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Gene Therapy May Improve Muscles

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    Gene Therapy May Improve Muscles

    Gene Therapy May Improve Muscles
    Mon Sep 16, 5:05 PM ET
    By PAUL RECER, AP Science Writer

    WASHINGTON (AP) _The crippling effects of muscular dystrophy were partially corrected in laboratory mice by the insertion of a new gene that restored to the muscles a protein lacking in victims of the fatal disease.

    Researchers at the University of Washington, Seattle, fused a gene that makes a muscle chemical with a modified virus and injected the combination into the hind leg muscles of mice that have a disorder that mimics Duchenne muscular dystrophy.

    Within a month, the test mice had a 40 percent improvement in muscle action compared to muscular dystrophy mice that received no injection, said Christiana DelloRusso, lead author of the study that appears in this week's Proceedings of the National Academy of Sciences ( news - web sites).

    "We measured the force produced before and after the muscle is stretched and it was much better with the mice that were injected compared to the ones that weren't," DelloRusso said Monday.

    Duchenne muscular dystrophy is a muscle-wasting disease caused by the mutation of the gene that produces a muscle protein called dystrophin. The disorder, linked to the X chromosome, is inherited in about one of every 3,500 males born in the United States, and about 12,000 patients are now living with the disease.

    The disease originates from a gene that fails to produce dystrophin, a protein that helps the muscles stretch and contract normally. Without this protein, the muscles tear faster than the body can repair them, a process called contraction injury. Over time, the muscles waste away.

    Patients generally are diagnosed by age 4, and they usually are using a wheelchair by age 12. Most die in their 20s, although improved care has allowed some patients to live until their early 30s. Muscles in the heart and pulmonary system are affected, generally leading to death from respiratory or heart failure.

    To control the disease, researchers are trying to replace the flawed gene with a normal gene that would produce dystrophin.

    In the University of Washington study, researchers engineered a virus, called an adenovirus, so that it lacked the genes to make viral particles. The viral genes were replaced by the gene that makes dystrophin. When injected, the virus infects cells and inserts the new gene into the DNA of the target muscle cells.

    The researchers injected the virus-gene combination into the hind legs muscles of MDX mice, laboratory animals that develop Duchenne muscular dystrophy. For comparison's sake, some mice received the gene therapy while others received neutral injections.

    One month after injection, the legs of the test mice were about 40 percent more resistant to contraction injury than were the other animals' legs.

    DelloRusso said an analysis of the muscle around the injection site showed that the tissue was making dystrophin at a level 25 to 30 percent of normal.

    Sharon Hesterlee, director of research development at the Muscular Dystrophy Association, said the report by DelloRusso and her colleagues "is an important paper" because it showed the technique can improve the muscle action around the injection site.

    The disease will not be controlled, however, until researchers find a way to deliver the correct gene to muscles throughout the body, she said.

    "The major technical hurdle is that muscle makes up 40 to 50 percent of body mass, and we don't have a good way yet to deliver these genes to all the muscles," said Hesterlee, a neuroscientist. "The virus injected directly into a muscle doesn't really travel very far. For this gene therapy to really be an effective therapy, we're going to have to develop some sort of systemic delivery. That's still a big problem."

    Also, said Hesterlee, there are misgivings about the safety of the adenovirus used as the carrier of the gene. Other studies have shown that the adenovirus can cause serious side effects.

    DelloRusso said the study used what is called a "gutted adenovirus" because it lacks many of the genes that can cause side effects. But she acknowledged that the safety of the adenovirus would have to be extensively tested before the gene therapy could tested in humans.


    On the Net: Proceedings of the National Academy of Sciences:

    Muscular Dystrophy Association:

    "It has been said that for the truth to exist, it takes two people - one to speak it...and another to hear it. Mankind will be forever doomed to destruction if we continue to ask for the truth...but then refuse to listen.." Outer Limits( To Tell The Truth )

    Researchers Fix Muscular Dystrophy Damage in Mice

    Researchers Fix Muscular Dystrophy Damage in Mice
    Mon Sep 16, 5:47 PM ET
    By Linda Carroll

    NEW YORK (Reuters Health) - Researchers may have found a way to treat one of the most common forms of muscular dystrophy by using a stripped-down version of a cold virus to carry gene therapy to damaged muscles.

    A month after researchers injected the modified virus into adult mice with a condition similar to Duchenne muscular dystrophy, the mice showed significant improvements in muscle strength, according to the study published in the Proceedings of the National Academy of Sciences ( news - web sites).

    "Now we know that there is a great potential to reverse muscle damage in boys who have already developed significant weakness," study co-author Jeffrey S. Chamberlain, a professor in the department of neurology at the University of Washington School of Medicine in Seattle, said in an interview with Reuters Health.

    Duchenne muscular dystrophy is a fatal muscle-wasting disease that strikes approximately 1 in every 3,500 boys. The disease is caused by defects in the dystrophin gene, which is found on the X chromosome.

    Previous attempts to treat the disorder with gene therapy have failed because of immune responses to the virus carrying the corrected copy of the dystrophin gene, Chamberlain noted.

    For the new study, researchers created a "gutted" version of the cold virus. "The only thing remaining from the original virus is a piece of DNA that is required for both replication--making more of it--and assembling the viral DNA into an infectious shell of proteins," Chamberlain explained. "This shell allows the vector to enter the cell, as it binds to specific proteins on the surface of the muscle cells and allows it to be pulled inside the cell."

    Once inside the cell, the corrected gene for dystrophin is transported into the cell's nucleus and the cell begins making the dystrophin protein, Chamberlain said.

    "By removing the viral genes, we created a 'stealth' virus that no longer triggers an immune response," Chamberlain said.

    Chamberlain and his colleagues injected the gutted virus carrying the dystrophy gene into a leg muscle in each mouse in the study. Within a month, the researchers found dystrophin production in the treated muscle was up by 25% to 30%. They also found an improvement in symptoms related to the disease.

    And the effects of the therapy seem to be relatively long-lasting. "So far, we see persistence for 6 months," Chamberlain said. "But I suspect it will slowly go away over 2 years. Thus, we need to either find a way to repeat the injections, or get the dystrophin gene to remain stable in the muscle. We are pursuing both approaches."

    SOURCE: Proceedings of the National Academy of Sciences Early Edition 2002;10.1073/pnas.202300099.

    "It has been said that for the truth to exist, it takes two people - one to speak it...and another to hear it. Mankind will be forever doomed to destruction if we continue to ask for the truth...but then refuse to listen.." Outer Limits( To Tell The Truth )