Translational development of splice-modifying antisense oligomers.
Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention. Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints. Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.
a Centre for Neuromuscular and Neurological Disorders , University of Western Australia , Nedlands , Western Australia , Australia.|b Western Australian Neuroscience Research Institute , Nedlands , Western Australia , Australia.|c Centre for Comparative Genomics , Murdoch University , Western Australia , Australia.
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Fletcher
b Western Australian Neuroscience Research Institute , Nedlands , Western Australia , Australia.|c Centre for Comparative Genomics , Murdoch University , Western Australia , Australia.
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Bellgard
a Centre for Neuromuscular and Neurological Disorders , University of Western Australia , Nedlands , Western Australia , Australia.|b Western Australian Neuroscience Research Institute , Nedlands , Western Australia , Australia.|c Centre for Comparative Genomics , Murdoch University , Western Australia , Australia.
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Price
b Western Australian Neuroscience Research Institute , Nedlands , Western Australia , Australia.|c Centre for Comparative Genomics , Murdoch University , Western Australia , Australia.|d Shiraz Pharmaceuticals, Inc , Chapel Hill , NC , USA.
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Akkari
a Centre for Neuromuscular and Neurological Disorders , University of Western Australia , Nedlands , Western Australia , Australia.|b Western Australian Neuroscience Research Institute , Nedlands , Western Australia , Australia.|c Centre for Comparative Genomics , Murdoch University , Western Australia , Australia.
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Wilton
D000818:Animals; D001691:Biological Therapy / Q000379:methods / Q000639:trends; D016189:Dystrophin / Q000235:genetics; D005091:Exons / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods / Q000639:trends*; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics*; D057170:Translational Research, Biomedical / Q000379:methods* / Q000639:trends
D016189:Dystrophin; D016376:Oligonucleotides, Antisense
Duchenne muscular dystrophy; Rare diseases; adaptive clinical trial; alternative splicing; antisense oligomer; dystrophin; exon skipping; spinal muscular atrophy