Researchers from the University of Pennsylvania School of Veterinary Medicine and Children’s Hospital of Philadelphia (CHOP) have identified a link between mitochondrial dysfunction in the blood-brain barrier (BBB) and neuropsychiatric disease in patients with 22q11.2 deletion syndrome (22qDS), also known as DiGeorge syndrome. The study, published in Science Translational Medicine, suggests that cholesterol drugs approved by the FDA could potentially be repurposed to address this dysfunction.
The BBB acts as a separation between the brain and the rest of the body, and its maintenance is important for brain health. Problems with the BBB have been associated with several neurological disorders, including autism, schizophrenia, multiple sclerosis, and Alzheimer’s disease.
The research focused on 22qDS because it involves six mitochondrial genes and increases susceptibility to neurodevelopmental and neurodegenerative diseases. People with this condition are at higher risk for psychosis; one in four develops schizophrenia.
CHOP operates what it describes as the world’s largest clinic dedicated to treating children, adolescents, and some adults with 22qDS. Teams at both CHOP and Penn use this condition to better understand neurodevelopmental diseases.
“We previously established that the BBB is compromised in 22qDS, indicating that the crosstalk between the brain and the periphery can be affected,” says co-senior study author Jorge Iván Alvarez, PhD, an associate professor of pathobiology at Penn Vet. “With these findings in mind, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction in 22qDS.”
“This study really demonstrates the power of collaboration,” said co-senior study author Stewart A. Anderson, MD, Associate Chair for Research in the department of Child and Adolescent Psychiatry and Behavioral Sciences at CHOP and associate director of the CHOP/Penn Lifespan Brain Institute. “By combining our respective expertise on mitochondrial function and the BBB, we have made an important discovery that may substantially help individuals with 22qDS.”
Using human stem cell-derived brain microvascular endothelial cells from patients with 22qDS as well as preclinical models, researchers found evidence of a weakened or “leaky” BBB.
Treatment with bezafibrate—a cholesterol drug known to activate mitochondrial generation—was shown to improve BBB function both in laboratory models using stem cells and animal models. In animals, treatment also corrected social memory deficits linked to both BBB dysfunction and schizophrenia. Researchers believe these results indicate potential for repurposing this class of drugs if further clinical trials confirm their findings.
While centered on 22qDS patients, investigators suggest their results could apply more broadly to other neuropsychiatric conditions where mitochondrial dysfunction affects BBB integrity.
Funding for this work came from several sources including Stanford University’s Maternal and Child Health Research Institute Uytengsu-Hamilton Program; National Institutes of Health grants; Multiple Sclerosis Canada; Howard Hughes Medical Institute; Blavatnik Family Foundation; Penrose Family; Brain and Behavior Research Foundation; among others.
The full article can be found online: Crockett et al., “Bezafibrate improves mitochondrial function, blood-brain barrier integrity, and social deficits in models of 22q11.2 deletion syndrome.” Sci Transl Med. Online August 20, 2025. DOI: 10.1126/scitranslmed.ads2116.
