Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Arechavala‐Gomeza, Virginia; Anthony, Karen; Morgan, Jennifer E.; Muntoni, Francesco

doi:10.2174/156652312800840621

Cited by 77 publications

(62 citation statements)

References 117 publications

(61 reference statements)

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“…145,165 ASOs can be designed to either block factor binding to a cis element, preventing splicing from occurring at that specific site and resulting in enhanced inclusion of a specific exon, or to target splicing enhancers or silencers to either block or promote splicing. This approach has been used with some success, mainly in the treatment of neurodegenerative diseases such as Duchenne muscular dystrophy 166 and spinal muscular atrophy. 167,168 Targeting the cis elements by ASOs has major advantages over targeting the splicing factors directly.…”

Section: Targeted Modulation Of Splicing By Antisense Oligonucleotidesmentioning

confidence: 99%

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Shilo

Siegfried

Karni

2014

Molecular & Cellular Oncology

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In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing.

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Section: Targeted Modulation Of Splicing By Antisense Oligonucleotidesmentioning

confidence: 99%

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Shilo

Siegfried

Karni

2014

Molecular & Cellular Oncology

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“…Antisense oligonucleotide (AO)-mediated exon skipping aims to restore the DMD reading frame to allow the production of an internally deleted dystrophin protein and, hopefully, a functional benefit to patients with DMD who have out-offrame (OOF) deletions. [12][13][14] The restoration of dystrophin and members of the dystrophin-associated protein complex has been achieved following local and systemic injections of AOs targeting exon 51. [15][16][17][18][19] Efforts are now focused on targeting other exons 12,20 ; however, the skipping of some exons may be more efficacious than others.…”

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confidence: 99%

Biochemical Characterization of Patients With In-Frame or Out-of-FrameDMDDeletions Pertinent to Exon 44 or 45 Skipping

et al. 2014

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muscular dystrophy (DMD), the reading frame of an out-of-frame DMD deletion can be repaired by antisense oligonucleotide (AO)-mediated exon skipping. This creates a shorter dystrophin protein, similar to those expressed in the milder Becker muscular dystrophy (BMD). The skipping of some exons may be more efficacious than others. Patients with exon 44 or 45 skippable deletions (AOs in clinical development) have a less predictable phenotype than those skippable for exon 51, a group in advanced clinical trials. A way to predict the potential of AOs is the study of patients with BMD who have deletions that naturally mimic those that would be achieved by exon skipping.OBJECTIVE To quantify dystrophin messenger RNA (mRNA) and protein expression in patients with DMD deletions treatable by, or mimicking, exon 44 or 45 skipping. DESIGN, SETTING, AND PARTICIPANTSRetrospective study of nondystrophic controls (n = 2), patients with DMD (n = 5), patients with intermediate muscular dystrophy (n = 3), and patients with BMD (n = 13) at 4 university-based academic centers and pediatric hospitals. Biochemical analysis of existing muscle biopsies was correlated with the severity of the skeletal muscle phenotype. MAIN OUTCOMES AND MEASURES Dystrophin mRNA and protein expression.RESULTS Patients with DMD who have out-of-frame deletions skippable for exon 44 or 45 had an elevated number of revertant and trace dystrophin expression (approximately 19% of control, using quantitative immunohistochemistry) with 4 of 9 patients presenting with an intermediate muscular dystrophy phenotype (3 patients) or a BMD-like phenotype (1 patient). Corresponding in-frame deletions presented with predominantly mild BMD phenotypes and lower dystrophin levels (approximately 42% of control) than patients with BMD modeling exon 51 skipping (approximately 80% of control). All 12 patients with in-frame deletions had a stable transcript compared with 2 of 9 patients with out-of-frame deletions (who had intermediate muscular dystrophy and BMD phenotypes).CONCLUSIONS AND RELEVANCE Exon 44 or 45 skipping will likely yield lower levels of dystrophin than exon 51 skipping, although the resulting protein is functional enough to often maintain a mild BMD phenotype. Dystrophin transcript stability is an important indicator of dystrophin expression, and transcript instability in DMD compared with BMD should be explored as a potential biomarker of response to AOs. This study is beneficial for the planning, execution, and analysis of clinical trials for exon 44 and 45 skipping.

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“…Antisense oligonucleotides, including PMO compounds, are in clinical testing for the induction of exon skipping in subgroups of Duchene muscular dystrophy patients. 22 In that case, ASOs are designed to force the splicing machinery to bypass a mutation-containing exon in the dystrophin mRNA and join with the next in-frame splice junction to yield a truncated yet functional dystrophin protein.…”

Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease

Clayton¹,

Nelson²,

Weeden³

et al. 2015

Molecular Genetics and Metabolism

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Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Cited by 77 publications

References 117 publications

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Biochemical Characterization of Patients With In-Frame or Out-of-FrameDMDDeletions Pertinent to Exon 44 or 45 Skipping

Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease

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