SRDA-01 DYNAMIC CONTROL OF CEREBROSPINAL FLUID FLOW TO ACHIEVE PERSONALIZED DRUG DELIVERY IN THE CENTRAL NERVOUS SYSTEM

Abstract BACKGROUND Systemically delivered therapeutics have limited access to the brain due to the tightly regulated blood brain barrier. There is a fine balance between production, volume, and removal of cerebrospinal fluid (CSF). The active efflux makes CNS therapeutics particularly challenging. With direct delivery to the CSF is increasingly utilized but penetration deep into the brain parenchyma is poor. Ideally, a CSF delivery system would have the capability to deliver therapeutics broadly, while improving parenchymal exposure. METHODS Sheep were used as a model. The EnTrega drug delivery system utilizes two CSF access points and extracorporeal pump to control the speed and direction of CSF flow. Sensors continuously monitore pressure, respiration, and heart rate. Imaging studies with dye determined the best parameters for controlling CSF flow. Administration of methotrexate was followed by a protocol to move CSF between the two access points. Methotrexate levels were measured with LC/MS in CSF, blood, and tissues. RESULTS Omnipaque dye was observed to move between the two ventricles. Safe pressures (< 25 mmHg or 34 cm water) were sustained in all subjects. Effective levels of >1 ug/mg methotrexate were measured in all brain tissues, including deeper brain tissues such as the striatum. Importantly, methotrexate levels were significantly lower in lumbar region of the spinal cord, kidney, and liver–potential sources of toxicity. CONCLUSIONS In this large animal study, with EnTrega, we demonstrate dye movement between the two ventricles in a controlled fashion resulting in improved distribution of methotrexate. EnClear’s system delivered high levels of methotrexate that penetrated the parenchyma of deep brain structures. To the authors knowledge, this first intraCSF drug delivery device to show improved distribution throughout the CNS including deep brain structures, while keeping spinal cord, liver, and kidney levels very low. Clinical trials with the device are currently being planned.