Researchers uncover a promising new therapeutic target for Barth syndrome

Researchers at The Hospital for Sick Children (SickKids) have uncovered a promising new therapeutic target for Barth syndrome, a rare genetic condition with no current cure. 

Barth syndrome is an X-linked genetic condition affecting about 500 people worldwide, most of whom are males. The rare condition causes muscle weakness, frequent infections and cardiomyopathy. While heart transplants can manage cardiac symptoms, many children with Barth syndrome do not live past early childhood. 

The research, published in Nature, was an international effort involving academic and industry collaborations, and revealed that blocking a newly described gene called ABHD18 can restore mitochondrial health and improve heart function in preclinical models of Barth syndrome. The discovery offers a potential path to targeted therapies for this rare condition. 

The purpose of so many genes remains unknown, but that's exactly why genomic research is such a powerful tool to advance Precision Child Health. Now we know that ABHD18 plays an essential role in the development of healthy mitochondria, we can explore new therapies for Barth syndrome and potentially other cardiac conditions." 

Dr. Jason Moffat, study lead, Senior Scientist and Program Head of the Genetics & Genome Biology program

A hidden gene with big impact 

Barth syndrome is caused by changes in a gene called TAFAZZIN, which provides instructions for making a protein called TAFAZZIN. TAFAZZIN is essential to the healthy function of mitochondria, which are responsible for energy production, by modifying a special type of fat called cardiolipin. 

When the TAFAZZIN gene doesn't work properly, as it does in children with Barth syndrome, the body produces less cardiolipin and much more of a harmful lipid called monolysocardiolipin (MLCL) in tissues. This build-up of MLCL disrupts the function and structure of mitochondria, making it harder to generate the energy cells need to function normally. As a result, children can develop serious heart problems. 

To better understand this pathway, Dr. Sanna Masud, a former PhD candidate in the Moffat Lab, conducted a genetic screen to identify genes that interact with TAFAZZIN and identified ABHD18. "ABHD18 was initially an uncharacterized gene and had no described function. After a number of experiments and with the help of collaborators, we discovered that ABHD18 encodes a key regulator of CL metabolism," says Masud. 

Small molecules block ABHD18 and restore heart health 

The researchers found that ABHD18 acts as a suppression gene that affects the pathway involved in the production of cardiolipin. A suppression gene is a gene that can reduce or counteract the effects of another gene when that gene is not working properly. While fixing TAFAZZIN directly is complex, blocking this suppression gene offers a way to bypass the problem and improve mitochondrial function. 

"Rather than attempting to repair the faulty TAFAZZIN gene directly, we focused on this secondary gene that amplifies the damage when TAFAZZIN is missing," explains Moffat. 

"By turning off ABHD18, we were also able to reverse the effects of TAFAZZIN deficiency in a preclinical model. It's one of the most striking examples of a disease modifier that this research team has ever seen," says Dr. Vincent Blomen, study co-lead and Sr. Director of Discovery Sciences at Scenic Biotech. 

By blocking ABHD18 with a small-molecule drug called ABD646, they were able to reduce MLCL levels in multiple preclinical models of Barth syndrome. Using a zebrafish model developed by Dr. Ian Scott's lab at the SickKids Zebrafish Genetics and Disease Model Core Facility and patient-derived cells provided by Dr. Seema Mital, the team observed improved mitochondrial health and heart function. 

"ABHD18 gives us a direct path to correcting the underlying problem of this rare condition and can provide real hope for patients and families," says Moffat. "This is a perfect example of how research can inform new therapies and care for some of the rarest conditions." 

Research funded by the Azrieli Precision Child Health Platform, Canadian Institutes of Health Research (CIHR), Barth Syndrome Foundation, Cancer Research UK, and Ontario Research Fund.