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.