Cholesterol Drug Repurposed to Improve Blood-Brain Barrier and Neuropsychiatric Outcomes in DiGeorge Syndrome

Recent research indicates that targeting mitochondrial dysfunction at the blood-brain barrier (BBB) could offer new therapeutic avenues for individuals with DiGeorge syndrome (22qDS), a genetic disorder associated with increased risk of neuropsychiatric conditions such as schizophrenia. A collaborative effort between the University of Pennsylvania School of Veterinary Medicine (Penn Vet) and Children's Hospital of Philadelphia (CHOP) has uncovered that mitochondrial deficits contribute to a compromised BBB, leading to neurodevelopmental challenges in 22qDS patients.

The BBB is a vital vascular structure that maintains brain homeostasis, preventing harmful substances from entering the brain while allowing essential nutrients through. Interestingly, the BBB contains a higher mitochondrial content compared to peripheral blood vessel endothelial cells, underscoring its reliance on mitochondrial health. In 22qDS, which involves the deletion of six mitochondrial genes, this mitochondrial impairment results in a 'leaky' BBB, contributing to neuropsychiatric symptoms such as psychosis. Approximately one in four individuals with 22qDS may develop schizophrenia, highlighting the urgency for targeted treatments.

The study focused on human-induced pluripotent stem cell-derived brain microvascular endothelial cells from patients with 22qDS and BBB models from preclinical studies. Findings demonstrated that mitochondrial dysfunction weakens BBB integrity, but encouragingly, treatments can restore function. The team tested bezafibrate, an FDA-approved cholesterol-lowering drug known to activate mitochondrial biogenesis and turnover. Treatment with bezafibrate improved mitochondrial health, strengthened BBB function, and corrected social memory deficits in animal models—abnormalities linked to BBB impairment and schizophrenia.

These promising results suggest that existing cholesterol drugs like bezafibrate could be repurposed to address mitochondrial and BBB dysfunction in neuropsychiatric conditions. While initial studies centered on 22qDS, researchers believe that the implications extend to other neuropsychiatric disorders involving mitochondrial pathology, including idiopathic psychosis and neurodegenerative diseases. Further clinical investigations are necessary to confirm these findings.

This groundbreaking work emphasizes the importance of mitochondrial health in maintaining BBB integrity and its impact on neuropsychiatric disorders, offering a new perspective on treatment strategies. The full research is published in Science Translational Medicine. (source: https://medicalxpress.com/news/2025-08-repurposing-cholesterol-drug-benefit-digeorge.html)