Injecting a therapeutic molecule into muscle appears to jump-start the production of a crucial protein that's missing in patients with Duchenne muscular dystrophy, British researchers report.

The treatment so far is only applicable to about 13 percent of people with the debilitating and ultimately fatal disease, but scientists are hopeful that similar molecules might expand the treatment to a wider range of patients.

Duchenne muscular dystrophy affects about one in 3,500 males, and involves a progressive wasting of muscle due to a genetic inability to produce the protein dystrophin, a key component of muscle structure.

Recently, molecules called antisense oligonucleotides have shown some promise. These molecules work by "skipping over" portions of the defective gene that would otherwise block dystrophin production.

In their study, published online Aug. 25 in The Lancet Neurology, researchers at the University College London Institute of Child Health selected seven patients for whom a particular oligonucleotide molecule, called AVI-4658, appeared suitable. In these patients, the molecule "skipped" exon 51 -- the portion of the dystrophin-blocking gene that appeared to get in the way of effective dystrophin production.

Injecting the molecule into the muscles of these seven patients resulted in increased dystrophin production in all treated muscles, according to a journal news release.

"Intramuscular AVI-4658 was safe and induced the expression of dystrophin locally within treated muscles," the team wrote. "On the basis of these observations, we have initiated a dose-ranging study to assess the safety and efficacy of repeated doses of systemic intravenous AVI-4658."

In a commentary, Annemieke Aartsma-Rus and Gert-Jan van Ommen, from Leiden, the Netherlands, noted that while only about 13 percent of Duchenne muscular dystrophy patients can be expected to be helped by AVI-4658, molecules that skip other exons on the gene could be used, potentially spreading the benefit to more than 70 percent of patients.

What is Muscular Dystrophy?

The muscular dystrophies (MD) are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms of MD are seen in infancy or childhood, while others may not appear until middle age or later. The disorders differ in terms of the distribution and extent of muscle weakness (some forms of MD also affect cardiac muscle), age of onset, rate of progression, and pattern of inheritance.

Duchenne MD is the most common form of MD and primarily affects boys. It is caused by the absence of dystrophin, a protein involved in maintaining the integrity of muscle. Onset is between 3 and 5 years and the disorder progresses rapidly. Most boys are unable to walk by age 12, and later need a respirator to breathe. Girls in these families have a 50 percent chance of inheriting and passing the defective gene to their children. Boys with Becker MD (very similar to but less severe than Duchenne MD) have faulty or not enough dystrophin.

Facioscapulohumeral MD usually begins in the teenage years. It causes progressive weakness in muscles of the face, arms, legs, and around the shoulders and chest. It progresses slowly and can vary in symptoms from mild to disabling.

Myotonic MD is the disorder's most common adult form and is typified by prolonged muscle spasms, cataracts, cardiac abnormalities, and endocrine disturbances. Individuals with myotonic MD have long, thin faces, drooping eyelids, and a swan-like neck.
Is there any treatment?

There is no specific treatment to stop or reverse any form of MD. Treatment may include physical therapy, respiratory therapy, speech therapy, orthopedic appliances used for support, and corrective orthopedic surgery.

Drug therapy includes corticosteroids to slow muscle degeneration, anticonvulsants to control seizures and some muscle activity, immunosuppressants to delay some damage to dying muscle cells, and antibiotics to fight respiratory infections. Some individuals may benefit from occupational therapy and assistive technology. Some patients may need assisted ventilation to treat respiratory muscle weakness and a pacemaker for cardiac abnormalities.

What is the prognosis?

The prognosis for people with MD varies according to the type and progression of the disorder. Some cases may be mild and progress very slowly over a normal lifespan, while others produce severe muscle weakness, functional disability, and loss of the ability to walk.

Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations.

There are two emerging therapies designed to repair the primary genetic defect, called 'exon skipping' and 'nonsense codon suppression'.

RECENT FINDINGS: A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops.

Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo.

Both approaches have concluded phase I trials with no serious adverse events.

SUMMARY: These therapies act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans.

Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy.