Oral drug shows promise for treating Barth syndrome

Tohoku University researchers have discovered that an oral drug called MA-5 can improve both heart and muscle problems in Barth syndrome, a rare genetic disorder affecting one in 300,000 births worldwide. Their work has been published in The FASEB Journal.

Barth syndrome is caused by mutations in the TAZ gene that leave patients — mostly young boys — with weakened hearts, muscle fatigue and increased rates of infection. Many require heart transplants, and current treatments only manage symptoms without addressing the underlying cause.

The research team, led by Professor Takaaki Abe, Professor Takafumi Toyohara and Yoshiyasu Tongu, tested MA-5 on cells from four Barth syndrome patients and in fruit fly (Drosophila) models of the disease. MA-5 was chosen as a treatment because it enhances interactions between two crucial mitochondrial proteins — mitofilin and ATP synthase — leading to more efficient energy production. As such, this mechanism directly addresses the cause of cellular dysfunction in Barth syndrome.

“What excites us most is that MA-5 works by targeting the fundamental problem in Barth syndrome — defective energy production in mitochondria,” Abe explained. “Unlike current treatments that only manage symptoms, MA-5 actually improves the root cause of how cells generate energy.”

The team’s findings reveal that MA-5 boosted cellular energy (ATP) production by up to 50% and protected cells from oxidative stress-induced death. In human muscle cells derived from Barth syndrome iPS cell models, MA-5 corrected abnormal mitochondrial structures and reduced cellular stress markers.

When tested in Drosophila with Barth syndrome, the drug dramatically improved their climbing ability (capacity for physical exertion) and normalised their elevated heart rates — two key symptoms that mirror how the disease affects humans. Furthermore, MA-5 restored normal mitochondrial structure in the Drosophila muscle tissue.

These promising results suggest that MA-5 addresses the largest challenges faced by patients with Barth syndrome, which would significantly improve their quality of life. Phase I clinical trials in Japan have been completed successfully, and the research team is preparing to start Phase II trials soon.

“We’ve validated MA-5 using patient cells, iPS cell models and a Drosophila model of Barth syndrome,” Abe said. “The evidence from all of these studies supports its potential effectiveness in patients with Barth syndrome, which we hope to examine more in the next clinical trial.”

Critically, MA-5 can be taken orally, which makes administration significantly easier for paediatric patients. It is understood to be the first oral medication for Barth syndrome to progress to the clinical trial stage, and could very well become the first disease-modifying treatment for Barth syndrome.

Image credit: iStock.com/ArtMarie