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Novel Delivery of Molecular Therapeutics to the Heart Using Non-biologic Constructs (PPMO/Morpholino) in Muscular Dystrophy

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Translational Cardiology

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

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Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by the absence of the cytoskeletal protein dystrophin. There is no effective treatment and affected individuals die from respiratory failure and cardiomyopathy by age 30. One recent approach to treating DMD is antisense-mediated exon skipping to restore dystrophin protein. Most mutations causing DMD disrupt the open reading frame, leading to aberrant translation and the lack of dystrophin protein. The related allelic disorder Becker muscular dystrophy (BMD) is caused by mutations that create shortened, but in-frame transcripts, producing a partially functional dystrophin, leading to a milder phenotype. Antisense-induced exon-skipping strategies aim to remove the mutated or additional exon(s) to restore the reading frame and, consequently, induce the expression of these “BMD-like” shortened forms of the dystrophin protein, retaining crucial functions. Various types of antisense oligonucleotides (AOs) exist and have been shown to cause exon skipping in vivo and improve skeletal muscle function in animal models and, in two independent phase I clinical trials, to cause exon skipping in humans. More recently, phosphorodiamidate morpholino oligomers (PMOs) have been directly conjugated to cell-penetrating peptides (CPPs), to form PPMOs, thereby improving their efficacy and allowing for a more systemic delivery. This conjugation allows PPMOs to reach the heart, restoring full cardiac function in animal models, at non-toxic doses. These PPMOs show great potential for improving function of both skeletal and cardiac muscle in DMD patients, though a number of hurdles remain to be overcome.

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Acknowledgments

This work was supported by the UK Medical Research Center, the Muscular Dystrophy Campaign, the Muscular Dystrophy Association USA, the Association Monegasque contre les myopathies and the Duchenne Parent Project France.

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Authors and Affiliations

  1. Department of Physiology, Anatomy, & Genetics, MRC Functional Genomics Unit, University of Oxford, Oxford, UK

    Alastair Crisp & Aurélie Goyenvalle

  2. Department of Physiology, Anatomy, & Genetics, University of Oxford, Parks Road, Oxford, UK, OX1 3PT

    Kay Elizabeth Davies

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  1. Alastair Crisp
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  2. Aurélie Goyenvalle
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  3. Kay Elizabeth Davies
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Correspondence to Kay Elizabeth Davies .

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Editors and Affiliations

  1. , The University of North Carolina, McAllister Heart Institute, 6022 - Burnett Womack Building, Chapel Hill, 27599-7075, North Carolina, USA

    Cam Patterson

  2. , The University of North Carolina, McAllister Heart Institute, 103 Mason Farm Road, Chapel Hill, 27599-7525, USA

    Monte S. Willis

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Crisp, A., Goyenvalle, A., Davies, K.E. (2012). Novel Delivery of Molecular Therapeutics to the Heart Using Non-biologic Constructs (PPMO/Morpholino) in Muscular Dystrophy. In: Patterson, C., Willis, M. (eds) Translational Cardiology. Molecular and Translational Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-891-7_13

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  • DOI: https://doi.org/10.1007/978-1-61779-891-7_13

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