Gene Therapy Shows Proof of Concept for Treating Hydrocephalus at Its Source

Hydrocephalus, one of the most common and most feared neurological conditions, has been treated for decades with essentially the same blunt instrument: a silicone shunt that drains excess cerebrospinal fluid from the brain and shunts it elsewhere in the body. The surgery is invasive, the device is prone to failure, and patients often face repeated operations over a lifetime. Now, a team at the University of Cincinnati College of Medicine, working with collaborators at the University of California, Davis, has published the first proof-of-concept study showing that an experimental gene therapy can reduce hydrocephalus-associated tissue damage in animal models, offering a glimpse of a fundamentally different treatment strategy, one that targets fluid overproduction at its source rather than simply draining the consequences.

The research, led by Agnes (Yu) Luo, PhD, professor in the UC College of Medicine and the study’s corresponding author, was published in the journal Fluids and Barriers of the CNS, a publication devoted to the specialized biology of cerebrospinal fluid and the barriers that protect the central nervous system. The work was supported by grant funding from the National Institutes of Health, underscoring its translational ambition: to move a laboratory discovery toward real-world medical practice for a condition that remains life-threatening despite more than half a century of modern neurosurgery.

To understand why the approach is significant, it helps to understand what cerebrospinal fluid does and what goes wrong in hydrocephalus. CSF circulates throughout the brain, supporting brain function, regulating brain development, and carrying nutrients, hormones, and signaling molecules. Hydrocephalus occurs when excess CSF builds up inside the brain, raising intracranial pressure that can compress delicate neural tissue and cause neurological impairment. The current standard of care requires invasive brain surgery to implant a shunt that drains the excess fluid, but shunts are notoriously prone to failure, blocking, breaking, or becoming infected, often necessitating revision surgeries. Neurosurgeons sometimes offer an alternative endoscopic approach that partially cauterizes the choroid plexus, the tissue that produces cerebrospinal fluid, but this can only improve symptoms without substantially reducing fluid volumes, and it is constrained by technical and safety limits. New, less invasive, and more comprehensive treatments are urgently needed.

The experimental therapy developed in Luo’s lab is built on an adeno-associated virus, or AAV, a modified virus that has become one of the most widely used vehicles in gene therapy because it can efficiently deliver therapeutic genetic material into a patient’s cells without causing disease. In this case, the AAV construct is designed to target and reduce the specific cell types that produce cerebrospinal fluid, limiting its production and its spread into brain tissue. Rather than mechanically draining fluid after it has accumulated, the therapy aims to turn down the tap itself.

“It efficiently targets the correct cells and reduces CSF production,” said Aleksandr Taranov, PhD, the study’s lead author, who was a neuroscience graduate student in Luo’s lab at the time of the research and is now a postdoctoral fellow at the University of Pennsylvania. The precision of that targeting matters enormously: the choroid plexus sits at the interface between blood and cerebrospinal fluid, and any therapy that disrupts it must hit the fluid-producing cells while sparing surrounding brain structures.

Equally notable is the potential route of delivery. Because many hydrocephalus patients already carry an implanted shunt, the therapy could conceivably be administered through that existing hardware, an injection through a device that is already in place. “This would allow us to have a minimally invasive and feasible treatment for hydrocephalus,” Taranov said. For a condition whose current treatments involve opening the skull or threading endoscopes deep into the ventricles, the prospect of a shunt-delivered gene therapy represents a strikingly less invasive alternative.

To explore the clinical implications, the Cincinnati team partnered with neurosurgery researchers at UC Davis, where Cameron Sadegh, MD, PhD, and Olga Chechneva, PhD, co-led the animal studies. The Davis team induced hydrocephalus in adult animal models and then treated them with the experimental gene therapy developed by Luo’s group. The treatment proved effective at preventing edema, the accumulation of excess fluid, from entering brain tissue outside the ventricles, the fluid-filled chambers where CSF normally resides. Preventing that parenchymal edema is critical, because fluid invading brain tissue is a major driver of the neurological damage hydrocephalus causes. The Cincinnati team then validated the findings with a blinded analysis of MRI data provided by the UC Davis team, adding an extra layer of rigor to the cross-institutional result.

“Hydrocephalus is a life-threatening condition, and our treatment options are surprisingly limited and outdated,” said Sadegh, a pediatric neurosurgeon-scientist and assistant professor in the UC Davis School of Medicine’s Department of Neurological Surgery. “Shunt treatment frequently fails, and alternative endoscopic treatments are not possible for many patients. We are eager to contribute to the preclinical development and safety testing of new, cell-targeted approaches to treat this devastating condition.” Chechneva, a project scientist in Sadegh’s lab, emphasized that the findings reach beyond therapy development. “Showing that choroid plexus ablation reduces brain swelling does more than point to a new therapy,” she said. “It sheds light on the mechanisms behind hydrocephalus and the brain injury it causes, knowledge that is critical for developing better treatments.”

The study builds directly on a 2024 paper from the Luo Lab published in the Proceedings of the National Academy of Sciences, in which the team became the first to directly ablate adult choroid plexus tissue, reducing cerebrospinal fluid in adult animal models. That result was considered a major breakthrough in the field, because it demonstrated for the first time that the fluid-producing tissue in adults could be selectively reduced. The new work extends that foundation by showing that a gene therapy approach can achieve a similar effect and, crucially, that doing so attenuates the brain swelling associated with hydrocephalus.

Important questions remain, and the researchers are candid about them. Cerebrospinal fluid plays a role in postnatal neurogenesis, the generation of new neurons after birth in the hippocampus, a brain region central to memory, and this process remains poorly understood. Because reducing CSF production is central to the therapy’s effectiveness, understanding any downstream effects on neurogenesis is a critical next step. Initial animal testing shows that a loss of CSF production moderately reduces the brain’s ability to produce new neurons. Yet Luo and Taranov note that the current state of hydrocephalus treatment leaves patients with a persistent, lifelong risk of repeated brain surgeries that can cumulatively diminish cognitive performance, so a careful risk/benefit analysis is needed to weigh reduced neurogenesis against the burden of repeated operations. Either way, Luo said, the results are clear: animal models that received the AAV gene therapy had much less fluid in their brain tissue. The next phase will test the therapy in larger animal models and human tissues, ideally followed by human clinical trials. “This is continuous work,” Luo said. Luo and Taranov are both inventors on a pending patent related to the work, and contributors from both labs, including Sage Hamm, Eric Kniffen, Joshua Peter, Felissa Wallace, Olivia Lullmann, and Lucas McClain at Cincinnati and Florian Mayrhofer at UC Davis, helped bring the proof of concept to fruition.

Subject of Research: AAV gene therapy targeting choroid plexus to reduce cerebrospinal fluid production in hydrocephalus

Article Title: University of Cincinnati study shows proof-of-concept for hydrocephalus gene therapy

Article References: University of Cincinnati study shows proof-of-concept for hydrocephalus gene therapy. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: hydrocephalus, gene therapy, adeno-associated virus, cerebrospinal fluid, choroid plexus, University of Cincinnati, UC Davis, shunt surgery, brain edema, neurogenesis, preclinical study, Fluids and Barriers of the CNS