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Researchers from The Hospital for Sick Children (SickKids) have identified a genetic target that may provide a path toward treatment for Barth syndrome, a rare mitochondrial disorder that affects approximately 500 individuals globally. The findings, published in Nature, suggest that inhibiting a previously uncharacterized gene called ABHD18 improves mitochondrial function and cardiac health in preclinical models.

Barth syndrome is an inherited X-linked disorder that primarily affects males. It is caused by mutations in the TAFAZZIN gene, leading to disruptions in mitochondrial lipid metabolism and resulting in symptoms such as cardiomyopathy, muscle weakness and recurrent infections. Although cardiac transplantation can provide temporary relief, no curative therapies currently exist.

A genetic screen identifies a new metabolic regulator

The team at SickKids, in collaboration with academic and industry partners, employed a genetic screening approach to identify gene interactions that could modify the effects of TAFAZZIN deficiency. This led to the identification of ABHD18, a gene with no previously known biological function.

In preclinical models, including patient-derived cells and a zebrafish system, researchers observed that loss of ABHD18 restored balance in mitochondrial lipid metabolism. Specifically, inhibition of ABHD18 led to a decrease in monolysocardiolipin (MLCL), a lipid that accumulates to harmful levels when TAFAZZIN is not functioning correctly. MLCL buildup disrupts mitochondrial membranes and interferes with energy production, contributing to the cardiomyopathy seen in Barth syndrome.

Targeting ABHD18 improves heart function

In animal and cellular models, researchers demonstrated that blocking ABHD18 helps bypass the primary defect in the TAFAZZIN gene. Rather than repairing the defective gene directly, which poses technical challenges, inhibiting this newly described gene allowed for restoration of cardiolipin balance and mitochondrial integrity.

The study also tested a small-molecule compound, ABD646, designed to block ABHD18. Treated models showed reduced MLCL accumulation and signs of improved cardiac function. These results provide a preclinical proof of concept for targeting ABHD18 as a disease-modifying strategy.

The study was supported by the Azrieli Precision Child Health Platform, Canadian Institutes of Health Research, Barth Syndrome Foundation, Cancer Research UK, and the Ontario Research Fund.

 

Reference: Masud SN, Srivastava A, Mero P, et al. Genetic suppression features ABHD18 as a Barth syndrome therapeutic target. Nature. 2025. doi:10.1038/s41586-025-09373-5

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