Central Nervous System Drug Delivery Techniques

中枢神经系统给药技术

• 批准号: 10018688
• 负责人: Richard James Youle
• 金额: $ 30.56万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10018688
• 关键词: Adverse effects; Affect; Agonist; Anatomy; Area; Autoradiography; Behavioral; Bilateral; Blood; Blood - brain barrier anatomy; Botulinum Toxins; Brain; Brain Injuries; Brain Stem; Brain Stem Glioma; Cannulas; Catheters; Central Nervous System Agents; Central Nervous System Diseases; Characteristics; Chemicals; Childhood Brain Neoplasm; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Convection; Data; Deep Brain Stimulation; Degenerative Disorder; Dependovirus; Development; Diffuse; Diffuse intrinsic pontine glioma; Dose; Drug Delivery Systems; Drug Monitoring; Effectiveness; Electric Stimulation; Electrodes; Enrollment; Epilepsy; Excision; Exotoxins; Extracellular Space; Foundations; GABA Agonists; Gadolinium DTPA; Genes; Glioma; Grant; Hippocampus (Brain); Human; Image; Infusion procedures; Interleukin-13; Intractable Epilepsy; Investigation; Laboratories; Laboratory Animals; Lead; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Manufacturer Name; Manuscripts; Medical; Methods; Modeling; Molecular Weight; Monitor; Muscimol; Nerve Growth Factors; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotransmitters; Operative Surgical Procedures; Parkinson Disease; Pathologic; Patients; Perfusion; Pharmaceutical Preparations; Phase; Primates; Production; Property; Pseudomonas; Publishing; Pump; Radiation; Reporting; Research; Rodent; Rodent Model; STN stimulation; Safety; Seizures; Serotyping; Site; Structure; Structure of subthalamic nucleus; Study Subject; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxin; Tracer; Virus; Work; X-Ray Computed Tomography; base; bench to bedside; cell type; clinical effect; clinically relevant; cohort; design; dopaminergic neuron; drug distribution; experience; gamma-Aminobutyric Acid; gene therapy; glial cell-line derived neurotrophic factor; image guided; improved; insight; nervous system disorder; neuro-oncology; neurosurgery; non-invasive imaging; non-invasive monitor; nonhuman primate; palliative; pediatric patients; pre-clinical; preclinical study; putamen; real-time images; recruit; success; time use; treatment site; tumor; uptake; vector

Preclinical Studies Real-time imaging of convection-enhanced delivery (CED). Because the volumetric and anatomic distribution of infusate will differ with treatment site and because various pathologic conditions will cause differences in tissue properties that affect CED parameters, it will be important to monitor CED delivery in real-time to further develop and perfect this delivery method in the clinical setting. To image CED in real-time, we have developed small and large molecular weight computed tomography (CT)- and magnetic resonance (MR)-imaging tracers that can be co-infused with therapeutic agents. We have shown that by combining (or co-infusing) therapeutic molecules and surrogate imaging tracers, CED of putative therapeutic agents can be precisely monitored in real-time using serial CT- or MR-imaging. The capability to non-invasively monitor infusate delivery in real-time permits exploration of a variety of parameters (i.e., rate, effect of flow characteristics, effect of anatomic boundaries) associated with CED, reveals areas for improvement in the CED technology (i.e., catheter design, pump design), improves the infusion accuracy/reliability, confirms adequate target treatment, and permits determining if an infused agent is efficacious if delivered to the target tissue. Preclinical to Clinical Therapeutic Applications Exploiting the unique delivery properties of CED has allowed investigation of new paradigms for the research and treatment of central nervous system (CNS) disorders. We ended a clinical study using IL13-pseudomonas exotoxin to treat diffuse intrinsic pontine glioma (brainstem glioma) because the manufacturer discontinued production of this agent. A manuscript describing the results of this study is under review. We used a bench-to-bedside approach to treat the neurodegenerative disorder, Parkinson's disease, by convective delivery of Adeno-Associated Virus type 2 carrying the Human Glial cell line-Derived Neurotrophic Factor gene (AAV2-hGDNF). The study used escalating doses of AAV2-hGDNF, with 6 patients being treated at the lowest 2 doses and 1 patient being treated at the next highest dose. After treating 13 subjects we stopped enrollment due to slow patient accrual. We will continue to follow all these subjects until 5 years after the last subject was treated. We will report the final study results shortly thereafter. Neuro-Oncology. Diffuse infiltrative brainstem gliomas are pediatric brain tumors that are uniformly fatal (median survival of less than 1 year). Complete surgical resection is not possible, and radiation is only palliative. Putative therapeutic compounds have been developed and are available to treat