Experimental gene therapy offers non-surgical option for hydrocephalus

Researchers at the University of Cincinnati College of Medicine have published the first proof-of-concept study showing the potential of an experimental gene therapy for hydrocephalus. The preclinical research from the lab of Agnes (Yu) Luo, PhD, was recently published in the prestigious journal Fluids and Barriers of the CNS, which focuses on specialized cerebrospinal fluid (CSF) biology.

Cerebrospinal fluid circulates throughout the brain, supporting brain function, regulating brain development, and carrying nutrients, hormones and signaling molecules. 

Hydrocephalus occurs when excess cerebrospinal fluid builds up in the brain, increasing pressure that can compress the brain and cause neurological impairment. Current treatment requires invasive brain surgery to drain excess fluid with a shunt, which is prone to failure. 

Neurosurgeons sometimes offer an alternative endoscopic approach to partially cauterize the choroid plexus tissue that produces cerebrospinal fluid. This solution can improve symptoms but doesn't substantially reduce fluid volumes, and is limited by technical and safety constraints. New, less invasive and more comprehensive treatments are urgently needed. 

What is this potential new gene therapy?

Luo, the study's corresponding author and a College of Medicine professor, has worked with members of her lab and collaborators at the University of California, Davis, to test an adeno-associated virus (AAV) gene therapy, a modified virus commonly used to deliver therapeutic genetic material into a patient's cells. This new AAV gene therapy targets and reduces the cell types that produce cerebrospinal fluid, limiting its production and spread into brain tissue.

"It efficiently targets the correct cells and reduces CSF production," said Aleksandr Taranov, PhD, the study's lead author, a neuroscience graduate student in Luo's lab at the time of the research and now a postdoctoral fellow at the University of Pennsylvania.

Notably, the therapy could have a less invasive delivery, possibly even injection through an existing shunt. "This would allow us to have a minimally invasive and feasible treatment for hydrocephalus," said Taranov.

The Luo Lab received grant funding from the National Institutes of Health (NIH) to support this research, underscoring its translational nature: a laboratory discovery that bridges real-world medical practice to improve human health.

The students in my lab are a critical driving force behind our research. It is especially rewarding to see them contribute to innovative and potentially impactful work while still in training."

Agnes (Yu) Luo, PhD, University of Cincinnati

University of California, Davis collaboration

To explore the potential clinical implications, the Cincinnati team partnered with neurosurgery researchers at UC Davis.

Cameron Sadegh, MD, PhD, and Olga Chechneva, PhD, co-led the UC Davis portion of the research. They induced hydrocephalus in adult animal models and then treated them with the experimental gene therapy developed by Luo's team. It proved effective at preventing edema, or excess fluid, from entering brain tissue outside the ventricles.

"Hydrocephalus is a life-threatening condition, and our treatment options are surprisingly limited and outdated. 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," said Sadegh, a pediatric neurosurgeon-scientist and assistant professor in the UC Davis School of Medicine's Department of Neurological Surgery.

"Showing that choroid plexus ablation reduces brain swelling does more than point to a new therapy. It sheds light on the mechanisms behind hydrocephalus and the brain injury it causes, knowledge that is critical for developing better treatments," said Chechneva, a project scientist in Sadegh's lab.

The Cincinnati team then validated the findings with a blinded analysis of the MRI data provided by the UC Davis team.

How does this build on previous research?

This research builds on prior Cincinnati research published in the Proceedings of the National Academy of Sciences in 2024, in which the Luo Lab was the first to directly ablate adult choroid plexus tissue, reducing cerebrospinal fluid in adult animal models and marking a major breakthrough in the field.

What are areas for further study?

Cerebrospinal fluid is clearly critical, but its role in postnatal neurogenesis - the process by which new neurons are generated after birth in the hippocampus region of the brain - remains poorly understood. Because reducing CSF production is central to this therapy's effectiveness, understanding any downstream effects on neurogenesis is an important next step.

Initial animal model testing shows that a loss of cerebrospinal fluid production moderately reduces the ability of the brain to produce new neurons. 

Despite concerns that reduced neurogenesis may affect the cellular networks underlying memory, the current state of hydrocephalus treatment leaves patients with a persistent, lifelong risk of repeated brain surgeries that can cumulatively diminish cognitive performance. So Luo and Taranov said further research, including a risk/benefit analysis, is needed. 

Either way, Luo said the results are clear: Animal models that received the AAV gene therapy had much less fluid in their brain tissue.

What are the next steps?

Luo said further research will test the AAV gene therapy in larger animal models and human tissues. Ideally, that will be followed by human clinical trials. Ultimately, the goal is to develop an effective treatment for hydrocephalus.

"This is continuous work," said Luo. 

Luo and Taranov are both inventors on a pending patent related to this work.