Exon skipping
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Diverse alternative back-splicing and alternative splicing landscape of circular RNAs Open
Circular RNAs (circRNAs) derived from back-spliced exons have been widely identified as being co-expressed with their linear counterparts. A single gene locus can produce multiple circRNAs through alternative back-splice site selection and…
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Tepotinib in Non–Small-Cell Lung Cancer with <i>MET</i> Exon 14 Skipping Mutations Open
Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or hig…
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CADD-Splice—improving genome-wide variant effect prediction using deep learning-derived splice scores Open
Background Splicing of genomic exons into mRNAs is a critical prerequisite for the accurate synthesis of human proteins. Genetic variants impacting splicing underlie a substantial proportion of genetic disease, but are challenging to ident…
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A new view of transcriptome complexity and regulation through the lens of local splicing variations Open
Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSV…
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Eteplirsen in the treatment of Duchenne muscular dystrophy Open
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500-5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by lo…
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N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing Open
N6-methyladenosine (m6A) is the most abundant base modification found in messenger RNAs (mRNAs). The discovery of FTO as the first m6A mRNA demethylase established the concept of reversible RNA modification. Here, we present a comprehensiv…
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Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping Open
ClinicalTrials.gov Identifier: NCT02740972.
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The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer Open
Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologi…
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Precise correction of Duchenne muscular dystrophy exon deletion mutations by base and prime editing Open
Base and prime genome editing correct Duchenne muscular dystrophy mutations to restore dystrophin in mice and human cells.
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Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia Open
Spliceosome mutations are frequently found in myelodysplasia. Splicing alterations induced by these mutations, their precise targets, and the effect at the transcript level have not been fully elucidated. Here we report transcriptomic anal…
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Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues Open
Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated e…
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<i>ABCA4</i>midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease Open
Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying p…
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Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools Open
The identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the…
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FDA Approval Summary: Capmatinib and Tepotinib for the Treatment of Metastatic NSCLC Harboring MET Exon 14 Skipping Mutations or Alterations Open
The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non–small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal–epit…
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<i>DMD</i> genotypes and loss of ambulation in the CINRG Duchenne Natural History Study Open
As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
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The golden retriever model of Duchenne muscular dystrophy Open
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and …
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Opportunities and challenges for antisense oligonucleotide therapies Open
Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence‐specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in th…
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Safety, tolerability, and pharmacokinetics of casimersen in patients with <span>D</span>uchenne muscular dystrophy amenable to exon <span>45</span> skipping: A randomized, double‐blind, placebo‐controlled, dose‐titration trial Open
Introduction/Aims Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to bypass frameshift DMD mutations and produ…
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Origin of exon skipping-rich transcriptomes in animals driven by evolution of gene architecture Open
We suggest that the increase of exon skipping rates in animals followed a two-step process. First, exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their exon s…
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A framework for individualized splice-switching oligonucleotide therapy Open
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases 1 , but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencin…
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Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington's Disease Open
Huntington's disease (HD) is a neurodegenerative disorder caused by accumulation of CAG expansions in the huntingtin (HTT) gene. Hence, decreasing the expression of mutated HTT (mtHTT) is the most upstream approach for treatment of HD. We …
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Current and emerging treatment strategies for Duchenne muscular dystrophy Open
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature d…
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Exon skipping: a first in class strategy for Duchenne muscular dystrophy Open
Exon skipping is a therapeutic approach for Duchenne muscular dystrophy (DMD) that has been in development for close to two decades. This approach uses antisense oligonucleotides (AONs) to modulate pre-mRNA splicing of dystrophin transcrip…
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Exon-skipping advances for Duchenne muscular dystrophy Open
Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle wasting that has currently no cure. Exon-skipping strategy represents one of the most promising therapeutic approaches that aim to restore ex…
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Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models Open
Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated in many hu…
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Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial Open
The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week,…
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<i>In vitro</i>and<i>in vivo</i>rescue of aberrant splicing in<i>CEP290</i>-associated LCA by antisense oligonucleotide delivery Open
Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991 + 1655A > G) that creates a c…
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<i>MET</i> Exon 14 Skipping in Non-Small Cell Lung Cancer Open
Background. Non-small cell lung cancers (NSCLCs) harboring specific genetic alterations can be highly sensitive to targeted therapies. Materials and Methods. We performed a targeted rearrangement assay on 54 NSCLCs across all stages that w…
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Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial Open
Background Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. Objective To report results from PROMOVI, …
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SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes Open
Misregulated alternative RNA splicing (AS) contributes to the tumorigenesis and progression of human cancers, including glioblastoma (GBM). Here, we showed that a major splicing factor, serine and arginine rich splicing factor 3 (SRSF3), w…