6th Edition of Neurology World Conference 2026

Abstract

Accumulating physiologically relevant amounts of drugs within the central nervous system (CNS) remains a major hurdle in treating many encephalopathies. For example, temozolomide (TMZ) chemotherapy is administered at the maximum tolerated dose to patients with glioblastoma (GBM) but imparts only a few months of survival benefit. To improve TMZ efficacy via enhanced CNS accumulation, we developed a method to reduce the clearance rate of TMZ from the brain. Recent glymphatic studies demonstrate the interconnectivity between the fluid in the brain's parenchymal and ventricular spaces. We reasoned that enhancing the accumulation of a drug in the cerebral spinal fluid (CSF) of the ventricular space will also improve the accumulation of the drug in the parenchyma, where many encephalopathies, including GBM, present. We altered the biophysical properties of motile ependymal cilia to improve the accumulation of a blood-brain barrier penetrating therapeutic in the CSF. Ependymal cells coat the ventricles and display motile cilia that mechanically propel CSF through the ventricular space. We propose impairing ciliary motion slows CSF turnover without affecting the overall amount of CSF in the CNS. We identified FDA-approved therapeutics known to impair airway cilia as a “side effect” and demonstrated that these drugs also impair ependymal cilia. A panel of cilia inhibitors was administered into the ventricle of mice bearing orthotopic GBM in combination with systemic temozolomide (TMZ). Five of the seven cilia-inhibiting drugs significantly improved overall survival when combined with TMZ compared to controls. The lead candidate, lidocaine, demonstrated a synergistic relationship with TMZ, and 100% of animals treated with the combination regimen survived to the study endpoint tumor-free. Combining intraventricular lidocaine with TMZ is well tolerated and results in a 40-fold increase in brain temozolomide levels throughout the study compared to controls. Finally, we observe 100% tumor-free survival after treating mice bearing a human PDX orthotopic xenograft GBM with the combination of lidocaine and TMZ and 40% tumor-free survival when treating mice bearing an un-methylated MGMT human PDX orthotopic xenograft GBM that is resistant to TMZ treatment alone. These studies offer a new concept for treating malignant brain tumors and a potential scheme to improve the treatment of other encephalopathies via enhanced brain accumulation of CNS penetrating drugs.