Special Issue "Therapeutic Alternative Splicing: Mechanisms and Applications"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 October 2016).

Special Issue Editors

Guest Editor
Prof. Dr. Susan Fletcher

Centre for Comparative Genomics, Murdoch University, 90 South St, Murdoch, WA 6150, Australia
Website | E-Mail
Guest Editor
Prof. Dr. Steve Wilton

Western Australian Neuroscience Research Institute and Centre for Comparative Genomics, Murdoch University, Murdoch, WA 6150, Australia
Website | E-Mail

Special Issue Information

Dear Colleagues,

Induced exon skipping is currently the only treatment strategy to have restored dystrophin expression and altered the natural history of Duchenne muscular dystrophy.  Antisense oligomers can also be used to alter splice site selection to enhance exon inclusion, promote alternative splicing or suppress aberrant pre-mRNA processing. While splice modifying therapeutics are being developed for several human diseases, the techniques are also applicable to induction of animal models and to the study of gene expression. Not surprisingly, given the central role of splicing regulation in gene expression, aberrant splicing has been recognized as a major cause of human disease, and presents opportunities for intervention. In a single issue of Genes, we will summarize the current state of antisense oligomer mediated exon selection. We welcome reviews and original articles in the area of induced alternative splicing, including therapeutic applications, mechanistic studies, and oligomer design, delivery and evaluation.

Prof. Susan Fletcher
Prof. Steve Wilto
Guest Editors

Manuscript Submission Information

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Keywords

  • Antisense oligomer
  • pre-mRNA splicing
  • Duchenne muscular dystrophy
  • exon selection
  • oligonucleotide therapeutics

Published Papers (6 papers)

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Research

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Open AccessArticle
Antisense Oligonucleotides Used to Target the DUX4 mRNA as Therapeutic Approaches in FaciosScapuloHumeral Muscular Dystrophy (FSHD)
Received: 26 December 2016 / Revised: 16 February 2017 / Accepted: 22 February 2017 / Published: 3 March 2017
Cited by 9 | PDF Full-text (3720 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome [...] Read more.
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Review

