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Gene Therapy Stops Brain Deterioration in Mice

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  • Gene Therapy Stops Brain Deterioration in Mice

    Gene Therapy Stops Brain Deterioration in Mice
    Library: MED
    Description: Scientists from the University of Texas Medical Branch at Galveston and the University of Florida have used gene therapy to hinder destruction of brain tissue in mice that are subject to Canavan disease, a rare genetic disorder that is fatal in children. (Molecular Therapy)

    University of Texas Medical Branch at Galveston
    Public Affairs Office
    301 University Boulevard, Suite 3.102
    Galveston, Texas 77555-0144
    (409) 772-2618 (800) 228-1841

    FOR RELEASE April 1, 2003

    CONTACT: UTMB - Jim Kelly
    (409) 772-8791

    UF- John Pastor
    (352) 392-3845


    GALVESTON, Texas -- Scientists from the University of Texas Medical Branch at Galveston and the University of Florida have used gene therapy to hinder destruction of brain tissue in mice that are subject to Canavan disease, a rare genetic disorder that is fatal in children.

    Researchers injected a corrective gene into the brains of mice specially engineered to carry the gene responsible for Canavan disease, which causes healthy brain tissue to develop pockets of fluid and air that render it spongy and nonfunctional. Carried into the mouse brain cells by a harmless virus, the new gene replaced the Canavan gene and stopped the structural breakdown characteristic of the disorder.

    "The results give tremendous hope, not just for helping children with the disease but for the method of treating it," said UTMB professor of pediatric genetics Reuben Matalon, lead author of a paper on the research published in the journal Molecular Therapy (available on-line at, in the "Articles in Press" section) and head of the team that developed the genetically engineered mice used in the experiments. "This is the first data ever about Canavan disease collected from an animal experiment. Further, this strategy to deliver the corrective gene via an adeno-associated virus may be used to correct many other diseases."

    For example, Tay-Sachs disease, another fatal genetic brain disorder, might be treated by using a similar technique.

    Canavan disease may occur in any ethnic group, but it primarily affects children of Eastern and Central European Jewish--specifically Ashkenazi--origin, according to the National Institute of Neurological Disorders and Stroke. About 90 percent of Jewish people in the United States are of Ashkenazi descent, and one in 40 carries the Canavan gene.

    The gene causes a deficiency of the enzyme called aspartoacylase, which causes the destructive chemical compound N-acetyl-L-aspartic acid, or NAA, to accumulate in the brain. NAA erodes myelin -- the brain's protective coating of white matter, an essential part of the nervous system. The buildup of NAA causes mental retardation, blindness and tremors.

    Currently, there is no cure for Canavan disease, which usually becomes apparent when infants are 3 to 9 months old. Symptoms often include rapidly increasing head circumference, lack of head control and abnormal muscle tone, such as stiffness or floppiness. Most children with Canavan disease do not reach 10 years of age.

    In the study, 30 mice were divided into three groups of 10 -- one group of normal mice and two groups of mice with the single-gene defect that causes Canavan's disease. Of the 20 mice with the disease, 10 were randomly selected to receive the corrective gene.

    Researchers encoded DNA with the missing enzyme and loaded it into the adeno-associated virus, which had been stripped of its own genetic information. Then they injected it into the thalamus of the mouse brains -- an area that is severely affected by the disease. Images taken of the brains of the live mice that received gene therapy showed a remarkable lack of spongy degeneration of the thalamus and reduced levels of NAA, researchers said.

    "The results in the mice are absolutely remarkable," said Ronald J. Mandel, a neuroscientist with the University of Florida Genetics Institute and UF's Evelyn F. and William L. McKnight Brain Institute. "Tissue that would otherwise be damaged looks normal. We have not determined matters of how the brain would function, but the structure of the brain improved."

    Three to five months later, the corrective material kept the mouse brains clear of NAA at the injection site and in a small area surrounding it, which suggests that an encouraging "bystander effect" took place within the cells, researchers said.

    "The good news is it's not just the cells that receive the gene that remain clear, but the cells in the small, immediate area surrounding those cells," said Nicholas Muzyczka, Ph.D., the American Cancer Society Edward R. Koger eminent scholar at UF and the interim director of the UF Genetics Institute. "You can picture it as injecting food coloring into a bowl of gelatin. Canavan's disease is extremely challenging because you have to fix the problem in the whole brain, unlike Parkinson's disease, where only a small region of the brain is affected. The questions are how far the corrective genes can travel, and how many injections would be necessary to clear the whole brain."

    Continued improvements in the brain for as many as five months after the mice were treated suggest the destructive nature of the disease was reversed; however, further study will be needed to determine whether the corrective gene continues to express itself for a year or longer, researchers said.

    "Lots of technical details regarding the gene vectors and where to inject them have to be worked out, and it's preferable to do those basic studies in animals," said Hugo W. Moser, M.D., director of the Neurogenetics Research Center at the Baltimore, Md.-based Kennedy Krieger Institute. "This is a good step in a long series of steps toward human treatment."

    --- UTMB ---