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.

项目总结/摘要 用于神经系统疾病的新型分子疗法的快速发展导致了神经系统疾病治疗的快速进展。 转化管道：迄今为止，有多个活跃的临床试验，一种治疗方法已经获得批准 FDA。最常见的是，基因疗法依赖于腺相关病毒（AAV），由于其安全性、转导性和生物相容性， 效率和长期基因表达。在AAV将货物运送到受限大脑区域的程序中， 需要直接脑内注射例如，在帕金森病（PD）和亨廷顿病（HD）中， 被称为壳核的前脑核通常是目标。然而，全面覆盖和高效 用AAV转导整个壳核具有挑战性。目前的交付方法需要多个 立体定向注射。这些注射的连续性质不仅耗时， 但增加了多次脑穿透和目标反复移位的风险。此外，即使在 在最成功的情况下，通过单点注射递送的基因载体的转导效率< 50%，这最终严重影响治疗效果。除了基因治疗，不充分的交付也是 严重影响了许多其他依赖于直接脑递送的疗法的功效，例如化学疗法。 和治疗胶质母细胞瘤的分子平台。在这一关键的未满足需求的启发下，我们开发了 一种用于高效脑内注射的新型装置，可将风险降至最低。多点注射技术 （MINT）包括一个中心导管，该中心导管集成了三个连接到中心致动器的可移动微插管。 精确定位和定位的机制，以及最大化的体积覆盖。相比 目前的单套管系统，MINT允许从多个微套管同时注射， 消除了对连续轨迹的需要，并潜在地显著降低了复杂性、持续时间和成本， 手术此外，MINT与磁共振成像（MRI）兼容，可以无缝地 与基于MR引导和监测的当前手术工作流程相结合。最后，径向 构造和沿沿着每个微插管的多个注射部位导致更均匀的 组织中的输注物，从而使体积分布最大化，并能够靶向不同的大脑 地区在这个项目中，我们将通过验证这种高效的脑内注射技术， 在非人灵长类动物中进行MR引导注射，并进行实验室试验和体内试验。在这个项目完成后， 我们希望通过开发和验证一种新的输送设备来推动该领域的发展， 提高覆盖率，同时减少手术时间和经皮质轨迹的数量。总的来说，这一建议 将确立多点注射装置的未来临床潜力， 实现基于基因、分子和药理学的高效脑内递送的解决方案 该研究为神经系统疾病的临床护理的根本创新铺平了道路。

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

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

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