The potential of antisense oligonucleotides as a therapy for Duchenne muscular dystrophy in human and canine models of the disease

Graham Patrick McClorey

    Research output: ThesisDoctoral Thesis

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    Abstract

    [Truncated] Duchenne muscular dystrophy (DMD) is an X-linked, fatal, muscle wasting disorder that causes boys to lose ambulation in their early teens, with death in the third decade of life. Despite identification of the gene responsible twenty years ago, there has been no cure for this debilitating disease, with current treatments focusing on prolonging muscle function without addressing the underlying genetic defect. DMD is caused by mutations in the DMD gene that precludes the synthesis of functional dystrophin, a structural protein that provides stability to the muscle during contraction. A recently proposed therapeutic strategy has been the use of antisense oligonucleotides (AOs) to manipulate pre-mRNA splicing to remove exons from the dystrophin transcript such that the DMD mutation is removed or bypassed to allow a semi-functional protein to be produced. The majority of DMD research to date, has utilised the mdx mouse model, which exhibits a relatively mild dystrophic phenotype. In contrast, a canine model, the Golden Retriever Muscular :Qystrophy or GRMD model, has a much more severe phenotype with pathological similarities to that observed in DMD patients. This body of work addresses the hypothesis that A Os could be used to correct the dystrophin mutation in this more clinically relevant model and hence provide an alternate model for optimising this approach prior to application to the human condition. To this end, AOs were developed to correct the dystrophin mutation both in vitro and in vivo, such that near-full length dystrophin protein could be detected. Various AO chemistries were also simultaneously tested for their ability to induce dystrophin to provide further knowledge of the optimal treatment using this approach.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • The University of Western Australia
    DOIs
    Publication statusUnpublished - 2007

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