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access icon openaccess Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients

  • Author(s): Marthe Helene Solberg 1 ; Maryam Shariatzadeh 2 ; Samantha L Wilson 2
    • View affiliations
  • Source: Volume 4, Issue 3, December 2020, p. 37 – 42
    DOI:  10.1049/enb.2020.0017 , Online ISSN 2398-6182
This is an open access article published by the IET under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/)
Received 02/09/2020, Accepted 30/11/2020, Revised 26/11/2020, Published 01/12/2020

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.

Inspec keywords: molecular biophysics; cardiology; genetics; diseases; muscle; neurophysiology; gene therapy; biochemistry; patient diagnosis; microorganisms; genomics; cellular biophysics

Other keywords: reduced life expectancy; antisense oligonucleotide-mediated exon; exon skipping drugs; long-term efficacy; Duchenne muscular dystrophy patients; potential therapeutic benefits; severe DMD phenotypes; AO-mediated exon skipping; therapeutic benefit; gene-editing strategies; gene modification strategies; genetic disease; dystrophin protein expression; milder disease course; adeno-associated viral-delivered CRISPR-Cas9 gene editing; patients experience muscle weakness; adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat; developed genetic editing strategies aim

Subjects: Patient diagnostic methods and instrumentation; Patient care and treatment; Probability theory, stochastic processes, and statistics; Physics of subcellular structures; Physical chemistry of biomolecular solutions and condensed states; Biomolecular interactions, charge transfer complexes; Macromolecular configuration (bonds, dimensions); Biomolecular structure, configuration, conformation, and active sites; Patient care and treatment; Biomedical measurement and imaging; Biophysics of neurophysiological processes

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