Central Nervous System Drug Delivery Techniques

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Preclinical Studies Real-time imaging of convection-enhanced delivery (CED) Monitoring CED delivery in real-time is essential because the treatment site and pathologic condition affect an infusate’s volumetric and anatomic distribution. We developed computed tomographic (CT)- and magnetic resonance (MR)-imaging tracers for real-time CED imaging that can be co-infused with therapeutic agents. Co-infusing therapeutic molecules and surrogate imaging tracers allowed real-time serial CT- or MR-imaging to monitor the distribution of putative therapeutic agents. Non-invasive monitoring of infusate delivery in real-time permitted exploration of many parameters (i.e., rate, flow characteristics, anatomic boundaries) associated with CED, spurred improved CED technology (i.e., catheter design, pump design), improved infusion accuracy, and assessed target coverage by infusate. 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, and gadolinium-DTPA infused bilaterally into the subthalamic nuclei. The distribution of muscimol was seen in real-time MRI. We published our report on muscimol distribution and behavioral effects in research animals in 2019. This work could support a clinical trial of muscimol infusion into the subthalamic nucleus during deep brain stimulation (DBS) surgery, exploring the effects of neural inhibition of the subthalamic nucleus in Parkinson’s disease. Convection-enhanced delivery of agents acting on specific neurotransmitters and brain structures is a chemical neurosurgery technique that potentially could treat patients with degenerative disorders. Epilepsy Surgically remediable drug-resistant epilepsy (DRE) usually originates from a hippocampal seizure focus. DRE could be relieved without surgically removing the hippocampus by selectively suppressing the epileptic focus. Our laboratory showed that convectively perfusing the epileptic focus reduced rodent seizures. In 2019, we published a manuscript describing botulinum toxin, an agent inactivating synaptic activity, infused by CED into the non-human primate hippocampus. We also studied the toxicity and distribution of chronically infused muscimol into the hippocampus of 10 non-human primates. Depth electrode studies showed that muscimol suppressed hippocampal electrical activity. Autoradiography of infused muscimol showed muscimol delivery throughout the hippocampus. Muscimol CED was tolerated without brain injury or permanent adverse effects. We published this study in 2020. Clinical Trials Neuro-Oncology Diffuse midline glioma of the pons, previously known as Diffuse Intrinsic Pontine Glioma (DIPG), is an unresectable, uniformly fatal pediatric brain tumor. Radiotherapy is palliative. Putative therapeutic compounds developed and available to treat diffuse brainstem gliomas are ineffective and cannot cross the blood-brain barrier. To overcome this limitation, we investigated the CED of a targeted anti-glioma agent (interleukin-13 bound to Pseudomonas toxin, IL13-PE) in the brainstem. We co-infused a surrogate MR-imaging tracer (gadolinium-DTPA) to monitor drug distribution in rodents and primates. The model was safe in animals. We then developed a clinical protocol to treat diffuse midline glioma in pediatric patients with IL13-PE co-infused with gadolinium-DTPA. We safely treated five patients with CED of IL13-PE. Gadolinium-DTPA 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 may be used for other CNS malignancies. Dr. Banasavadi collaborated with investigators to develop virotherapy for glioblastoma. Virotherapy evokes oncolytic and immunologic effects that can potentially extend glioblastoma patient survival (1). Convection-enhanced delivery techniques may spread a viral vector more broadly than direct injection and improve virotherapy’s efficacy. We also collaborated with Dr. Sadhana Jackson and Dr. Edjah Nduom on using intratumoral microdialysis to measure drug levels in brain tumor tissue after systemic drug delivery to assess if therapeutic levels are achieved. 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 prevents the death of dopaminergic neurons in culture and animal models of Parkinson’s disease (PD). Our study used escalating doses of AAV2-hGDNF, with six advanced Parkinson’s disease patients treated at the lowest dose, six at a higher dose, and 1 treated at the highest dose. Pre-operatively and at 6-12-month intervals post-operatively, the Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 assessed motor function. 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. MRI tracked AAV2-GDNF infusion as it distributed to 22% of the putaminal volume. Patients 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. Increased 18FDOPA uptake in the infused areas was seen bilaterally in 10/13 patients at six months and 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. Dr. Bankiewicz and our group also analyzed the long-term impact of AAV2-GDNF infusion on the infused brain area. We published an article showing that MRI findings were limited to the catheter track. One AAV-GDNF study subject died after cervical spondylosis surgery at another institution. The family consented to postmortem brain examination and histopathology, which was performed and organized into a case report this year (2). In this patient, Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD (2). The final study patient completed the study, and we are writing 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 three seizure surgery candidates for the clinical study. The subjects underwent 1 to 2-day infusions into the seizure focus of muscimol. The infusions were well-tolerated. Recruitment ended after three subjects. We published an article in 2019 with the study’s findings. We are enthusiastic about translational development of drug-resistant epilepsy (DRE) therapeutic agents that selectively modulate or permanently inactivate the epileptic focus. Peripheral Nerve Disorders The SNB supplied sensory nerve biopsies in an NINDS clinical trial of intrathecally delivered gene therapy for Giant Axonal Neuropathy. This study was published this year (3). Pain We collaborated with Dr. Andrew Mannes, Department of Perioperative Medicine, and his research team on a clinical study of intrathecal resiniferatoxin (RTX) for intractable cancer pain. RTX is a selective TRPV1 (transient receptor potential vanilloid 1) agonist that results in the selective eradication of pain pathways. An interim report on the safety and efficacy of intrathecal RTX was published this year (4). It demonstrated that the rate and volume of RTX delivery into the intrathecal space affected the regional extent of RTX's action on nervous system targets.