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: 10471044
• 负责人: TIMOTHY H LUCAS
• 金额: $ 7.85万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471044
• 关键词: Affect; Area; 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; Pharmacology; Positioning Attribute; Procedures; Prosencephalon; Protocols documentation; Radial; Radiology Specialty; Reporter; Risk; Safety; Signal Transduction; Site; Speed; Structure; System; Technology; Testing; Time; Tissues; Treatment Efficacy; Type 1 Spinocerebellar Ataxia; adeno-associated viral vector; base; clinical care; clinical translation; cost; gene therapy; image guided; improved; in vivo; innovation; mechanical properties; multidisciplinary; nervous system disorder; neurosurgery; nonhuman primate; novel; phantom model; pressure; programs; prototype; putamen; risk minimization; 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 治疗神经疾病的新的分子疗法的快速发展导致了在 翻译流水线：到目前为止，有多项积极的临床试验，一种疗法已经获得批准 由FDA批准。最常见的基因治疗依赖于腺相关病毒(AAV)，因为它是安全的，转导 效率和长期的基因表达。在AAV将货物运送到受限大脑区域的项目中，它 需要直接脑内注射。例如，在帕金森氏症(PD)和亨廷顿病(HD)中， 被称为壳核的前脑核通常是靶子。然而，全面覆盖和高效 用AAV转导整个壳核是一项具有挑战性的工作。目前的交付方式需要多个 通过单个插管进行立体定向注射。这些注射的串联性质不仅耗时， 但增加了多次脑穿透和靶子反复移位的风险。此外，即使在 最成功的例子是，通过单点注射传递的基因载体的转导效率是&lt； 50%，最终严重影响治疗效果。除了基因治疗，分娩不充分也是 严重影响其他一些依赖于直接脑给药的疗法的疗效，如化学疗法 以及治疗胶质母细胞瘤的分子平台。在这一关键的未得到满足的需求的鼓舞下，我们开发了 一种将风险降至最低的高效脑内注射的新型设备。多点注射技术 (MINT)由一个中心导管组成，该中心导管将三个可移动的微导管连接到一个中心致动器 用于精确定位和定位的机制，以及最大限度地扩大数量覆盖。与.相比 目前的单管系统，MINT允许从多个微管同时注射，因此 消除了对序列轨迹的需要，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 与当前基于MR引导和监控的外科工作流程相结合。最后，径向 结构和沿每个微管的多个注射部位导致更均匀的分布 组织中的输液，从而最大化体积分布，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来推动它的发展 在非人类灵长类动物中进行台式试验和活体MR引导注射。在这个项目完成后， 我们希望通过生成和验证一种新的交付设备来推动该领域的发展，该设备将显著 提高覆盖范围，同时减少手术时间和经皮质轨迹的数量。总体来说，这项建议 将确立多点注射装置的未来临床潜力，作为一种潜在的变革性和 实现基于基因、分子和药物的高效脑内传递的解决方案 治疗方法，并为神经系统疾病的临床护理的根本创新铺平道路。