Central Nervous System Drug Delivery Techniques

中枢神经系统给药技术

基本信息

批准号：
7735338
负责人：
Russell Lonser
金额：
$ 206.81万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
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/7735338
关键词：
Adverse effects Alzheimer&apos s Disease Anatomy Animals Apoptotic Ataxia Autoradiography Back Binding Blood Brain Brain Injuries Brain Neoplasms Brain Stem Brain Stem Glioma Bypass Catheters Cause of Death Central Nervous System Agents Central Nervous System Diseases Characteristics Chemicals Child Childhood Chronic Clinical Clinical Protocols Clinical Research Condition Convection Cranial Nerves Data Depth Development Diffuse Diffusion Disease Drug Delivery Systems Drug Monitoring Effectiveness Electrodes Ensure Epilepsy Essential Tremor Excision Extracellular Space GABA Agonists Gadolinium DTPA Glioma Grant Growth Factor Heterogeneity Hippocampus (Brain)Image Imagery Infusion procedures Interleukin-13 Intractable Epilepsy Laboratories Limb structure Localized Location Magnetic Resonance Imaging Malignant Glioma Malignant Neoplasms Metabolic Diseases Methods Modeling Molecular Weight Monitor Movement Disorders Muscimol Nature Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Nuclear Structure Numbers Operative Surgical Procedures Pain Parkinson Disease Pathologic Patients Perfusion Pharmaceutical Preparations Primates Process Property Pseudomonas Radiation Rate Recruitment Activity Research Rodent Rodent Model Seizures Sensory Site Syndrome Techniques Technology Therapeutic Therapeutic Agents Time Tissues Toxic effect Toxin Tracer United States Food and Drug Administration Work X-Ray Computed Tomography base bench to bedside cell type chemotherapy cytokine day design drug distribution improved insight interstitial motor deficit nervous system disorder neuro-oncology neurosurgery nonhuman primate pre-clinical preclinical study success time use treatment site tumor

项目摘要

Preclinical Studies Real-time imaging of convection-enhanced delivery (CED). Since the volume of distribution and the anatomic distribution will vary with the site of treatment and because the distribution of flow in the extracellular space of the brain is influenced by tissue heterogeneity, direct visualization of the distribution of the infused compound in the central nervous system (CNS) during infusion will be critical for further development and for optimal clinical use of convective delivery. We have recently developed small and large molecular weight computed tomography (CT)- and magnetic resonance (MR)-imaging surrogate tracers that can be co-infused with therapeutic compounds during CED. We have shown that mixing therapeutic agents and surrogate imaging tracers allows for precise monitoring of drug (small and large molecule) distribution in real-time using serial CT- or MR-imaging. The ability to non-invasively monitor distribution of infusate in real-time now permits exploring a variety of parameters (rate, effect of flow characteristics, effect of anatomic boundaries) associated with CED, allows for improvements in the technology (catheter design) associated with CED, enhances the accuracy of infusion, ensures adequate target perfusion and permits for the accurate determination of the efficacy of various therapeutic agents. Preclinical to Clinical Therapeutic Applications Exploiting the unique delivery properties of CED has permitted us to investigate several new research and treatment paradigms for CNS disorders. Currently, we are using a bench-to-bedside (and back in some cases) approach to treat malignant tumors, neurodegenerative and metabolic disorders in various regions of the CNS by convective delivery of putative therapeutic agents. Neuro-oncology. Diffuse brainstem gliomas are the main cause of death by brain tumors in children and are uniformly fatal (median survival of less than 1 year). These tumors cause ataxia, cranial nerve deficits and motor and sensory deficits of the extremities. Because of the location and infiltrative nature of these tumors, excision is not possible. Current therapy includes radiation and chemotherapy, which are palliative at best. While putative therapeutic compounds exist for treatment of diffuse brainstem gliomas, they have not been effective in part because of the inability of systemically administered compounds to cross the blood nervous system barrier (BNSB) in therapeutic amounts. 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 in animals and used a CED paradigm that permits monitoring of drug distribution by using 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 have safely treated a patient with CED of IL13-PE and gadolinium-DTPA and successfully tracked the distribution of drug in real-time using intraoperative MR-imaging. These early findings and further data from this ongoing effort could represent a new paradigm for monitoring drug delivery and treatment of diffuse brainstem gliomas, as well as other CNS malignancies including malignant gliomas. Neurodegenerative disorders. The properties of CED permit it to be used to selectively manipulate distinct subsets of neurons (and other cell types) for therapy. We are investigating targeted pharmacologic approaches to manipulate diseased nuclear structures and circuitry within the brain. A number of neurological disorders associated with localized neuronal dysregulation such as Parkinsons disease (PD), movement disorders other than PD (e.g., essential tremor) and certain pain syndromes may prove amenable to targeted treatment of diseased CNS structures with therapeutic compounds. In these pathologic conditions, convection is being explored to selectively distribute putative therapeutic (non-ablative) molecules to defined pathologic CNS sites, permitting a targeted, site-specific means of chemical neurosurgery. Information from these studies, including the downstream effects of targeted treatment with therapeutic compounds with defined cellular effect, should provide direct and indirect insight into the pathophysiologic basis of a variety of disorders. This should stimulate further critical laboratory bench work (i.e., a bench-to-bedside and back approach). Currently, we are examining the use of growth factors, cytokines and anti-apoptotic agents to slow or reverse the effects of PD in the MPTP-primate model and other neurodegenerative disorders (e.g., Alzheimers disease). 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 has granted us approval for intracerebral CED of muscimol to brain. Candidates for seizure surgery are being recruited for our 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 have entered this trial and have undergone 1 to 2 day infusions into the seizure focus of the study drug, muscimol (a GABA agonist) under an FDA IND. Subsequent subjects will receive progressively longer infusions. If this paradigm is successful, we will explore if other agents can be used to permanently and selectively inactivate the epileptic focus.