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Open AccessReview
Splice-Switching Therapy for Spinal Muscular Atrophy
Received: 21 April 2017 / Revised: 26 May 2017 / Accepted: 2 June 2017 / Published: 12 June 2017
Cited by 6 | PDF Full-text (418 KB) | HTML Full-text | XML Full-text
Abstract
Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved [...] Read more.
Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA. Whilst approval of oligonucleotide-based therapies for SMA should be celebrated, we also discuss some of the limitations of this approach and alternate genetic strategies that are currently underway in clinical trials. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Open AccessReview
Dystrophic Cardiomyopathy—Potential Role of Calcium in Pathogenesis, Treatment and Novel Therapies
Received: 28 November 2016 / Revised: 16 March 2017 / Accepted: 21 March 2017 / Published: 24 March 2017
Cited by 3 | PDF Full-text (6851 KB) | HTML Full-text | XML Full-text
Abstract
Duchenne muscular dystrophy (DMD) is caused by defects in the DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly [...] Read more.
Duchenne muscular dystrophy (DMD) is caused by defects in the DMD gene and results in progressive wasting of skeletal and cardiac muscle due to an absence of functional dystrophin. Cardiomyopathy is prominent in DMD patients, and contributes significantly to mortality. This is particularly true following respiratory interventions that reduce death rate and increase ambulation and consequently cardiac load. Cardiomyopathy shows an increasing prevalence with age and disease progression, and over 95% of patients exhibit dilated cardiomyopathy by the time they reach adulthood. Development of the myopathy is complex, and elevations in intracellular calcium, functional muscle ischemia, and mitochondrial dysfunction characterise the pathophysiology. Current therapies are limited to treating symptoms of the disease and there is therefore an urgent need to treat the underlying genetic defect. Several novel therapies are outlined here, and the unprecedented success of phosphorodiamidate morpholino oligomers (PMOs) in preclinical and clinical studies is overviewed. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Open AccessReview
Targeting Splicing in the Treatment of Human Disease
Received: 16 December 2016 / Revised: 14 February 2017 / Accepted: 17 February 2017 / Published: 24 February 2017
Cited by 11 | PDF Full-text (1696 KB) | HTML Full-text | XML Full-text
Abstract
The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding [...] Read more.
The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes. Several tools, including antisense oligonucleotides and trans-splicing, have been developed to target and alter splicing to correct misregulated gene expression or to modulate transcript isoform levels. At present, deregulated AS is recognized as an important area for therapeutic intervention. Here, we summarize the major hallmarks of the splicing process, the clinical implications that arise from alterations in this process, and the current tools that can be used to deliver, target, and correct deficiencies of this key pre-mRNA processing event. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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Open AccessReview
Targeting MDM4 Splicing in Cancers
Received: 8 November 2016 / Accepted: 15 February 2017 / Published: 20 February 2017
Cited by 7 | PDF Full-text (205 KB) | HTML Full-text | XML Full-text
Abstract
MDM4, an essential negative regulator of the P53 tumor suppressor, is frequently overexpressed in cancer cells that harbor a wild‐type P53. By a mechanism based on alternative splicing, the MDM4 gene generates two mutually exclusive isoforms: MDM4-FL, which encodes the full‐length MDM4 protein, [...] Read more.
MDM4, an essential negative regulator of the P53 tumor suppressor, is frequently overexpressed in cancer cells that harbor a wild‐type P53. By a mechanism based on alternative splicing, the MDM4 gene generates two mutually exclusive isoforms: MDM4-FL, which encodes the full‐length MDM4 protein, and a shorter splice variant called MDM4-S. Previous results suggested that the MDM4-S isoform could be an important driver of tumor development. In this short review, we discuss a recent set of data indicating that MDM4-S is more likely a passenger isoform during tumorigenesis and that targeting MDM4 splicing to prevent MDM4-FL protein expression appears as a promising strategy to reactivate p53 in cancer cells. The benefits and risks associated with this strategy are also discussed. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
Open AccessReview
2′-O-Methyl RNA/Ethylene-Bridged Nucleic Acid Chimera Antisense Oligonucleotides to Induce Dystrophin Exon 45 Skipping
Received: 13 December 2016 / Revised: 2 February 2017 / Accepted: 7 February 2017 / Published: 10 February 2017
Cited by 4 | PDF Full-text (2472 KB) | HTML Full-text | XML Full-text
Abstract
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease characterized by dystrophin deficiency from mutations in the dystrophin gene. Antisense oligonucleotide (AO)-mediated exon skipping targets restoration of the dystrophin reading frame to allow production of an internally deleted dystrophin protein with functional benefit [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disease characterized by dystrophin deficiency from mutations in the dystrophin gene. Antisense oligonucleotide (AO)-mediated exon skipping targets restoration of the dystrophin reading frame to allow production of an internally deleted dystrophin protein with functional benefit for DMD patients who have out-of-frame deletions. After accelerated US approval of eteplirsen (Exondys 51), which targets dystrophin exon 51 for skipping, efforts are now focused on targeting other exons. For improved clinical benefits, this strategy requires more studies of the delivery method and modification of nucleic acids. We studied a nucleotide with a 2′-O,4′-C-ethylene-bridged nucleic acid (ENA), which shows high nuclease resistance and high affinity for complementary RNA strands. Here, we describe the process of developing a 2′-O-methyl RNA(2′-OMeRNA)/ENA chimera AO to induce dystrophin exon 45 skipping. One 18-mer 2′-OMeRNA/ENA chimera (AO85) had the most potent activity for inducing exon 45 skipping in cultured myotubes. AO85 was administered to mdx mice without significant side effects. AO85 transfection into cultured myotubes from 13 DMD patients induced exon 45 skipping in all samples at different levels and dystrophin expression in 11 patients. These results suggest the possible efficacy of AO-mediated exon skipping changes in individual patients and highlight the 2′-OMeRNA/ENA chimera AO as a potential fundamental treatment for DMD. Full article
(This article belongs to the Special Issue Therapeutic Alternative Splicing: Mechanisms and Applications)
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