最大程度地减少风险。多点注入技术 （MINT）由中央导管组成，该导管整合了连接到中央致动的三个可移动的微扫描 精确靶向和定位的机制，以及体积覆盖率的最大化。相比 当前的单个套管系统，薄荷允许多个微扫描的简单注射，因此 消除了对串行轨迹的需求，并有可能显着降低复杂性，持续时间和成本 手术。此外，薄荷与磁共振成像（MRI）兼容，并且可以无缝 基于MR指导和监测，与当前的手术工作流程集成在一起。最后，径向 沿每个微通道的配置和多个注射位点导致更均匀的分布 在组织中注入液，从而最大化体积分布并实现不同大脑的靶向 地区。在这个项目中，我们将通过验证该项目来推进这种高效的脑注射技术 MR指导了台式测试和非人类隐私的体内注射。完成该项目后， 我们希望通过生成和验证新的交付设备来向前推进该领域 改善覆盖范围，同时减少手术时间和跨皮层轨迹的数量。总体而言，这一建议 将确定多点注射装置的未来临床潜力作为潜在的变革和 启用解决方案，用于高效的基因，分子和药物的脑内递送 疗法和为神经系统疾病的临床护理中的基本创新铺平道路。

项目成果

Design and Characterization of Pressure Monitoring and Insertion system for Intraparenchymal Convection Enhanced Delivery.

用于实质内对流增强输送的压力监测和插入系统的设计和表征。

• DOI: 10.1109/embc40787.2023.10341013
• 发表时间: 2023
• 期刊: Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
• 作者: Michiels,Jakob;Vitale,Flavia
• 通讯作者: Vitale,Flavia

Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain.

• DOI: 10.3389/fmedt.2021.725844
• 发表时间: 2021
• 期刊: Frontiers in medical technology
• 作者: Prezelski K;Keiser M;Stein JM;Lucas TH;Davidson B;Gonzalez-Alegre P;Vitale F
• 通讯作者: Vitale F

Stability of Ti3C2Tx MXene Films and Devices under Clinical Sterilization Processes.

• DOI: 10.1021/acsnano.3c01525
• 发表时间: 2023-05
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Spencer Averbeck;Doris Xu;Brendan B. Murphy;Kateryna Shevchuk;S. Shankar;Mark Anayee;Marcelo Der Torossian Torres;Michael S Beauchamp;César de la Fuente-Nunez;Y. Gogotsi;Flavia Vitale