Barth syndromeis a rare metabolic disease caused by mutation of a gene calledtafazzinorTAZ. It can cause life-threatening heart failure and also weakens the skeletal muscles, undercuts the immune response, and impairs overall growth. Because Barth syndrome is X-linked, it almost always occurs in boys. There is no cure or specific treatment.

In 2014, to get a better understanding of the disease,William Pu, MD, and colleagues at Boston Childrens Hospital collaborated with the Wyss Institute to create a beatingheart on a chip model of Barth syndrome. The model used heart-muscle cells with theTAZmutation, derived from patients own skin cells.It showedthatTAZis truly at the heart of cardiac dysfunction: the heart muscle cells did not assemble normally, mitochondria inside the cells were disorganized, and heart tissue contracted weakly. Adding a healthyTAZgene normalized these features, suggesting that gene replacement therapy could be a viable treatment.

But to fully capture Barth syndrome and its whole-body effects, Pu and colleagues needed an animal model. The animal model was a hurdle in the field for a long time, says Pu, director of Basic and Translational Cardiovascular Research at Boston Childrens and a member of the Harvard Stem Cell Institute. Efforts to make a mouse model using traditional methods had been unsuccessful.

As described in the journalCirculation Research, most mice with the whole-bodyTAZdeletion died before birth, apparently because of skeletal muscle weakness. But some survived, and these mice developed progressive cardiomyopathy, in which the heart muscle enlarges and loses pumping capacity. Their hearts also showed scarring, and, similar to human patients with dilatedcardiomyopathy, the hearts left ventricle was dilated and thin-walled.

Mice lackingTAZjust in their cardiac tissue, which all survived to birth, showed the same features. Electron microscopy showed heart muscle tissue to be poorly organized, as were the mitochondria within the cells.

Pu, Wang, and colleagues then used gene therapy to replaceTAZ, injecting an engineered virus under the skin (in newborn mice) or intravenously (in older mice). Treated mice with whole-bodyTAZdeletions were able to survive to adulthood.TAZgene 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-onlyTAZdeletions.

Thats where the challenge will lie in translating the results to humans. Simply scaling up the dose of gene therapy wont work: In large animals like us, large doses risk a dangerous inflammatory immune response. Giving multiple doses of gene therapy wont work either.

The problem is that neutralizing antibodies to the virus develop after the first dose, says Pu. 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 correctedTAZgene remained fairly stable in the hearts of the treated mice, they gradually declined in skeletal muscles.

The biggest takeaway was that the gene therapy was highly effective, says Pu. 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."

Reference: Wang et al. (2020).AAV Gene Therapy Prevents and Reverses Heart Failure in A Murine Knockout Model of Barth Syndrome.Circulation Research.https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.119.315956.

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Gene Therapy Reverses Heart Failure in Mouse Model - Technology Networks