Abstract
In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending spliceswitching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of “fusion therapies”, including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, Dystrophin, Antisense oligomer, Exon skipping, Molecular medicine
Current Pharmaceutical Design
Title: Splice Modification to Restore Functional Dystrophin Synthesis in Duchenne Muscular Dystrophy
Volume: 16 Issue: 8
Author(s): Steve. D. Wilton and Susan Fletcher
Affiliation:
Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, Dystrophin, Antisense oligomer, Exon skipping, Molecular medicine
Abstract: In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending spliceswitching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of “fusion therapies”, including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
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Cite this article as:
Wilton D. Steve. and Fletcher Susan, Splice Modification to Restore Functional Dystrophin Synthesis in Duchenne Muscular Dystrophy, Current Pharmaceutical Design 2010; 16 (8) . https://dx.doi.org/10.2174/138161210790883480
DOI https://dx.doi.org/10.2174/138161210790883480 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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