Medical Professional Publications

Clinical Trial for Duchene Muscular Dystrophy Gene Therapy Begins

(From the December 2017 issue of Research Now)

Study aims to test safety as well as the age to give treatment

Investigators from Nationwide Children’s Hospital are beginning a clinical trial testing a gene therapy that could potentially benefit up to 70 percent of children with Duchenne muscular dystrophy (DMD).

The therapy is designed to replace the mutated dystrophin gene with a small or micro version of a healthy gene. In pre-clinical testing, researchers have found that a micro-dystrophin, which has repeated domains removed, can act as a surrogate for the missing dystrophin protein, avoiding muscle membrane fragility and the consequent muscle fiber breakdown, resulting in DMD.

Duchenne muscular dystrophy is the most common fatal genetic disease diagnosed in childhood and effects boys almost exclusively. The mutated dystrophin gene causes progressive muscle deterioration and weakness.

Symptoms usually appear by age 3 or 4. As skeletal muscles deteriorate, boys become less active and may begin to use wheelchairs and other assistive devices. Failing heart and respiratory muscles can cause death.

The trial will test the safety and efficacy of the treatment among six children 3- months- to 3-years-old, and among six children 4- to 7-years old. It will be the first test of a gene therapy on children with DMD as young as 3-months.

“If we treat three-month-olds with enough of the therapy, we believe there is plenty of time to correct their gene,” said Jerry Mendell, MD, who, with Louise Rodino-Klapac, PhD, lead the trial. Drs. Mendell and Rodino-Klapac are principal investigators in the Center for Gene Therapy in The Research Institute at Nationwide Children’s.

By testing the second cohort, “We’ll see if age 4 to 7 is less effective or if the treatment is efficacious with this group,” said Rodino-Klapac, who is also an associate professor of pediatrics at The Ohio State University College of Medicine.

To create a dystrophin gene therapy has long been a challenge. The gene is the largest in the human genome and does not fit in the typical viral vectors used to deliver other corrected genes in modern medicine, Rodino-Klapac explained.

This therapy uses a modified gene first tested by Scott Harper, PhD, another principal investigator at the Center for Gene Therapy while he was a graduate student in the lab of Jeff Chamberlain, PhD, now the McCaw Endowed Chair in Muscular Dystrophy at the University of Washington School of Medicine. This micro-dystrophin fits in the disarmed AAV virus used as a delivery vector. The team added a promoter, MHCK7, which resulted in dystrophin expression in skeletal, diaphragm and heart muscle in prior testing.

The researchers expect to begin treating the first of 12 volunteers later this month. The trial will last three years.

At three months, they will test each volunteer for gene expression. Because researchers don’t know how much expression is required for muscle health, the children’s activity, including timed walks of 100 meters, will be compared with the natural history data of children in each age group with untreated disease.

The study is funded by the biopharmaceutical company Sarepta Therapeutics and Parent Project Muscular Dystrophy.

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