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.
Showing the most recent 10 out of 22 publications