临床前研究对流增强传递 (CED) 的实时成像。由于分布体积和解剖分布会随着治疗部位的不同而变化，并且由于大脑细胞外空间中的血流分布受到组织异质性的影响，因此可以直接可视化所输注化合物在中枢神经系统中的分布。输注过程中的中枢神经系统（CNS）对于进一步发展和对流输送的最佳临床应用至关重要。我们最近开发了小分子量和大分子量计算机断层扫描 (CT) 和磁共振 (MR) 成像替代示踪剂，可以在 CED 期间与治疗化合物共同注入。我们已经证明，混合治疗剂和替代成像示踪剂可以使用连续 CT 或 MR 成像实时精确监测药物（小分子和大分子）的分布。现在，非侵入性实时监测输液分布的能力允许探索与 CED 相关的各种参数（速率、流动特性的影响、解剖边界的影响），从而可以改进与 CED 相关的技术（导管设计）。 CED，提高输注的准确性，确保足够的目标灌注，并允许准确确定各种治疗药物的功效。临床前到临床治疗应用利用 CED 的独特传递特性，我们能够研究中枢神经系统疾病的几种新的研究和治疗范例。目前，我们正在使用从实验室到床边（在某些情况下还包括背部）的方法，通过对流输送假定的治疗药物来治疗中枢神经系统各个区域的恶性肿瘤、神经退行性疾病和代谢性疾病。神经肿瘤学。弥漫性脑干胶质瘤是儿童脑肿瘤死亡的主要原因，并且都是致命的（中位生存期不到 1 年）。这些肿瘤导致共济失调、脑神经缺陷以及四肢运动和感觉缺陷。由于这些肿瘤的位置和浸润性质，不可能切除。目前的治疗方法包括放疗和化疗，它们充其量只是姑息治疗。虽然存在用于治疗弥漫性脑干神经胶质瘤的推定治疗化合物，但它们并不有效，部分原因是全身施用的化合物无法以治疗量穿过血液神经系统屏障(BNSB)。为了克服这一限制，我们研究了将靶向抗神经胶质瘤药物（与假单胞菌毒素 IL13-PE 结合的白细胞介素 13 结合）的 CED 用于动物脑干的可能性，并使用了 CED 范例，该范例允许通过使用共注入替代 MR 成像示踪剂（钆-DTPA）。基于这种给药模型在啮齿类动物和灵长类动物中安全、成功的使用，我们开发了一种临床方案，用 IL13-PE 与钆-DTPA 共输注来治疗儿科患者的弥漫性脑干胶质瘤。我们安全地治疗了一名患有 IL13-PE 和钆-DTPA 的 CED 患者，并使用术中 MR 成像成功地实时跟踪药物的分布。这些早期发现和来自这项持续努力的进一步数据可能代表了监测药物输送和治疗弥漫性脑干胶质瘤以及包括恶性胶质瘤在内的其他中枢神经系统恶性肿瘤的新范例。神经退行性疾病。 CED 的特性使其可用于选择性地操纵不同的神经元子集（和其他细胞类型）进行治疗。我们正在研究有针对性的药理学方法来操纵大脑内患病的核结构和电路。许多与局部神经元失调相关的神经系统疾病，例如帕金森病 (PD)、PD 以外的运动障碍 (例如特发性震颤) 和某些疼痛综合征，可能证明适合用治疗性化合物对患病 CNS 结构进行靶向治疗。在这些病理条件下，人们正在探索对流，以选择性地将假定的治疗（非消融）分子分配到特定的病理中枢神经系统部位，从而实现化学神经外科的有针对性的、特定部位的方法。这些研究的信息，包括使用具有明确细胞效应的治疗化合物进行靶向治疗的下游效应，应该可以直接和间接地了解各种疾病的病理生理学基础。这应该会刺激进一步关键的实验室工作台工作（即从工作台到床边和背部的方法）。目前，我们正在研究使用生长因子、细胞因子和抗凋亡剂来减缓或逆转 MPTP 灵长类动物模型中 PD 和其他神经退行性疾病（例如阿尔茨海默病）的影响。癫痫。海马体是医学上难治性癫痫的常见起源部位。如果开发出一种方法来选择性抑制海马体内的癫痫病灶，则可以缓解这种类型的癫痫。在利用癫痫病灶的对流灌注在啮齿类动物模型中成功消除癫痫发作后，我们的实验室对 10 只非人类灵长类动物的海马体中长期输注蝇蕈醇的毒性和分布进行了研究。深度电极研究表明，海马体的电活动可以被蝇蕈醇抑制。输注蝇蕈醇的放射自显影证明，通过对流灌注，可以将蝇蕈醇递送至整个海马。输注耐受性良好，没有脑损伤或永久性不良反应。 FDA 已批准我们对脑进行蝇蕈醇脑内 CED 治疗。我们正在招募癫痫手术的候选者来参加我们的临床研究，该研究将蝇蕈醇注入海马体以暂时灭活癫痫病灶的神经元。 18 名受试者中的前 3 名受试者已进入该试验，并根据 FDA IND 向癫痫病灶部位注射了研究药物蝇蕈醇（一种 GABA 激动剂），为期 1 至 2 天。随后的受试者将接受逐渐更长的输注时间。如果这种范例成功，我们将探索是否可以使用其他药物来永久且选择性地灭活癫痫病灶。