Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy

  title={Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy},
  author={Kasia Dzierlega and Toshifumi Yokota},
  journal={Gene Therapy},
Duchenne muscular dystrophy (DMD) is one of the most common lethal muscle-wasting disorders affecting young boys caused by mutations in the DMD gene. Exon skipping has emerged as a promising therapy for DMD. Antisense oligonucleotides (AONs) are designed to induce the skipping of exon(s), in order to restore the reading frame, and therefore, allow for dystrophin expression. Eteplirsen and golodirsen, AONs for DMD exons 51 and 53 skipping, have been recently approved by the FDA. Viltolarsen, an… 
Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update.
This paper reviews and discusses the available information on the efficacy, safety, and tolerability data of eteplirsen and SRP-5051 from preclinical and clinical trials.
Gene editing and modulation for Duchenne muscular dystrophy.
Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies.
This Review outlines the most interesting and recent studies addressing the secondary outcomes of DMD and how to better deliver the therapeutic agents.
Immortalized Canine Dystrophic Myoblast Cell Lines for Development of Peptide-Conjugated Splice-Switching Oligonucleotides
Using dystrophin-deficient immortalized myoblast lines, it is demonstrated that a novel cell-penetrating peptide (Pip8b2)-conjugated SSO markedly improved multiexon skipping activity compared with the respective naked phosphorodiamidate morpholino oligomers.
Current Pharmacological Strategies for Duchenne Muscular Dystrophy
A meta-analysis of gene profiling in DMD patients has been performed and the rationale and efficacy of each agent in pre-clinical or clinical studies are presented, to understand the molecular mechanisms of DMD.
Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation
The results demonstrate the therapeutic potential and clinical benefit of ASO-based splicing modulation for genetic diseases caused by splicing mutations and identify a highly potent lead ASO.
Dystrophin gene editing stability is dependent on dystrophin levels in skeletal but not cardiac muscles.
Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849 + 10 kb C-to-T splicing mutation
The Efficacy of Naïve versus Modified Mesenchymal Stem Cells in Improving Muscle Function in Duchenne Muscular Dystrophy: A Systematic Review
MSCs seem to improve pulmonary and cardiac functions and thereby improve survival regardless of them being naïve or modified, and this systematic review focused on elucidating the therapeutic efficacy of MSCs on the DMD in vivo model.
Matrilineal analysis of mutations in the DMD gene in a multigenerational South Indian cohort using DMD gene panel sequencing
A precise and timely molecular detection of DMD mutations encourages interventions such as carrier genetic counselling and in undertaking therapeutic measures for the DMD patients.


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Development of Antisense‐Mediated Exon Skipping as a Treatment for Duchenne Muscular Dystrophy
An overview of the available mouse models and it is proposed that different chemistries should be further developed in parallel in order to hasten the transfer of the exon skipping therapy to the clinic.
Optimizing exon skipping therapies for DMD.
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A review of recent progress in exon skipping therapy for Duchenne Muscular Dystrophy summarizes recent progress and discusses future strategies.
Immortalized Muscle Cell Model to Test the Exon Skipping Efficacy for Duchenne Muscular Dystrophy
The challenges associated with primary muscle cell lines are illustrated and a novel approach that utilizes immortalized cell lines to quantitatively evaluate the exon skipping efficacy in in vitro studies is described.
Multi-exon Skipping Using Cocktail Antisense Oligonucleotides in the Canine X-linked Muscular Dystrophy
A cocktail of antisense morpholinos targeting exon 6 and exon 8 was designed and it restored dystrophin expression in body-wide skeletal muscles and evaluation of the efficacy and safety of multi-exon skipping in the CXMD dog model are presented.
Exon‐skipping therapy for Duchenne muscular dystrophy
  • A. Nakamura, S. Takeda
  • Medicine
    Neuropathology : official journal of the Japanese Society of Neuropathology
  • 2009
The genetic basis of DMD is summarized, and the potential and perspectives of exon skipping as a promising therapy for this disease are summarized.
Therapeutic exon skipping for dysferlinopathies?
The dysferlin protein domains and DYSF mutations are analyzed and what exons are promising targets with regard to applicability and feasibility are described and it is shown that DysF exon skipping seems to be as straightforward as DMD exon skipped, as AONs to induce efficient skipping of four DYSf exons were readily identified.
Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients.
The broad therapeutic applicability of the antisense-induced skipping of targeted exons from the pre-mRNA is demonstrated in cultured muscle cells from six DMD patients carrying different deletions and a nonsense mutation, restoring dystrophin synthesis in over 75% of cells.
Bodywide skipping of exons 45–55 in dystrophic mdx52 mice by systemic antisense delivery
A unique successful demonstration of effective rescue by exon 45–55 skipping in a dystrophin-deficient animal model is demonstrated.
Exons 45-55 Skipping Using Mutation-Tailored Cocktails of Antisense Morpholinos in the DMD Gene.
  • Y. Echigoya, K. Lim, +11 authors T. Yokota
  • Medicine, Biology
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2019