By Jill Pease and Jacky Scott
Using innovative methods to measure changes in muscle, a UF team has shown that after treatment with an investigational gene therapy, three young boys with Duchenne muscular dystrophy had considerably lower fat infiltration in their muscles than boys receiving standard treatment. The findings were published in JAMA Network Open.
Duchenne is a severe form of muscular dystrophy that affects about 1 in 3,500 males born each year in the United States. It causes muscles to progressively weaken and lose the ability to regenerate after an injury, eventually replacing muscle tissue with fat and collagen. Many children with Duchenne muscular dystrophy may require a wheelchair by adolescence, and heart and respiratory systems are affected as the disease advances.
“Seeing the boys’ muscle fat fractions stay so low over the study period is really exciting,” said the study’s lead author Rebecca Willcocks, Ph.D., a research assistant professor in PHHP’s department of physical therapy.
Duchenne muscular dystrophy is caused by a mutation in the gene for dystrophin, a protein essential for muscle growth and health. The therapy under study, known as rAAVrh74.MHCK7.micro-dystrophin, delivers a form of the dystrophin gene directly to the muscles. In study findings from a clinical trial led by researchers at The Ohio State University and Nationwide Children’s Hospital in Columbus, Ohio that were published last year in JAMA Neurology, four boys with Duchenne who received the treatment showed improvement in function over one year, as demonstrated by improved scores on the North Star Ambulatory Assessment, a rating scale used to measure functional motor abilities in ambulant children with Duchenne.
The UF study of three boys between the ages of 4 and 7 who received the gene therapy compared them with age-matched boys with Duchenne receiving standard treatment and provides more information on how the therapy affected their muscles.
UF researchers, led by Krista Vandenborne, Ph.D., a distinguished professor and chair of the department of physical therapy and senior author of the new study, have pioneered the use of MRI biomarkers to capture highly accurate and noninvasive measures of muscle changes in children with Duchenne. Using these MRI biomarkers, the UF team can provide rapid feedback on the effects of new Duchenne therapies in clinical trials while generating an objective measure of muscle quality.
“The original clinical trial results showed that these boys improved functionally, but because the boys are so young, it’s hard to tell how much of the motor function gains are due to the gene therapy treatment and how much are due to normal growth and maturation,” Willcocks said. “The MRI biomarker measurements aren’t affected by growth and maturation.”
Vandenborne and her team recently received a $6.25 million grant from the National Institutes of Health to support their continued efforts to develop MRI biomarkers for individuals with Duchenne, and expand the study, known as ImagingDMD, to include people with Becker muscular dystrophy. They plan to develop new MRI biomarkers that are sensitive across a wide range of ages and mobility stages, including in individuals who can no longer walk. Additionally, since the disease also affects the ability to breathe, UF researchers will test MRI measures of respiratory muscle health that can be used in clinical trials targeting participants in more advanced disease stages.
“We are honored that the NIH values the ImagingDMD study, as evidenced by the 15 years of funding, and look forward to continuing to work with the boys and families to help find a cure for this devastating disease,” Vandenborne said. “Expansion of the ImagingDMD study will greatly benefit the DMD community as a whole, as ImagingDMD natural history data are shared with academic colleagues and industry partners across the country to help design new trials and pursue novel therapeutic strategies.”