U. of Missouri-led scientists improve gene transfer in Duchenne therapy

Duchenne muscular dystrophy
A new gene therapy vector preserves a binding site on the dystrophin gene for an enzyme that plays a role in blood flow. (Edwin P. Ewing, Jr., CDC)

The idea of treating Duchenne muscular dystrophy by replacing defective dystrophin genes with normal ones is not new, but previous approaches have been limited by the gene's size. A University of Missouri-led team has developed a new gene transfer method to solve this problem.

Duchenne is caused by mutations in the dystrophin gene, which codes for a protein of the same name. Without the stabilizing dystrophin protein, muscle fibers, including those in the heart, eventually weaken and die.

Gene therapy seeks to treat DMD by restoring dystrophin production. Adeno-associated viruses (AAV) are used to deliver the gene, as they do not cause disease in humans. But because the dystrophin gene is too large for the virus to carry, researchers had to develop modified versions of the gene, dubbed mini- or microdystrophin, for gene therapy.

Problem is, editing the gene can leave out a binding site for the enzyme nNos, which is important for blood flow during muscle contraction, the researchers said. So the team, which also includes scientists from the University of Washington, developed a new AAV microdystrophin vector that has an nNos binding site and a component that promotes dystrophin expression in muscle cells.

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They injected the vector into mouse models that resemble DMD. Fifteen weeks later, they found all 10 of the treated mice had high levels of the microdystrophin protein in all of their skeletal muscles. The treatment reduced inflammation, scarring and hardening in the mice’s muscles and restored their muscle strength.

The research, published in Molecular Therapy—Methods & Clinical Development, is encouraging, but a new treatment is a few years off.

"There is still a lot to learn about the dystrophin gene, the dystrophin protein, Duchenne muscular dystrophy disease mechanisms, and gene transfer vectors," said senior author Dongsheng Duan, of the University of Missouri, in a press release. "Future studies will hopefully allow us to develop a more effective therapy to treat Duchenne muscular dystrophy in the coming years."

Most of the recent attention in DMD has gone to Sarepta, which got its controversial Duchenne drug past the FDA after much debate. Now the company is chasing other treatments for the disease. In January, Sarepta penned a microdystrophin research deal with Nationwide Children’s Hospital and in June, it inked a deal that gave it the option to co-develop France-based Genethon’s microdystrophin program.

Sarepta’s drug, Exondys 51, only works in patients with a particular mutation, about 13% of the total DMD patient population. Its new research partnerships could yield gene therapies that would treat many more patients.