First treatment for muscular dystrophy in sight: Scientists successfully harness exon-skipping

March 16, 2009

Genetic researchers at Children's National Medical Center and the National Center of Neurology and Psychiatry in Tokyo published the results of the first successful application of "multiple exon-skipping" to curb the devastating effects of Duchenne muscular dystrophy in an animal larger than a mouse. Multiple exon-skipping employs multiple DNA-like molecules as a "DNA band-aids" to skip over the parts of the mutated gene that block the effective creation of proteins.

The study, conducted in Japan and the United States, published this month in the peer-reviewed journal of the American Neurological Association, the Annals of Neurology, treated dogs with naturally occurring canine X-linked , a disease which is genetically homologous to the that strikes 1 of every 3,500 boys born in the United States and worldwide each year.

Duchenne muscular dystrophy, one of the most common lethal genetic disorders, is an X-linked genetic mutation that causes an inability of the body's cells to effectively create —which builds . "Exon-skipping" employs synthetic DNA-like molecules called antisense as a DNA band-aid to skip over the parts of the gene that block the effective creation of dystrophin. Because the gene's mutation could affect any of its 79 exons and sometimes more than one single at a time, scientists employed a "cocktail" of antisense called morpholinos to extend the range of this application. By skipping more than a single exon, this so-called DNA band-aid becomes applicable to between 80 and 90 percent of Duchenne muscular dystrophy patients, including the mutation found in dogs.

"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, PhD, lead author of the study. "Of course this success has also introduced even more avenues for investigation, but these findings finally overcome a significant hurdle to our progress—we've solved the riddle of an effective system-wide delivery to muscle tissue, and seen promising results."

A new state-of-the-art facility at the National Center of Neurology and Psychiatry in Japan was utilized to carry out the research.

"This study delivers the proof-of-concept that systemic anti-sense therapy can be done in a large organism, in Duchenne muscular dystrophy or any disease", says Eric Hoffman, PhD, a senior author of the study and director of the Center for Genetic Medicine at Children's National Medical Center.

"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," Shin'ichi Takeda, MD, another senior author, said. "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.

The authors do note that significant steps still remain. Successful systemic treatment with morpholinos requires large doses of the antisense molecules—and the technology is costly and difficult to obtain. Additionally, treatment in this study showed diminished success at curbing muscle deterioration of the heart, meaning that a more effective and specific delivery system is needed to rescue the organ's delicate tissue in Duchenne muscular dystrophy patients. However, these early successes do show much promise for the oft-discussed exon-skipping method as an effective treatment for Duchenne muscular dystrophy and some other genetic disorders.

More information: Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs, Toshifumi Yokota, Qi-long Lu, Terence Partridge, Masanori Kobayashi, Akinori Nakamura, Shińichi Takeda, Eric Hoffman, Annals of Neurology

Source: Children's National Medical Center (news : web)

Related Stories

Recommended for you

Pitch imperfect? How the brain decodes pitch may improve cochlear implants

November 22, 2017
Picture yourself with a friend in a crowded restaurant. The din of other diners, the clattering of dishes, the muffled notes of background music, the voice of your friend, not to mention your own – all compete for your ...

Team constructs whole-brain map of electrical connections key to forming memories

November 22, 2017
A team of neuroscientists at the University of Pennsylvania has constructed the first whole-brain map of electrical connectivity in the brain based on data from nearly 300 neurosurgical patients with electrodes implanted ...

Now you like it, now you don't: Brain stimulation can change how much we enjoy and value music

November 20, 2017
Enjoyment of music is considered a subjective experience; what one person finds gratifying, another may find irritating. Music theorists have long emphasized that although musical taste is relative, our enjoyment of music, ...

Schizophrenia originates early in pregnancy, 'mini-brain' research suggests

November 20, 2017
Symptoms of schizophrenia usually appear in adolescence or young adulthood, but new research reveals that the brain disease likely begins very early in development, toward the end of the first trimester of pregnancy. The ...

MRI uncovers brain abnormalities in people with depression and anxiety

November 20, 2017
Researchers using MRI have discovered a common pattern of structural abnormalities in the brains of people with depression and social anxiety, according to a study presented being next week at the annual meeting of the Radiological ...

Deletion of a stem cell factor promotes TBI recovery in mice

November 20, 2017
UT Southwestern molecular biologists today report the unexpected finding that selectively deleting a stem cell transcription factor in adult mice promotes recovery after traumatic brain injury (TBI).

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.