Breakthrough in Targeted Gene Therapy Offers New Hope for Barth Syndrome Patients

Researchers at The Hospital for Sick Children (SickKids) have identified a promising new target for treating Barth syndrome, a rare and often severe genetic disorder with no current cure. The study, published in the journal Nature, highlights how blocking a specific gene called ABHD18 can restore mitochondrial function and enhance heart health in preclinical models.

Barth syndrome is an inherited condition that primarily affects males and is characterized by muscle weakness, frequent infections, and heart muscle disease known as cardiomyopathy. Despite the use of heart transplants to manage cardiac symptoms, many affected children do not survive past early childhood. The new research offers hope for more targeted therapies by uncovering the role of the ABHD18 gene.

The study revealed that mutations in the TAFAZZIN gene cause a reduction in cardiolipin, a vital fat involved in mitochondrial energy production. This deficiency leads to mitochondrial dysfunction, impairing the cell’s ability to generate energy, which contributes to the disease's severity. Genetic screening identified ABHD18 as a key regulator that influences cardiolipin metabolism.

By developing molecules that inhibit ABHD18, scientists successfully improved mitochondrial health and cardiac function in models of Barth syndrome, including zebrafish and patient-derived cells. The small molecule ABD646 effectively lowered levels of harmful lipids, improving energy production and heart function. This discovery demonstrates that targeting secondary regulators like ABHD18 can bypass complex genetic defects and offer new therapeutic avenues.

Dr. Jason Moffat emphasized the significance of these findings for precision medicine, explaining that understanding how ABHD18 interacts within mitochondrial pathways allows for potential development of tailored treatments. The team’s work illustrates how genomic research can accelerate the discovery of novel therapies for rare genetic conditions, bringing hope to families affected by Barth syndrome.

This innovative approach marks a major step toward targeted gene-based therapies, providing a foundation for future clinical development aimed at restoring mitochondrial integrity and improving quality of life for patients with Barth syndrome.