Gene therapy for heart, skeletal muscle disorder shows promise in preclinical model

Barth syndrome stalks young patients, weakening heart and skeletal muscles, stunting growth and shortening their lives. University of Florida Health researchers and their colleagues have now discovered a promising solution: a gene replacement therapy that delivered significant improvement in mice.

The researchers tested a trio of promoters — genetic “cues” that initiate the expression of a gene’s DNA sequence. In Barth syndrome patients, mutations in a specific gene deprive the heart and skeletal muscles of the ability to efficiently perform their highly energetic functions. One of the promoters tested, known as Des, was particularly effective at providing the necessary levels of gene expression and improving heart and skeletal muscle function in both young and adult Barth mice. The findings were published recently in an online version of the journal Human Gene Therapy.

It is the first time that a potential treatment has been shown to normalize many aspects of Barth syndrome, said Christina A. Pacak, Ph.D., a pediatrics researcher in the UF College of Medicine. Barth syndrome is a relatively rare genetic disorder that affects about one in 300,000 people worldwide, according to the National Institutes of Health. In addition to enlarging and weakening the heart and diminishing muscles used for movement, it also reduces white blood cells and patients’ height.

To establish their findings, researchers tested the promoters’ effectiveness in a mouse model of Barth syndrome with deficient levels of TAZ — a gene that provides instructions for producing a protein called tafazzin. In Barth syndrome patients, missing or malfunctioning tafazzin weakens heart and other muscle cells by reducing their ability to produce energy.

Groups of newborn and 3-month-old mice with Barth syndrome were treated using a gene therapy technique that packages the genetic promoter and gene of interest within a small, harmless virus. At 5 months of age, the mice were evaluated for TAZ gene function, heart function, muscle strength and exercise fatigue and other indicators of improved cellular and overall health. The mice were tested for the number of times they stood on their hind legs and their performance in exploring an activity arena. All of the treated mice showed a clear improvement in their ability to move about and explore, which researchers said is an indicator that the treatments are effective.

The Des promoter produced the most optimal levels of TAZ genetic activity in heart and skeletal muscle following both the young and adult treatment times, the researchers found. They were also encouraged by the Des promoter’s minimal effects on the liver and other organs because that would potentially improve safety and effectiveness in human patients, Pacak said.

While Pacak does not yet consider the therapy to be a cure, she said it normalizes many of Barth syndrome’s negative aspects without using a high-dose treatment. The treatment’s broadly positive effect on cells, organs and the entire body is particularly promising, she said.

“Whole-body activity was clearly better in the treated mice. Holistically, they were much healthier,” Pacak said.

The findings are an important step in establishing which of the promoters will provide the desired benefits while also being the safest for patients, Pacak added.

Next, Pacak and her collaborators at UF Health and Washington University in St. Louis are pursuing funding for a clinical trial to study the therapy in humans. Pacak said they first need to study the treatment’s effect at higher doses in normal, healthy mice to determine if an overactive TAZ gene is problematic.

Funding for the research was provided by the Barth Syndrome Foundation, the American Heart Association, the Children’s Miracle Network and the National Institutes of Health.

About the researchers: Christine A. Pacak, Ph.D., is an assistant professor with the Child Health Research Institute, part of the College of Medicine’s department of pediatrics. Her research collaborators included W. Todd Cade, Ph.D., a professor of physical therapy at the Washington University School of Medicine in St. Louis, and Barry J. Byrne, M.D., Ph.D., a professor of pediatrics at the UF College of Medicine’s department of pediatrics and director of the UF Powell Gene Therapy Center.