Splice-switching antisense oligonucleotides as therapeutic drugs

Havens, Mallory A.; Hastings, Michelle L.

doi:10.1093/nar/gkw533

Cited by 416 publications

(328 citation statements)

References 168 publications

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“…Exon splice-modulating therapy has arrived in the clinic with the recent approval of AONs for the treatment of DMD and SMA (24,39). The field of RNA-targeting therapeutics continues to expand with new splice-switching oligonucleotide therapies designed to treat multiple disorders (40). In the current study, we evaluated an AON-mediated exon-skipping strategy to treat LGMD 2C.…”

Section: Discussionmentioning

confidence: 99%

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Wyatt¹,

Demonbreun²,

Kim³

et al. 2018

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Wyatt¹,

Demonbreun²,

Kim³

et al. 2018

JCI Insight

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“…Currently, AOs are being used to treat various muscular and neurodegenerative diseases at varying stages of clinical trials, as well as a variety of other disease such as cancer [205]. A recent review showed that over 25 genes have been targeted using splice-switching AOs.…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

“…A recent review showed that over 25 genes have been targeted using splice-switching AOs. These AOs are used as therapeutics to redirect pre-mRNA splicing, in which sequences vital to pre-mRNA processing are targeted, effectively blocking binding of the splicing factors to the region [205,206]. These types of AOs can be used to restore gene function, correct aberrant splicing, produce a novel transcript or even down regulate gene expression [205].…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

“…These AOs are used as therapeutics to redirect pre-mRNA splicing, in which sequences vital to pre-mRNA processing are targeted, effectively blocking binding of the splicing factors to the region [205,206]. These types of AOs can be used to restore gene function, correct aberrant splicing, produce a novel transcript or even down regulate gene expression [205]. Most notably are Exondys 51 and Nusinersen, which are treatments for Duchenne muscular dystrophy and spinal muscular atrophy, respectively [207,208].…”

Section: Suppression/modification Of Mutant Gene Expression and Protementioning

confidence: 99%

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Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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“…These numbers combined with the number of known splicing mutations indicate that up to one-third of all disease-causing mutations might change pre-mRNA splicing (27,28). It has been shown that using an ASO-based approach one can manipulate the outcome of splicing, so that a particular exon can be selectively removed or included (29,30). Therefore, ASOs represent an invaluable tool that could be used for therapeutic purposes to treat a human disease caused by aberrant splicing.…”

Section: Introductionmentioning

confidence: 99%

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

Singh

Luo

Singh

2018

Methods in Molecular Biology

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Pre-mRNA splicing, a dynamic process of intron removal and exon joining, is governed by a combinatorial control exerted by overlapping cis-elements that are unique to each exon and its flanking intronic sequences. Splicing cis-elements are usually 4-to-8-nucleotide-long linear motifs that provide binding sites for specific proteins. Pre-mRNA splicing is also influenced by secondary and higher order RNA structures that affect accessibility of splicing cis-elements. Antisense oligonucleotides (ASOs) that block splicing cis-elements and/or affect RNA structure have been shown to modulate splicing in vivo. Therefore, ASO-based strategies have emerged as a powerful tool for therapeutic manipulation of splicing in pathological conditions. Here we describe an ASO-based approach to increase the production of the full-length SMN2 mRNA in spinal muscular atrophy patient cells.

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Splice-switching antisense oligonucleotides as therapeutic drugs

Cited by 416 publications

References 168 publications

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Pre-mRNA Splicing Modulation by Antisense Oligonucleotides

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