diffuse brainstem gliomas but have not been effective when delivered systemically because they cannot cross the blood-brain barrier into the tumor. To overcome this limitation, we investigated the possibility of using CED of a targeted anti-glioma agent (interleukin-13 bound to Pseudomonas toxin, IL13-PE) to the brainstem while monitoring drug distribution with a co-infused surrogate MR-imaging tracer (gadolinium-DTPA). Based on the safe and successful use of this delivery model in rodents and primates, we developed a clinical protocol to treat diffuse brainstem gliomas in pediatric patients with IL13-PE co-infused with gadolinium-DTPA. We safely treated 5 patients with CED of IL13-PE and gadolinium-DTPA and successfully tracked the distribution of drug in real-time using intraoperative MR-imaging. We published an analysis of the accuracy of direct magnetic resonance imaging-guided placement of drug infusion cannulae in study subjects. This year we published our report of IL13-PE drug distribution and clinical effects. Our early findings provide foundational data on monitoring drug delivery and intratumoral treatment of diffuse brainstem gliomas, which may be applied to the treatment of other CNS malignancies including malignant gliomas. Neurodegenerative disorders. The properties of CED allow it to selectively manipulate distinct subsets of neurons (and other cell types) for therapy. We are investigating in a clinical trial a targeted gene-therapy approach to deliver the neurotrophic protein, GDNF, to the putamen in patients with Parkinson disease. In this condition, convection is being explored to selectively distribute AAV2-GNDF (adenoassociated virus type 2, carrying the human GDNF gene) and maintain dopaminergic neurons that would otherwise degenerate. We completed treatment of cohorts of 6 patients at 2 dose levels in this Phase I, dose-escalation study and treated 1 subject at the third dose level. Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased 18F FDOPA uptake in the putamina of study subjects suggested a neurotrophic effect on dopaminergic neurons. The method provides a targeted, site-specific means of restorative neurosurgery. In laboratory animals, we completed a study of the effect of convection-enhanced delivery of muscimol, a GABA-A agonist. A solution of muscimol and gadolinium-DTPA was infused bilaterally into the subthalamic nuclei. Distribution of muscimol was monitored in real-time by observing the distribution of gadolinium-DTPA in the infusion solution. Behavioral changes, safety, and distribution of muscimol were recorded. A report analyzing drug distribution and behavioral effects was published this year. This work was performed to support a clinical trial of infusion of muscimol into the subthalamic nucleus during deep brain stimulation (DBS) surgery. This clinical study would provide insight into the potential mechanism of action of electrical stimulation of the subthalamic nucleus. This work could ultimately lead to chemical neurosurgery, in which patients with degenerative disorders could be treated using convection-enhanced delivery of agents acting on specific neurotransmitters and brain structures. Epilepsy. The hippocampus is the usual site of origin of medically intractable epilepsy. Relief of this type of epilepsy could occur if a method were developed to selectively suppress the epileptic focus within the hippocampus. After success in ablating seizures in a rodent model using convective perfusion of the epileptic focus, our laboratory conducted a study of the toxicity and distribution of the chronic infusion of muscimol into the hippocampus of 10 non-human primates. Depth electrode studies showed that electrical activity in the hippocampus could be suppressed by muscimol. Autoradiography of infused muscimol demonstrated that muscimol could be delivered to the entire hippocampus using convective perfusion. The infusions were tolerated without brain injury or permanent adverse effects. The FDA granted us approval for intracerebral CED of muscimol to brain. Candidates for seizure surgery were recruited for the clinical study of the infusion of muscimol into the hippocampus to temporarily inactivate the neurons of the epileptic focus. The first 3 of 18 subjects entered this trial and underwent 1 to 2-day infusions into the seizure focus of the study drug, muscimol (a GABA agonist) under an FDA IND. The infusions were well-tolerated, but recruitment of more subjects was not successful because short-term muscimol infusion did not offer permanent treatment of epilepsy. A manuscript describing the results of the study was published this year. Based on this experience, we propose translational development of other agents for medically-intractable epilepsy that will permanently and selectively inactivate the epileptic focus. This year, we published a manuscript describing the distribution and toxicity of one of these agents, botulinum toxin, delivered by convection-enhanced delivery.

