Central Nervous System Drug Delivery Techniques

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Preclinical Studies. Real-time imaging of convection-enhanced delivery (CED): It is essential to monitor CED delivery in real-time because the treatment site affects an infusate's volumetric and anatomic distribution. Various pathologic conditions alter tissue properties and affect CED parameters. We developed small and large molecular weight computed tomographic (CT)- and magnetic resonance (MR)-imaging tracers for real-time CED imaging. These tracers can be co-infused with therapeutic agents to further develop clinical use of the CED method. We showed that co-infusing therapeutic molecules and surrogate imaging tracers allowed serial CT- or MR-imaging to monitor CED of putative therapeutic agents in real-time. Non-invasive monitoring of infusate delivery in real-time permitted exploration of many parameters (i.e., rate, the effect of flow characteristics, the impact of anatomic boundaries) associated with CED, revealed areas for improvement in CED technology (i.e., catheter design, pump design), improved infusion accuracy, assessed adequacy of target coverage by infusate, and predicted the effectiveness of the infusion to treat targeted tissue disease. 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 studied convection-enhanced delivery of muscimol, a GABA-A agonist. A solution of muscimol and gadolinium-DTPA was infused bilaterally into the subthalamic nuclei. The distribution of muscimol was monitored in real-time by MRI with gadolinium-DTPA in the infusion solution. We also noted behavioral changes and safety. We published our report on muscimol distribution and behavioral effects in research animals in 2019. This work was performed to support a clinical trial of muscimol infusion into the subthalamic nucleus during deep brain stimulation (DBS) surgery exploring the potential mechanism of electrical stimulation of the subthalamic nucleus in Parkinson's disease. Using convection-enhanced delivery of agents acting on specific neurotransmitters and brain structures to treat patients with degenerative disorders could be considered chemical neurosurgery. Epilepsy: The hippocampus is usually the origin of surgically remediable drug-resistant epilepsy (DRE)(2,3). DRE could be relieved without surgically removing the hippocampus by selectively suppressing the epileptic focus. After successfully reducing seizures in rodents by convectively perfusing the epileptic focus, our laboratory studied the toxicity and distribution of chronically infused muscimol into the hippocampus of 10 non-human primates. Depth electrode studies showed that muscimol suppressed electrical activity in the hippocampus. Autoradiography of infused muscimol demonstrated muscimol delivery throughout the hippocampus using CED. Muscimol CED was tolerated without brain injury or permanent adverse effects. We published this study in 2020. In 2019, we published a manuscript describing CED of botulinum toxin, an agent inactivating synaptic activity, to the non-human primate hippocampus. Clinical Trials. Neuro-Oncology: Diffuse infiltrative brainstem gliomas are unresectable, uniformly fatal pediatric brain tumors. Radiotherapy is palliative. Putative therapeutic compounds developed and available to treat diffuse brainstem gliomas cannot cross the blood-brain barrier into the tumor and are therefore ineffective. We investigated CED of a targeted anti-glioma agent (interleukin-13 bound to Pseudomonas toxin, IL13-PE) to the brainstem to overcome this limitation. We co-infused a surrogate MR-imaging tracer (gadolinium-DTPA) to monitor drug distribution. Based on this delivery model's safe and successful use 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 drug distribution in real-time using intraoperative MR-imaging. We published our findings in 2018. This study's method of monitoring drug delivery and intratumoral treatment of diffuse brainstem glioma may be applied in treatment of other CNS malignancies (1). Neurodegenerative Disorders: 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). Parkinson's disease is progressive and presently incurable. GDNF is a neurotrophic factor that prevented the death of dopaminergic neurons in culture and animal models of Parkinson's disease (PD). Our 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 Parkinson's 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 as it distributed to 22% of the putaminal volume. Patients with advanced Parkinson's 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,and in 12/13 patients at 18 months after infusion. In 2019, we published these PET findings of increased putaminal 18FDOPA uptake, which suggested that AAV2-hGDNF had a neurotrophic effect on dopaminergic neurons. Earlier this year, one subject in the study died after surgery for cervical spondylosis at another institution. The family consented to post-mortem brain examination and histopathology, which was performed and organized into a case report. In January 2022, the final study patient will complete the study, and we will write a final study report. Epilepsy: The FDA granted us an IND for intracerebral CED of muscimol to the brain to inactivate the epileptic focus temporarily. We recruited 3 seizure surgery candidates for the clinical study. These subjects entered this trial and underwent 1 to 2-day infusions into the seizure focus of muscimol (a GABA agonist). The infusions were well-tolerated. Recruitment ended after 3 subjects because short-term muscimol infusion did not permanently treat epilepsy. We published a manuscript in 2019 describing the study's findings. We remain enthusiastic about the translational development of therapeutic agents for drug-resistant epilepsy (DRE) that selectively modulate or permanently inactivate the epileptic focus. Muscle and Peripheral Nerve Disorders: The Surgical Neurology Branch provides protocol-related sensory nerve biopsies in a Neuromuscular and Neurogenetic Disorders of Childhood Section (NNDCS) NINDS clinical trial testing intrathecally-delivered gene therapy for Giant Axonal Neuropathy. The SNB also performed muscle biopsies in a clinical trial for GNE myopathy.