Correcting Barth Syndrome With Gene Therapy

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.



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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.


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