临床前研究 对流增强输送的实时成像（CED）。 由于注射液的体积和解剖分布将随治疗部位而异，并且由于各种病理状况会导致影响CED参数的组织特性差异，因此实时监视CED递送以进一步开发并完善此在此过程中的差异很重要。临床环境。为了实时映像CED，我们开发了大小分子量计算机断层扫描（CT）和磁共振（MR） - 成像示踪剂，可以与治疗剂共同介绍。 我们已经表明，通过使用串行CT或MR成像，可以精确地实时监测（或共同融合）治疗分子和替代成像示踪剂。在实时许可证中非侵入性监测注射液的能力探索了与CED相关的各种参数（即流量特征的速率，效果，解剖边界的效果），揭示了CED技术改善的领域（即导管设计，泵设计），提高输注精度/可靠性，确认足够的目标处理，并允许确定如果输送到目标组织，则确定注入剂是否有效。 临床上的临床治疗应用 利用CED的独特递送特性允许研究中枢神经系统（CNS）疾病的新范式。我们使用IL13-妊娠exotoxin来治疗弥漫性内在的蓬托胶质瘤（脑干神经胶质瘤）结束了一项临床研究，因为制造商停用了该药物的产生。描述这项研究结果的手稿正在综述中。我们使用基准对床的方法来治疗神经退行性疾病，帕金森氏病，通过对流递送载有人类神经胶质细胞系衍生的神经营养因子基因（AAV2-HGDNF）的2型腺相关病毒2。 该研究使用了AAV2-HGDNF的升级剂量，其中6例患者接受了最低剂量的治疗，1例患者接受了下一个最高剂量的治疗。 治疗13名受试者后，由于患者的应计缓慢，我们停止了入学率。 我们将继续遵循所有这些主题，直到对最后一个主题进行治疗5年。 此后不久，我们将报告最终的研究结果。 神经肿瘤学。 弥漫性浸润性脑干神经胶质瘤是统一致命的小儿脑肿瘤（中位生存期少于1年）。完全手术切除是不可能的，并且辐射仅是姑息治疗的。假定的治疗化合物已经开发出来，可用于治疗弥漫性脑干神经胶质瘤，但在系统地递送时没有有效，因为它们无法将血脑屏障越过肿瘤。为了克服这一局限性，我们研究了使用靶向抗脱脂瘤剂的CED（白介素-13与假单胞菌毒素，IL13-PE结合的ILL13-PE），同时使用共同注入的替代MR-IM-MIM-MIM-MIM-IM-IM-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIM-IM-MIR-IM-MIR-IM-MIR-IM-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IM-MIR-IMIMAGGATE（ Gadolinium-DTPA）。基于在啮齿动物和灵长类动物中的安全和成功使用，我们开发了一种临床方案，可以治疗与Gadolinium-DTPA共同融资的IL13-PE儿科患者的弥漫性脑干神经胶质瘤。我们安全地治疗了5例IL13-PE和Gadolinium-DTPA的CED患者，并使用术中MR成像成功地实时跟踪了药物的分布。 我们发表了对直接磁共振成像引导在研究对象中的直接磁共振成像引导的放置的准确性的分析。 今年，我们发表了有关IL13-PE药物分布和临床作用的报告。我们的早期发现提供了有关监测弥漫性脑干神经胶质瘤的药物输送和肿瘤内治疗的基础数据，这些数据可用于治疗其他中枢神经系统恶性肿瘤，包括恶性神经胶质瘤。 神经退行性疾病。 CED的特性使其可以选择性地操纵神经元（和其他细胞类型）的不同子集进行治疗。我们正在一项临床试验中调查一种靶向基因治疗方法，以将神经营养蛋白GDNF送给帕金森病患者的pe虫。在这种情况下，正在探索对流，以选择性地分布AAV2-GNDF（载有人类GDNF基因的2型病毒2型病毒）并维持否则会退化的多巴胺能神经元。 在此I期，我们以2剂水平的2剂量（剂量降低研究）完成了6例患者的治疗，并在第三剂量水平治疗了1名受试者。 腺相关病毒，携带神经胶质细胞系衍生的神经营养因子输注的血清型-2载体是安全且耐受性良好的。研究对象的putamina中增加了18F FDOPA的吸收表明对神经营养的影响 多巴胺能神经元。该方法提供了针对性的，特定于恢复性神经外科手术的方法。 在实验室动物中，我们完成了一项研究，研究了对流增强的Muscimol，Gaba-A激动剂。将肌酚和Gadolinium-DTPA的溶液双侧注入到丘脑下核中。通过观察输注溶液中Gadolinium-DTPA的分布，实时监测肌酚的分布。记录了麝香酚的行为变化，安全性和分布。 一份分析药物分布和行为影响的报告已于今年发表。进行这项工作是为了支持在深脑刺激（DBS）手术期间将麝香酚输注到丘脑下核中的临床试验。这项临床研究将洞悉丘脑下核的电刺激作用机理。这项工作最终可能导致化学神经外科，其中可以使用对特定神经递质和脑结构的对流增强药物的递送来治疗退行性疾病的患者。 癫痫。 海马是医学上顽固性癫痫的起源的通常位置。如果开发了一种选择性抑制海马内癫痫焦点的方法，可能会减轻这种癫痫的缓解。在使用癫痫焦点的对流灌注中，在啮齿动物模型中取得成功的癫痫发作成功后，我们的实验室研究了麝香酚长期注入10个非人类灵长类动物的海马的毒性和分布。深度电极研究表明，海马中的电活性可以被麝香酚抑制。注入麝香酚的放射自显影证明，可以使用对流灌注将麝香酚送到整个海马。在没有脑损伤或永久不良反应的情况下耐受输注。 FDA批准了我们墨西哥摩托酚的脑内CED的批准。招募了癫痫手术的候选者，以临床研究将肌酚输注到海马中，以暂时使癫痫焦点的神经元失活。 18名受试者中的前3名进入了这项试验，并在研究药物的癫痫发作重点下进行了1至2天的输注，其中FDA IND下的肌肉酚（GABA激动剂）。输注良好，但是更多受试者的招募并没有成功，因为短期肌霉菌输注没有提供癫痫的永久治疗。 描述研究结果的手稿已于今年发表。 基于这一经验，我们提出了其他药物的转化开发，以使医学上的癫痫病永久有选择地使癫痫焦点失活。 今年，我们发表了一份手稿，描述了这些药物之一的分布和毒性，肉毒杆菌毒素，通过对流增强的交付提供。