Barth Syndrome: Gene Therapy Offers Hope, But Challenges Remain for Rare Genetic Disorder

Key Takeaways:

• Barth syndrome, a rare X-linked disorder affecting males, causes heart defects, muscle weakness, and immune issues due to mutations in the TAZ gene.
• Boston researchers successfully reversed heart dysfunction in lab models using gene therapy, but sustaining treatment effects in humans remains a hurdle.
• Mouse studies highlight progress—and pitfalls—as neutralizing antibodies and declining corrected cells complicate long-term efficacy.

Barth syndrome is an X-linked metabolic disorder, affecting only males. It has widespread systemic effects presenting with cardiomyopathy, neutropenia, muscle weakness, stunted growth, exercise intolerance, and abnormal skeletal structures. In many cases, it results in stillbirth. It is strongly related to mutations in the tafazzin gene, also known as TAZ. Currently, only symptomatic treatment exists, and no definite cure has been developed for Barth syndrome.

Neutropenia

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Researchers at Boston Children’s Hospital have proposed gene therapy as a potential treatment method to inhibit processes that lead to heart failure. The researchers conducted the study on mouse models with Barth syndrome.

Research to better understand Barth syndrome was conducted in 2014 by William Pu, MD, and colleagues at Boston Children’s Hospital. Together, they created heart-on-chip models of Barth syndrome by using cardiac myocytes derived from patients with TAZ mutation. This led the researchers to discover the correlation between Barth syndrome and dysfunction. When the defective mutated TAZ myocytes were replaced by healthy TAZ gene myocytes, the cardiac dysfunction was spontaneously corrected.

Pu and colleagues realized that in order to fully understand the effects of Barth syndrome on the system, an animal body was crucial. Attempts at creating a whole-body model had previously been done but had not been successful.

Mice models of Barth Syndrome

The Beatson Institute for Cancer Research in the U.K has recently been successful in creating mouse models of Barth syndrome. Two categories of these mouse models were created, in the first category, the TAZ gene was deleted throughout the whole system whereas in the second category of mouse models the TAZ gene was deleted only from the cardiac myocytes.

The mouse models with whole-body TAZ deletion died before birth mostly due to hypotonic weak musculature. However, some of the mice survived and developed cardiomyopathy, similar to the dilated cardiomyopathy in humans. The heart’s left ventricle had thinner walls and dilated substantially which decreased the systolic pressure resulting in decreased cardiac output.

In those mice with deleted TAZ in heart muscle cells, all subjects survived but had cardiomyopathy issues and reduced cardiac output. Under an electron microscope, the heart muscles were found to have abnormal structures and poor organization.

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Using gene therapy, the researchers replaced the TAZ gene by administering a genetically engineered virus subcutaneously or intravenously. Whole-body TAZ deletion mice survived to an average life span of healthy mice. It successfully prevented cardiac dysfunction in all mice models.

Sustaining the levels of gene-corrected cells

Only when more than 70 percent of cardiac myocytes had taken up the modified TAZ gene, significant improvement was seen.

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

Post introduction of TAZ gene-corrected cells, the major problem was seen in sustaining the levels of modified gene cells. In comparison to cardiac myocytes, the number of corrected gene cells in skeletal muscles declined progressively.

FAQ: Gene Therapy and Barth Syndrome

1. What is Barth syndrome?
Barth syndrome is a rare genetic disorder caused by mutations in the TAZ gene, leading to heart defects, muscle weakness, and immune system issues, primarily affecting males.

2. How does Barth syndrome affect the heart?
It disrupts mitochondrial function, leading to dilated cardiomyopathy, where the heart’s ability to pump blood is weakened, often resulting in life-threatening complications.

3. What recent advancements have been made in treating Barth syndrome?
Researchers at Boston Children’s Hospital have developed a gene therapy approach that restored heart function in mouse models by delivering a healthy TAZ gene.

4. How successful was gene therapy in mice?
When 70% of heart cells received the corrected gene, heart function improved significantly, and mice with whole-body mutations lived normal lifespans.

5. What are the challenges of applying gene therapy to humans?
Human treatments face immune system responses that attack the virus used for delivery, and muscle cells lose corrected genes over time, reducing long-term effectiveness.

6. Can gene therapy fully cure Barth syndrome?
Not yet. While it shows promise in reversing heart damage, challenges like immune rejection and sustaining corrected genes in skeletal muscle must be addressed.

7. What treatments are currently available for Barth syndrome?
Standard treatments focus on managing symptoms, including medications for heart function, G-CSF for neutropenia, and physical therapy to support muscle function.

8. Are clinical trials for Barth syndrome gene therapy planned?
Researchers are working on improving viral vectors to bypass immune system attacks, with the goal of advancing to human trials in the near future.

9. What does this mean for families affected by Barth syndrome?
While gene therapy is not yet a cure, it represents a major step forward. Multidisciplinary care remains essential to managing the condition while research progresses.

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