Central Nervous System Drug Delivery Techniques

中枢神经系统给药技术

• 批准号: 10253920
• 负责人: Richard James Youle
• 金额: $ 30.88万
• 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/10253920
• 关键词: Adverse effects; Affect; Aftercare; Agonist; Anatomy; Animal Model; Area; Autoradiography; Behavioral; Bilateral; Blood; Blood - brain barrier anatomy; Botulinum Toxins; Brain; Brain Injuries; Brain Stem; Brain Stem Glioma; Catheters; Central Nervous System Agents; Cessation of life; Characteristics; Chemicals; Childhood Brain Neoplasm; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Convection; Data; Deep Brain Stimulation; Degenerative Disorder; Dependovirus; Development; Diagnostic radiologic examination; Diffuse; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Monitoring; Effectiveness; Electric Stimulation; Electrodes; Enrollment; Epilepsy; Excision; Extracellular Space; Foundations; GABA Agonists; Gadolinium DTPA; Genes; Glioma; Grant; Hippocampus (Brain); Human; Image; Infusion procedures; Interleukin-13; Intractable Epilepsy; Laboratories; Laboratory Animals; Lead; Magnetic Resonance Imaging; Malignant Glioma; Malignant Neoplasms; Manuscripts; Methods; Modeling; Molecular Weight; Monitor; Motor; Muscimol; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotransmitters; Operative Surgical Procedures; Parkinson Disease; Pathologic; Patients; Perfusion; Pharmaceutical Preparations; Positron-Emission Tomography; Postoperative Period; Primates; Property; Proteins; Pseudomonas; Publishing; Pump; Radiation; Reporting; Rodent; Rodent Model; STN stimulation; Safety; Seizures; Site; Structure; Structure of subthalamic nucleus; Study Subject; Synapses; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxin; Tracer; Work; X-Ray Computed Tomography; base; bench to bedside; cell type; clinically relevant; design; dopaminergic neuron; drug distribution; experience; gamma-Aminobutyric Acid; glial cell-line derived neurotrophic factor; improved; insight; nervous system disorder; neuro-oncology; neurosurgery; neurotrophic factor; non-invasive imaging; non-invasive monitor; nonhuman primate; palliative; pediatric patients; pre-clinical; preclinical study; presynaptic; prevent; real-time images; recruit; small molecule; success; therapeutic development; time use; treatment site; tumor; uptake

Preclinical Studies Real-time imaging of convection-enhanced delivery (CED) it is essential to monitor CED delivery in real-time because the volumetric and anatomic distribution of infusate differs with treatment site and because various pathologic conditions alter tissue properties that affect CED parameters. To image CED in real-time, we developed small and large molecular weight computed tomography (CT)- and magnetic resonance (MR)-imaging tracers that can be co-infused with therapeutic agents and further develop and perfect the CED method for clinical use. We showed that combining (or co-infusing) therapeutic molecules and surrogate imaging tracers allowed monitoring of CED of putative therapeutic agents in real-time using serial CT- or MR-imaging. The capability to non-invasively monitor infusate delivery in real-time permitted exploration of a variety of parameters (i.e., rate, effect of flow characteristics, effect of anatomic boundaries) associated with CED, revealed areas for improvement in the CED technology (i.e., catheter design, pump design), improved infusion accuracy/reliability, assessed adequacy of target coverage by infusate, and predicted the effectiveness of the infusion to treat disease in the targeted tissue. Preclinical to Clinical Therapeutic Applications 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). Parkinsons disease is progressive and presently incurable. GDNF is a neurotrophic factor that prevented the death of dopaminergic neurons in culture and animal models of Parkinsons disease (PD) and could slow Parkinsons disease progression. The study used escalating doses of AAV2-hGDNF, with 6 patients being treated at the lowest 2 doses and 1 patient being treated at a higher dose. Pre-operatively, and at 6-12-month intervals post-operatively, Unified Parkinsons Disease Rating Scale (UPDRS) Part 3 assessed motor function and positron emission tomography (PET) scanning with 18FDOPA assessed F-DOPA uptake, a sign of presynaptic dopaminergic integrity. After treating 13 subjects we stopped enrollment due to slow accrual. We found that MRI tracked AAV2-GDNF infusion within the bilateral putamina, covering 22% of their volume. These patients with advanced Parkinsons disease tolerated the infusions without short- or long-term clinical or radiographic toxicity. UPDRS Part 3 assessment scores remained stable between before and 18 months after infusion. AAV2-hGDNF infusion improved F-DOPA uptake assessed by comparing 18FDOPA positron emission tomography (PET) scanning before, 6-months, and 18-months after AAV2-GDNF infusion. Increased 18FDOPA uptake in the infused areas was seen bilaterally in 10/13 patients at 6 months (range: 5-274%, median: 36%), and in 12/13 patients at 18 months after infusion (range: 8-130%, median: 54%). PET findings of increased putaminal 18FDOPA uptake suggests that AAV2-hGDNF had a neurotrophic effect on dopaminergic neurons of (1). We will clinically evaluate all study subjects annually until 5 years after treatment. 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 available to treat diffuse brainstem gliomas but have been ineffective when delivered systemically because of their inability to 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. Gadolinium-DTPA successfully tracked the distribution of drug in real-time using intraoperative MR-imaging. We published this clinical study in 2018. Our findings provided 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. 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 by MRI 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 (2). 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 surgically remediable drug resistant epilepsy (DRE). Relief of this type of epilepsy could occur without surgically removing the hippocampus 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 CED. The CED infusions were tolerated without brain injury or permanent adverse effects. The FDA granted us an IND 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). The infusions were well-tolerated, but recruitment of more subjects was unsuccessful because short-term muscimol infusion did not permanently treat epilepsy. A manuscript describing the study was published this year (3). This year, we also published a manuscript describing convection-enhanced delivery to the non-human primate hippocampus of botulinum toxin, an agent that inactivates synaptic activity (4). Based on our experience with infusion of a small molecule and protein into the hippocampus using CED, we are enthusiastic about translational development of therapeutic agents for drug resistant epilepsy that could modulate or permanently and selectively inactivate the epileptic focus.

