Innovative systemic gene therapy for treating Parkinson's disease

治疗帕金森病的创新系统基因疗法

• 批准号: 10394379
• 负责人: Richard J. Price
• 金额: $ 50.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394379
• 关键词: Acoustics; Adhesives; Affect; Animal Model; Area; Behavior; Behavioral; Biochemical; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain region; Caring; Cells; Cerebrospinal Fluid; Clinic; Clinical; Clinical Research; Clinical Trials; Corpus striatum structure; DNA; DNA delivery; Data; Dependovirus; Disease; Disease Progression; Disease model; Dopamine; Dose; Drug Kinetics; Engineering; Environment; Enzymes; Extracellular Matrix; Feedback; Focused Ultrasound; Formulation; Functional disorder; Gene Delivery; Gene Transfer; Generations; Genes; Genetic; Goals; Histologic; Human; In Vitro; Infusion procedures; Injection of therapeutic agent; Injections; Journals; Kinetics; Lead; Letters; Libraries; Locomotion; Magnetic Resonance Imaging; Maximum Tolerated Dose; Mediating; Methods; Microbubbles; Modality; Modeling; Molecular; Neurodegenerative Disorders; Neurotoxins; Nucleic Acids; Operative Surgical Procedures; Parkinson Disease; Pathologic; Patients; Penetration; Persons; Pharmacology; Phase I Clinical Trials; Physiologic pulse; Physiological; Pilot Projects; Plasmids; Polymers; Pre-Clinical Model; Price; Property; Protocols documentation; Regimen; Reporting; Resistance; Rodent; Rodent Model; Safety; Serum; System; Technology; Testing; Therapeutic; Transfection; Translating; Treatment Efficacy; United States; base; blood-brain barrier disruption; blood-brain barrier penetration; brain cell; brain parenchyma; brain tissue; clinical investigation; clinical translation; clinically relevant; design; disease phenotype; effectiveness testing; gene therapy; glial cell-line derived neurotrophic factor; image guided; improved; in vivo; innovation; multidisciplinary; nano; nanoparticle; nervous system disorder; neurotrophic factor; novel; palliative; pre-clinical; preclinical study; preconditioning; seal; success; therapeutic gene; therapeutic nanoparticles; therapeutic protein; therapeutic transgene; therapeutically effective; transgene expression; vector control

PROJECT SUMMARY Parkinson's disease (PD) is an increasingly prevalent neurological disorder that currently affects about one million people in the United States and 10 million worldwide. Despite recent innovations, most advanced pharmacological and surgical therapeutic regimens remain moderately palliative and symptomatic at best. Gene therapy has emerged as an alternative promising means to halt the disease progression or potentially cure the disease. However, clinical trials of PD gene therapy up to this moment have failed to establish a meaningful therapeutic benefit due to an inability to achieve widespread and efficient gene transfer to the disease areas within the brain. The significance of this problem is highlighted by an ongoing human trial, wherein improving the penetration and efficiency of transfection is a primary goal. Further, lacking a reliable method to deploy gene therapy from the bloodstream to the brain tissue, all clinical studies to date have employed highly invasive administration modalities involving direct injection of the therapy into the brain. This reality has precluded the inclusion in clinical trials of early stage PD patients who are more likely to respond to the therapy. Thus, new methods to overcome long-standing barriers to systemic gene delivery throughout the PD-associated brain regions, including the tightly sealed blood-brain barrier (BBB) and the dense network of brain extracellular matrix (ECM), are sorely needed. To this end, we propose innovative delivery approaches exploiting: (i) clinically operable MR image-guided focused ultrasound (FUS) to transiently open the BBB for the penetration of gene therapy into the brain tissues and cells in a targeted manner, (ii) DNA-loaded nanoparticles possessing a unique capability to efficiently spread through the brain ECM to reach and transfect cells in the disease areas within the brain (i.e. DNA-loaded brain-penetrating nanoparticle or DNA-BPN), and (iii) FUS-mediated pre-conditioning that further enhances the dispersion of DNA-BPN within the brain by temporarily reducing ECM resistance. We recently showed in our pilot study that FUS-mediated, targeted BBB penetration of, and subsequent widespread gene transfer by, our first-generation DNA-BPN resulted in therapeutically relevant gene therapy of a conventional neurotoxin-based preclinical model of PD. As a next step towards clinical translation, we here propose to further refine and evaluate our combined delivery strategy in highly sophisticated and clinically-relevant preclinical models of familial and sporadic PD that closely mimic pathophysiological features and disease phenotypes observed in human PD. If successful, the proposed approach could be rapidly translated to the clinic using a gene-encoding a neurotrophic factor (that is currently under clinical investigation and will be studied here) while additional preclinical studies could be followed to test the effectiveness of novel genetic targets in these advanced PD models. In addition, the approach could also be applied to other neurological disorders characterized by highly disseminated disease areas within the brain.

项目概要 帕金森病 (PD) 是一种日益流行的神经系统疾病，目前影响约一个人 美国有 100 万人，全世界有 1000 万人。尽管最近出现了创新，但最先进的 药物和手术治疗方案充其量只能起到中等程度的姑息作用和对症状的作用。 基因疗法已成为阻止疾病进展或潜在的替代有前途的手段 治愈疾病。然而，迄今为止，PD基因治疗的临床试验尚未建立起有效的证据。 由于无法实现广泛且有效的基因转移到 大脑内的疾病区域。正在进行的人体试验凸显了这个问题的重要性， 其中提高转染的穿透力和效率是首要目标。此外，缺乏可靠的 迄今为止，所有临床研究都表明，将基因治疗从血流转移到脑组织的方法 采用高度侵入性的给药方式，包括将治疗直接注射到大脑中。这 现实已经排除了早期 PD 患者的临床试验，这些患者更有可能对药物产生反应。 治疗。因此，克服整个系统基因传递长期存在的障碍的新方法 与 PD 相关的大脑区域，包括紧密密封的血脑屏障 (BBB) 和密集的神经网络 大脑细胞外基质（ECM），是迫切需要的。为此，我们提出创新的交付方法 利用：(i) 临床上可操作的 MR 图像引导聚焦超声 (FUS) 暂时打开 BBB 基因治疗有针对性地渗透到脑组织和细胞中，(ii) DN​​A 负载 纳米颗粒具有独特的能力，可以有效地通过大脑 ECM 传播并到达并转染 大脑内疾病区域的细胞（即负载 DNA 的脑穿透纳米颗粒或 DNA-BPN），以及 (iii) FUS 介导的预处理，通过以下方式进一步增强 DNA-BPN 在大脑内的分散： 暂时降低 ECM 阻力。我们最近在试点研究中表明，FUS 介导的靶向 BBB 我们的第一代 DNA-BPN 的渗透以及随后的广泛基因转移导致 基于传统神经毒素的 PD 临床前模型的治疗相关基因治疗。作为下一个 迈向临床转化的一步，我们在此建议进一步完善和评估我们的联合交付策略 在高度复杂且与临床相关的家族性和散发性 PD 临床前模型中，该模型非常模仿 在人类 PD 中观察到的病理生理学特征和疾病表型。如果成功的话，建议 使用编码神经营养因子的基因（目前正在研究），该方法可以快速转化为临床 正在临床研究中，将在这里进行研究），同时可以进行额外的临床前研究来测试 这些先进的帕金森病模型中新的遗传靶标的有效性。此外，该方法还可以 可应用于以大脑内高度传播疾病区域为特征的其他神经系统疾病。