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Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides.
Nucleic Acid Ther. 2014 Feb; 24(1):57-68.NA

Abstract

Duchenne muscular dystrophy (DMD) is one of the most common and lethal genetic disorders, with 20,000 children per year born with DMD globally. DMD is caused by mutations in the dystrophin (DMD) gene. Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein. One major challenge has been its limited applicability. Multiple exon skipping has recently emerged as a potential solution. Indeed, many DMD patients need exon skipping of multiple exons in order to restore the reading frame, depending on how many base pairs the mutated exon(s) and adjacent exons have. Theoretically, multiple exon skipping could be used to treat approximately 90%, 80%, and 98% of DMD patients with deletion, duplication, and nonsense mutations, respectively. In addition, multiple exon skipping could be used to select deletions that optimize the functionality of the truncated dystrophin protein. The proof of concept of systemic multiple exon skipping using a cocktail of AOs has been demonstrated in dystrophic dog and mouse models. Remaining challenges include the insufficient efficacy of systemic treatment, especially for therapies that target the heart, and limited long-term safety data. Here we review recent preclinical developments in AO-mediated multiple exon skipping and discuss the remaining challenges.

Authors+Show Affiliations

1 Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, Alberta, Canada .No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

24380394

Citation

Echigoya, Yusuke, and Toshifumi Yokota. "Skipping Multiple Exons of Dystrophin Transcripts Using Cocktail Antisense Oligonucleotides." Nucleic Acid Therapeutics, vol. 24, no. 1, 2014, pp. 57-68.
Echigoya Y, Yokota T. Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides. Nucleic Acid Ther. 2014;24(1):57-68.
Echigoya, Y., & Yokota, T. (2014). Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides. Nucleic Acid Therapeutics, 24(1), 57-68. https://doi.org/10.1089/nat.2013.0451
Echigoya Y, Yokota T. Skipping Multiple Exons of Dystrophin Transcripts Using Cocktail Antisense Oligonucleotides. Nucleic Acid Ther. 2014;24(1):57-68. PubMed PMID: 24380394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides. AU - Echigoya,Yusuke, AU - Yokota,Toshifumi, Y1 - 2013/12/31/ PY - 2014/1/2/entrez PY - 2014/1/2/pubmed PY - 2014/10/21/medline SP - 57 EP - 68 JF - Nucleic acid therapeutics JO - Nucleic Acid Ther VL - 24 IS - 1 N2 - Duchenne muscular dystrophy (DMD) is one of the most common and lethal genetic disorders, with 20,000 children per year born with DMD globally. DMD is caused by mutations in the dystrophin (DMD) gene. Antisense-mediated exon skipping therapy is a promising therapeutic approach that uses short DNA-like molecules called antisense oligonucleotides (AOs) to skip over/splice out the mutated part of the gene to produce a shortened but functional dystrophin protein. One major challenge has been its limited applicability. Multiple exon skipping has recently emerged as a potential solution. Indeed, many DMD patients need exon skipping of multiple exons in order to restore the reading frame, depending on how many base pairs the mutated exon(s) and adjacent exons have. Theoretically, multiple exon skipping could be used to treat approximately 90%, 80%, and 98% of DMD patients with deletion, duplication, and nonsense mutations, respectively. In addition, multiple exon skipping could be used to select deletions that optimize the functionality of the truncated dystrophin protein. The proof of concept of systemic multiple exon skipping using a cocktail of AOs has been demonstrated in dystrophic dog and mouse models. Remaining challenges include the insufficient efficacy of systemic treatment, especially for therapies that target the heart, and limited long-term safety data. Here we review recent preclinical developments in AO-mediated multiple exon skipping and discuss the remaining challenges. SN - 2159-3345 UR - https://www.unboundmedicine.com/medline/citation/24380394/Skipping_multiple_exons_of_dystrophin_transcripts_using_cocktail_antisense_oligonucleotides_ L2 - https://www.liebertpub.com/doi/10.1089/nat.2013.0451?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -