Gene therapy for Barth syndrome

March 30, 2020

HSCI researchers reverse heart failure in mice

Microscopy image of heart tissue.
In a mouse model of Barth syndrome (left), the heart muscle tissue has high amounts of scarring (in red). When treated with gene therapy (right), scarring is reduced. Credit: Pu laboratory


HSCI researchers have successfully tested a gene therapy in mice for Barth syndrome, a rare disease that can cause life-threatening heart failure. Published in the journal Circulation Research, the study shows the potential for using gene therapy to treat patients.

William Pu, M.D. is a principal faculty member of HSCI and the director of Basic and Translational Cardiovascular Research at Boston Children’s Hospital. In 2014, Pu created a “heart-on-a-chip” model of Barth syndrome, using heart muscle cells derived from patient stem cells, which had a mutation in the gene tafazzin (TAZ). The model confirmed that the TAZ mutation is responsible for cardiac dysfunction: the heart muscle cells did not assemble normally, mitochondria inside the cells were disorganized, and heart tissue contracted weakly. Adding a healthy TAZ gene normalized these features, suggesting that gene replacement therapy could be a viable treatment.

In the new study, Pu and his colleagues developed an animal model of Barth syndrome to fully capture the disease and its whole-body effects. “The animal model was a hurdle in the field for a long time,” Pu said. “Efforts to make a mouse model using traditional methods had been unsuccessful.”

Modeling Barth syndrome in mice

Collaborator Douglas Strathdee at the Beatson Institute for Cancer Research overcame the challenge of creating Barth syndrome animal models, developing two types: one type where the TAZ gene was deleted in cells throughout the body, and one where TAZ was deleted just in the heart.

Pu and colleagues characterized the models. They found that most mice with the whole-body TAZ deletion died before birth, apparently because of skeletal muscle weakness. But some survived, and these mice developed progressive cardiomyopathy, where the heart muscle enlarges and loses pumping capacity. Their hearts also showed scarring, and, similar to human patients with dilated cardiomyopathy, the heart’s left ventricle was dilated and thin-walled.

Mice lacking TAZ just in their cardiac tissue all survived to birth, but otherwise showed the same features. Electron microscopy showed that heart muscle tissue was poorly organized, as were the mitochondria within the cells.

Delivering gene therapy

Pu and colleagues then used gene therapy to replace TAZ in the mice, injecting an engineered virus to deliver the gene. When mice with whole-body TAZ deletions received the gene therapy, were able to survive to adulthood. TAZ gene therapy also prevented cardiac dysfunction and scarring when given to newborn mice, and reversed established cardiac dysfunction in older mice — whether the mice had whole-body or heart-only TAZ deletions.

Further tests showed that TAZ gene therapy led to lasting improvement of the animals’ cardiomyocytes and skeletal muscle cells, but only when at least 70 percent of heart muscle cells had taken up the gene.

That’s where the challenge will lie in translating the results to patients. Simply scaling up the dose of gene therapy would not work — large doses risk a dangerous inflammatory immune response. Giving multiple doses of gene therapy won’t work either.

“The problem is that neutralizing antibodies to the virus develop after the first dose,” Pu said. “Getting enough of the muscle cells corrected in humans may be a challenge.”

Another challenge is maintaining populations of gene-corrected cells. While levels of the corrected TAZ gene remained fairly stable in the hearts of the treated mice, they gradually declined in skeletal muscles.

“We have some things to think about to maximize the percentage of muscle cell transduction, and to make sure the gene therapy is durable, particularly in skeletal muscle,” Pu said. But, he added, “the biggest takeaway was that the gene therapy was highly effective.”

The breakthrough research was supported in part by the Barth Syndrome Foundation and the Edwin August Boger, Jr. Fund.

Discover more

This story was originally published on the Boston Children’s Hospital website with the title “Gene therapy reverses heart failure in mouse model of Barth syndrome” on March 9, 2020.

Source article: Wang, S. et al. (2020). AAV Gene Therapy Prevents and Reverses Heart Failure in A Murine Knockout Model of Barth Syndrome. Circulation Research. DOI: 10.1161/CIRCRESAHA.119.315956

The study was supported by the National Institutes of Health (R01HL128694, R01GM115593), the Barth Syndrome Foundation, the Edwin August Boger, Jr. Fund, and Boston Children’s Department of Cardiology. Pu is a member of the Medical and Scientific Advisory Board of the Barth Syndrome Foundation.