Washington — Scientists from the United States and Japan successfully tested a treatment for Duchenne muscular dystrophy in dogs, paving the way for a possible treatment of the disease in humans.
The treatment allows cells to skip over lethal mutations in DNA and produce functional proteins.
Such “exon-skipping” therapy has never before been tested in an animal larger than a mouse. The results were published online March 13 in the journal Annals of Neurology.
"This trial makes the much-talked-about promise of exon skipping as a systemic treatment for Duchenne muscular dystrophy in humans a real possibility in the near term," said Toshifumi Yokota, lead author of the study.
“These findings demonstrate that exon skipping is a very real and promising treatment strategy for Duchenne muscular dystrophy,” said Sharon Hesterlee, senior vice president of the Muscular Dystrophy Association, a nonprofit organization that funds related research.
Dystrophic Dogs
Muscular dystrophies are a collection of more than 30 genetic diseases that cause progressive weakness of the skeletal muscles that control movement. The diseases vary in severity. Some, such as Becker muscular dystrophy, have mild symptoms, caused by mutations that produce a shortened form of the dystrophin protein.
Duchenne muscular dystrophy, the most common form, affecting approximately one in 3,500 males worldwide, is caused by mutations in the dystrophin gene that prevent the production of dystrophin protein. Symptoms begin between 3 years and 5 years of age and progress rapidly. Teenagers often cannot walk and require a respirator to breathe. Duchenne is fatal and, like all muscular dystrophies, there currently is no treatment.
The new study used beagles with a mutation in the canine dystrophin gene.
“Many efforts have focused on treating dogs with muscular dystrophy, as it is widely expected that what works in the dogs will work in humans," said Eric Hoffman, professor of pediatrics at Children's National Medical Center and a senior author of the study.
Exon Skipping
To produce a protein, disparate portions of DNA are stitched together, or spliced, to create a contiguous template for protein production. Exons are the portions of DNA that are spliced together.
In Duchenne muscular dystrophy, mutations tell the cellular machinery to prematurely stop making the protein. With the exon-skipping strategy, researchers use synthetic DNA to trick cells into skipping over the exon that contains the mutation. The cell will make a shorter version of the dystrophin protein, but, as in Becker muscular dystrophy, researchers hope the short version is enough to restore some function to muscle.
One complication is that multiple exons must be skipped in order to avoid the mutations and produce enough of the protein. Each exon requires a separate synthetic DNA sequence. The current study is the first to show that a cocktail of different DNA sequences can work together to treat muscular dystrophy.
"Systemic treatment of the majority of Duchenne dystrophy will require multiple sequences to be delivered in the blood, and this study also is the first proof-of-principle of multiple exon skipping in any organism," said Dr. Shin'ichi Takeda, a researcher at the National Center of Neurology and Psychiatry in Tokyo and a senior author of the study.
Hoffman, Takeda and their colleagues were able to restore dystrophin to 26 percent of normal levels, on average. The treatment dramatically improved dogs’ ability to walk and run.
Scientists administered the synthetic DNA cocktail intravenously to expose all muscles to the treatment, which does not appear to be toxic.
Despite the recovery of walking and running ability, the treatment’s effectiveness varied in muscles throughout the body. Dystrophin protein levels were not restored to similar levels in every muscle. Different levels were apparent in the same muscle on different sides of the body. In the heart, dystrophin was concentrated in small patches of muscle and present in “far lower levels” than in skeletal muscle, scientists found.
Future studies will test how much muscle function can be restored long term, will treat a greater number of animals and will experiment with ways to improve the treatment’s access to the heart, the authors wrote in the paper.
"In order to realize that promise in human trials, it also will be important to re-evaluate current measures of toxicity, efficacy, and marketing that ensure both safety for the patient, as well as rapid development and distribution of life-saving drugs,” Takeda said.
Hoffman said that these results are a proof-of-concept that therapy targeting specific pieces of DNA is effective in a large animal “for Duchenne muscular dystrophy or any disease."
“Of course, this success has also introduced even more avenues for investigation, but these findings finally overcome a significant hurdle to our progress,” Yokota said. “We've solved the riddle of an effective systemwide delivery to muscle tissue, and seen promising results.
" Videos by the researchers of an untreated dog and a treated dog are available on the YouTube Web site.
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