临床前研究 对流增强交付的实时成像（CED） 必须实时监测CED递送，因为注射位点的体积和解剖分布与治疗位点不同，并且由于各种病理条件改变了影响CED参数的组织特性。为了实时成像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，并进一步开发并完善临床使用的CED方法。 我们表明，使用串行CT或MR成像，将（或共同融合的）治疗分子和替代成像示踪剂结合允许实时监测推定治疗剂的CED。与CED相关的各种参数（即，流动特征的速率，效果，解剖学界限的效果，速率，效果，解剖界限的效果）在实时允许的探索中进行非侵入性监测的能力，揭示了CED技术的改善区域，以改善CED技术（即导管设计，泵设计，泵设计）的准确性/可靠性，评估效率的效率，以及效率的效果，以及对目标的效果，以及对目标的效果，以及覆盖的效率，以及覆盖的效率，覆盖范围，以及覆盖的效果，涵盖了覆盖物，并覆盖了目标。目标组织。 临床上的临床治疗应用 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。 帕金森氏病是进步性的，目前无法治愈。 GDNF是一种神经营养因素，可防止帕金森氏病培养和动物模型（PD）中多巴胺能神经元的死亡，并可能降低帕金森氏病的进展。 该研究使用了升级的AAV2-HGDNF剂量，其中6例患者接受了2剂的最低剂量治疗，1例患者接受了较高剂量的治疗。 术前，在术后6-12个月的间隔内，统一的帕金森氏病评级量表（UPDRS）第3部分评估了运动功能和正电子发射断层扫描（PET）扫描（PET），并评估了18FDOPA的F-DOPA UPTAKE，这是一种启发前多巴胺能完整性的标志。 治疗13名受试者后，我们由于应计缓慢而停止入学。 我们发现，MRI追踪双侧putamina中的AAV2-GDNF输注，占其体积的22％。 这些患有晚期帕金森氏病的患者忍受了没有短期或长期临床或影像学毒性的输注。 UPDRS第3部分评估评分在输注后至18个月之间保持稳定。 AAV2-HGDNF输注通过比较AAV2-GDNF输注后6个月和18个月的扫描，改善了通过比较18FDOPA正电子发射断层扫描（PET）扫描来评估的F-DOPA摄取。 在6个月（范围：5-274％，中位数：36％）的10/13例患者中，在注入区域的18FDOPA吸收增加，在输注后18个月的12/13例患者（范围：8-130％，中位数：54％）。 pet峰18fdopa摄取的宠物发现表明，AAV2-HGDNF对（1）的多巴胺能神经元具有神经营养作用。 我们将每年临床评估所有研究对象，直到治疗后5年。 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。推定的治疗化合物已经开发并可用来治疗弥漫性脑干神经胶质瘤，但由于无法将血脑屏障越过肿瘤，因此系统地递送时无效。为了克服这一限制，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），同时使用共同注入的替代替代物MR-IMIMIMANIMIMANGIMANG TACER（Gadolinium-DTPA）监测药物分布。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。我们安全治疗了5例IL13-PE CED患者。 Gadolinium-DTPA使用术中MR成像成功地实时跟踪了药物的分布。 我们在2018年发表了这项临床研究。我们的发现提供了有关监测药物递送和肿瘤内脑干神经胶质瘤的基础数据，这可能应用于其他CNS恶性肿瘤（包括恶性神经胶质瘤）的治疗。 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。 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。通过通过MRI观察到输注溶液中gadolinium-DTPA的分布，实时观察肌酚的分布。记录了麝香酚的行为变化，安全性和分布。 今年发表了一份分析药物分布和行为影响的报告（2）。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 海马是抗药性药物抗药性癫痫（DRE）的通常起源部位。如果开发了一种选择性抑制海马内癫痫焦点的方法，则可以在不手术上去除海马的情况下缓解这种癫痫病。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CED将麝香酚交付给整个海马。在没有脑损伤或永久不良反应的情况下耐受CED输注。 FDA授予我们墨西哥摩尔脑中脑中心的IND。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，并接受了1到2天的输注，以研究药物Muscimol（GABA激动剂）的癫痫发作重点。输注良好，但招募更多受试者是没有成功的，因为短期肌霉菌输注并未永久治疗癫痫病。 一项描述该研究的手稿已于今年发表（3）。 今年，我们还发表了一份手稿，描述了对对流增强作肉毒杆菌毒素非人类灵长类动物海马的递送，肉毒杆菌毒素是一种使突触活动灭活的药物（4）。 根据我们使用CED将小分子和蛋白输注到海马中的经验，我们热衷于对耐药性癫痫的治疗剂的转化开发，这些癫痫的治疗剂可以调节或永久并选择性地使癫痫焦点失活。