Researchers at the University of Cincinnati and UC Davis have demonstrated a proof-of-concept gene therapy that targets cells producing cerebrospinal fluid to reduce brain swelling in animal models of hydrocephalus, offering a potential alternative to traditional surgical shunts.
Targeting Cerebrospinal Fluid Production at Its Source
Hydrocephalus has long relied on mechanical drainage using silicone shunts that drain excess fluid from the brain to elsewhere in the body. While these devices relieve pressure, they are prone to failure and require patients to undergo repeat operations over a lifetime. Neurosurgeons also utilize endoscopic procedures, but that approach does not significantly lower fluid volume and remains unsafe for many patients.
Researchers sought a method to turn down fluid production rather than simply draining the consequences. A team at the University of Cincinnati College of Medicine tested an adeno-associated virus gene therapy designed to target and reduce the specific cells that produce cerebrospinal fluid, limiting its accumulation and spread into brain tissue.
It efficiently targets the correct cells and reduces CSF production.
Aleksandr Taranov, lead author and postdoctoral fellow at the University of Pennsylvania
The modified virus serves as a vehicle to deliver genetic material into the required cells without causing disease. Cameron Sadegh and Olga Chechneva co-led the UC Davis portion of the research, with Chechneva serving as a project scientist in Sadegh’s lab.
Preclinical Testing in Animal Models at UC Davis
To explore clinical implications, the Cincinnati research group partnered with neurosurgery researchers at UC Davis. Investigators induced hydrocephalus in adult animal models and administered the experimental gene therapy.
The treatment successfully prevented edema, or excess fluid, from entering brain tissue outside the ventricles. Investigators later reviewed MRI scans without knowing which animals received the treatment, a blinded analysis that confirmed the therapy reduced fluid buildup in brain tissues.
Hydrocephalus is a life-threatening condition, and our treatment options are surprisingly limited and outdated.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.
Cameron Sadegh, pediatric neurosurgeon-scientist and assistant professor at the UC Davis School of Medicine
It sheds light on the mechanisms behind hydrocephalus and the brain injury it causes, knowledge that is critical for developing better treatments.
Olga Chechneva, project scientist in Sadegh’s lab at UC Davis
Weighing Therapeutic Benefits Against Postnatal Neurogenesis
Because cerebrospinal fluid plays a role in postnatal neurogenesis—the generation of new nerve cells in the hippocampus—researchers examined whether suppressing fluid production alters the brain’s ability to produce new neurons. Initial animal testing indicates that a loss of cerebrospinal fluid production moderately reduces neurogenesis.
This reduction suggests that memory-related cellular networks may be affected. However, the current standard of care leaves hydrocephalus patients facing lifelong risks from repeated brain surgeries that can cumulatively diminish cognitive performance. Investigators emphasize that further research, including a comprehensive risk-benefit analysis, is required before clinical application.
Future Steps Toward Clinical Trials
Because many hydrocephalus patients already carry implanted shunts, researchers suggest the gene therapy could eventually be administered directly through existing hardware as a minimally invasive injection.
The study marks an initial step toward human translation. Investigators plan to test the adeno-associated virus platform in larger animal models and human tissues before pursuing clinical trials.
This is continuous work.
Agnes (Yu) Luo
Luo and Taranov are both listed as inventors on a pending patent related to the work.