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Gene Therapy Activity: A New Approach

written by: •edited by: Paul Arnold•updated: 5/15/2010

Human gene therapy is potentially taking a big leap forward with the development of a technology known as exon-skipping gene therapy. It is being developed to treat Duchenne Muscular Dystrophy and other genetic disorders.

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    Basics of Gene Therapy

    The basics of gene therapy are that you replace a duff gene in your body with a fully functioning version. The malfunctioning gene is one that is causing some kind of genetic disorder by either not producing the protein it should, or it produces an abnormal version of it. To the rescue comes a corrective gene that could be sent into your body like the cavalry coming over the hill. It would be packaged inside a virus, which would help it to find its way inside the nucleus of a cell to take over the role that the original gene is failing at. However, there are two main problems with gene therapy. 1) It's an extraordinarily complex technology; beautiful and elegant in theory, difficult in practise 2) Our expectations about it are probably a little to high.

    However, the field of human genetic engineering does not stand still, and some of the best scientific brains on the planet are turning their attention to developing novel gene therapy technologies. DNA scissors is one of them, and the other is the exotically titled exon-skipping gene therapy.

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    What is an exon? Genes are divided into regions called exons and introns. Exons are sections of DNA that code for the protein, and they are interspersed with introns.

    Exon-skipping has been showing off its gene therapy promise to scientists looking to treat and cure Duchenne Muscular Dystrophy (DMD), the most severe form of the many different types of muscle wasting diseases. The technology is designed in such a way that it skips over the mutated gene, in fact it completely ignores it.

    Duchenne Muscular Dystrophy is caused by a mutation of the dystrophin gene which is present on the X chromosome. It is a very long gene and in individuals with DMD it does not produce the dystrophin protein which is vital for muscle strength and stability.

    What happens in exon-skipping gene therapy is that instead of targeting the bad gene and replacing it with a good one, it is neatly sidestepped. The aim is to encourage the cellular machinery to ignore it.

    In the DMD research scientists are attempting to change the DMD mutation to the mutation that causes Becker's Muscular Dystrophy. It is a much milder disease and there is some dystrophin production, which does not occur in DMD.

    To do this they construct antisense oligonucleotides. These are RNA single-stranded structures of between 20-30 nucleotides in length and are designed specifically to bind to an exon that contains a mutation. The effect of this is that the exon mutation is hidden from the cellular machinery during protein production, and so it is not included in the messenger RNA molecule. The result of this is that a smaller protein is produced, but it is partially functional which reduces the severity of DMD.

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    Gene Therapy Promise

    Although the exon-skipping gene therapy has not been tried out in humans yet, that's not to be too despondent. The pace of science is sometimes very slow indeed, it has to be. However, proof of principal has been obtained. The technology has worked successfully in mice models and also in dogs. Scientists from the Washington, DC based Children's National Medical Center and the National Center of Neurology and Psychiatry in Tokyo conducted the first successful trial of the therapy in dogs and the study was published in the Journal of the American Neurological Association in March 2009.

    It will be a while before clinical studies are conducted on humans as more animal research is needed. While the results were promising, the therapy did not improve the condition of the dogs' hearts which were also affected by the faulty dystrophin gene. However, that part of the research was successful in such a large animal offers some glimmer of hope to DMD patients and their families, and is undoubtedly another gene therapy avenue worth pursuing.

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    Wilton SD, Fletcher S. Exon skipping and Duchenne muscular dystrophy: Hope, hype and how feasible?. Neurol India [serial online] 2008 [cited 2009 Mar 19];56:254-62. Available from: