Novel Biologics to ablate choroid plexus for the treatment of neonatal hydrocephalus

Project Summary Surgical treatment via ventriculoperitoneal shunt or endoscopic 3rd ventriculostomy is currently the most commonly used strategy to treat pediatric hydrocephalus. However, shunt-treated hydrocephalic patients continue to experience significant lifelong neurological problems and high malfunctioning shunt replacement

surgery rates. The endoscopic choroid plexus (ChP) coagulation helps manage cerebrospinal fluid (CSF) volume by surgically removing the primary CSF production organ in the brain ventricles. However, this surgical procedure requires neurosurgeons with extensive training and still achieves only partial ChP removal. This

study aims to evaluate a novel, potent, and less invasive ChP ablation tool in human ChP organoids and rodent brains that can support new ways of treating neonatal hydrocephalus. The NIH Funding Opportunity program announcement PAR-21-122 recognizes the unmet need for translational studies for neurotherapeutics agents for treating neurological or neuromuscular disorders and

new therapeutics. In response to this opportunity, our proposal focuses on developing a new ChP ablation tool via ChP-specific delivery of a clinically validated suicide gene. By utilizing cutting-edge techniques such as recombinant adeno-associated virus (AAV) vector targeting ChP, human ChP organoids, robust rodent

models of neonatal hydrocephalus, and advanced MRI, including DTI and animal behavior assays, our project aims to achieve rigorous efficacy and safety studies of this new tool. The completion of this study will determine (1) pharmacokinetics and off-target effects and (2) the therapeutic efficacy of this AAV-mediated ChP ablation tool, which has high potential to provide a new strategy for treating

pediatric hydrocephalus.