Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease affecting 1 in 5000 young males worldwide annually. Patients experience muscle weakness and loss of ambulation at an early age, with ∼75% reduced life expectancy. Recently developed genetic editing strategies aim to convert severe DMD...
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doaj-8f6808916fa3444a8421b75f0cebc28d2021-04-02T18:59:27ZengWileyEngineering Biology2398-61822020-12-0110.1049/enb.2020.0017ENB.2020.0017Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patientsMarthe Helene Solberg0Maryam Shariatzadeh1Samantha L Wilson2National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences Loughborough UniversityCentre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough UniversityCentre for Biological Engineering, Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough UniversityDuchenne muscular dystrophy (DMD) is an X-linked genetic disease affecting 1 in 5000 young males worldwide annually. Patients experience muscle weakness and loss of ambulation at an early age, with ∼75% reduced life expectancy. Recently developed genetic editing strategies aim to convert severe DMD phenotypes to a milder disease course. Among these, the antisense oligonucleotide (AO)-mediated exon skipping and the adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (adeno-associated viral (AAV)-delivered CRISPR/Cas9) gene editing have shown promising results in restoring dystrophin protein expression and functionality in skeletal and heart muscle in both animals and human cells in vivo and in vitro. However, therapeutic benefits currently remain unclear. The aim of this review is to compare the potential therapeutic benefits, efficacy, safety, and clinical progress of AO-mediated exon skipping and CRISPR/Cas9 gene-editing strategies. Both techniques have demonstrated therapeutic benefit and long-term efficacy in clinical trials. AAV-delivery of CRISPR/Cas9 may potentially correct disease-causing mutations following a single treatment compared to the required continuous AO/PMO-delivery of exon skipping drugs. The latter has the potential to increase the dystrophin expression in skeletal/heart muscle with sustained effects. However, therapeutic challenges including the need for optimised delivery must be overcome in to advance current clinical data.https://digital-library.theiet.org/content/journals/10.1049/enb.2020.0017patient diagnosiscellular biophysicsdiseasesmusclecardiologymicroorganismsmolecular biophysicsgeneticsneurophysiologybiochemistrygene therapygenomicsgene modification strategiesao-mediated exon skippingduchenne muscular dystrophy patientsgenetic diseasepatients experience muscle weaknessreduced life expectancydeveloped genetic editing strategies aimsevere dmd phenotypesmilder disease courseantisense oligonucleotide-mediated exondystrophin protein expressionpotential therapeutic benefitsgene-editing strategiestherapeutic benefitlong-term efficacyexon skipping drugsadeno-associated viral-delivered crispr-cas9 gene editingadeno-associated viral-delivered clustered regularly interspaced short palindromic repeat |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marthe Helene Solberg Maryam Shariatzadeh Samantha L Wilson |
spellingShingle |
Marthe Helene Solberg Maryam Shariatzadeh Samantha L Wilson Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients Engineering Biology patient diagnosis cellular biophysics diseases muscle cardiology microorganisms molecular biophysics genetics neurophysiology biochemistry gene therapy genomics gene modification strategies ao-mediated exon skipping duchenne muscular dystrophy patients genetic disease patients experience muscle weakness reduced life expectancy developed genetic editing strategies aim severe dmd phenotypes milder disease course antisense oligonucleotide-mediated exon dystrophin protein expression potential therapeutic benefits gene-editing strategies therapeutic benefit long-term efficacy exon skipping drugs adeno-associated viral-delivered crispr-cas9 gene editing adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat |
author_facet |
Marthe Helene Solberg Maryam Shariatzadeh Samantha L Wilson |
author_sort |
Marthe Helene Solberg |
title |
Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients |
title_short |
Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients |
title_full |
Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients |
title_fullStr |
Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients |
title_full_unstemmed |
Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients |
title_sort |
gene modification strategies using ao-mediated exon skipping and crispr/cas9 as potential therapies for duchenne muscular dystrophy patients |
publisher |
Wiley |
series |
Engineering Biology |
issn |
2398-6182 |
publishDate |
2020-12-01 |
description |
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease affecting 1 in 5000 young males worldwide annually. Patients experience muscle weakness and loss of ambulation at an early age, with ∼75% reduced life expectancy. Recently developed genetic editing strategies aim to convert severe DMD phenotypes to a milder disease course. Among these, the antisense oligonucleotide (AO)-mediated exon skipping and the adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (adeno-associated viral (AAV)-delivered CRISPR/Cas9) gene editing have shown promising results in restoring dystrophin protein expression and functionality in skeletal and heart muscle in both animals and human cells in vivo and in vitro. However, therapeutic benefits currently remain unclear. The aim of this review is to compare the potential therapeutic benefits, efficacy, safety, and clinical progress of AO-mediated exon skipping and CRISPR/Cas9 gene-editing strategies. Both techniques have demonstrated therapeutic benefit and long-term efficacy in clinical trials. AAV-delivery of CRISPR/Cas9 may potentially correct disease-causing mutations following a single treatment compared to the required continuous AO/PMO-delivery of exon skipping drugs. The latter has the potential to increase the dystrophin expression in skeletal/heart muscle with sustained effects. However, therapeutic challenges including the need for optimised delivery must be overcome in to advance current clinical data. |
topic |
patient diagnosis cellular biophysics diseases muscle cardiology microorganisms molecular biophysics genetics neurophysiology biochemistry gene therapy genomics gene modification strategies ao-mediated exon skipping duchenne muscular dystrophy patients genetic disease patients experience muscle weakness reduced life expectancy developed genetic editing strategies aim severe dmd phenotypes milder disease course antisense oligonucleotide-mediated exon dystrophin protein expression potential therapeutic benefits gene-editing strategies therapeutic benefit long-term efficacy exon skipping drugs adeno-associated viral-delivered crispr-cas9 gene editing adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat |
url |
https://digital-library.theiet.org/content/journals/10.1049/enb.2020.0017 |
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