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Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons.
Mol Ther. 2006 Sep; 14(3):401-7.MT

Abstract

Through antisense-induced single-, double-, and multiexon skipping, we have previously demonstrated restoration of dystrophin expression in Duchenne muscular dystrophy (DMD) patient-derived muscle cells in vitro. In this study we further explored the frontiers of this strategy by using specific combinations of 2'-O-methyl phosphorothioate antisense oligonucleotides (AONs) targeting either one or multiple exons. We show that skipping efficiencies may indeed be improved by targeting two putative splicing regulatory sequences within one exon. In particular, such double targeting was effective for the thus far "unskippable" exons 47 and 57. We previously reported the feasibility of multiexon skipping spanning exon 45 to exon 51, using a combination of AONs targeting both outer exons (45 and 51). This would be applicable to 13% of all DMD patients. We here explored the frontiers of multiexon skipping both to increase the number of patients that can be treated with the same set of AONs and to mimic large deletions found in relatively mildly affected BMD patients. We aimed at inducing larger multiexon-skipping stretches, such as exons 17-51, exons 42-55, and exons 45-59. However, this appeared complicated and may be dependent on cotranscriptional splicing and the size of the flanking introns.

Authors+Show Affiliations

DMD Genetic Therapy Group, Center for Human and Clinical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16753346

Citation

Aartsma-Rus, Annemieke, et al. "Exploring the Frontiers of Therapeutic Exon Skipping for Duchenne Muscular Dystrophy By Double Targeting Within One or Multiple Exons." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 14, no. 3, 2006, pp. 401-7.
Aartsma-Rus A, Kaman WE, Weij R, et al. Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. Mol Ther. 2006;14(3):401-7.
Aartsma-Rus, A., Kaman, W. E., Weij, R., den Dunnen, J. T., van Ommen, G. J., & van Deutekom, J. C. (2006). Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. Molecular Therapy : the Journal of the American Society of Gene Therapy, 14(3), 401-7.
Aartsma-Rus A, et al. Exploring the Frontiers of Therapeutic Exon Skipping for Duchenne Muscular Dystrophy By Double Targeting Within One or Multiple Exons. Mol Ther. 2006;14(3):401-7. PubMed PMID: 16753346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. AU - Aartsma-Rus,Annemieke, AU - Kaman,Wendy E, AU - Weij,Rudie, AU - den Dunnen,Johan T, AU - van Ommen,Gert-Jan B, AU - van Deutekom,Judith C T, Y1 - 2006/06/06/ PY - 2005/11/21/received PY - 2006/02/20/revised PY - 2006/02/22/accepted PY - 2006/6/7/pubmed PY - 2006/11/14/medline PY - 2006/6/7/entrez SP - 401 EP - 7 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol Ther VL - 14 IS - 3 N2 - Through antisense-induced single-, double-, and multiexon skipping, we have previously demonstrated restoration of dystrophin expression in Duchenne muscular dystrophy (DMD) patient-derived muscle cells in vitro. In this study we further explored the frontiers of this strategy by using specific combinations of 2'-O-methyl phosphorothioate antisense oligonucleotides (AONs) targeting either one or multiple exons. We show that skipping efficiencies may indeed be improved by targeting two putative splicing regulatory sequences within one exon. In particular, such double targeting was effective for the thus far "unskippable" exons 47 and 57. We previously reported the feasibility of multiexon skipping spanning exon 45 to exon 51, using a combination of AONs targeting both outer exons (45 and 51). This would be applicable to 13% of all DMD patients. We here explored the frontiers of multiexon skipping both to increase the number of patients that can be treated with the same set of AONs and to mimic large deletions found in relatively mildly affected BMD patients. We aimed at inducing larger multiexon-skipping stretches, such as exons 17-51, exons 42-55, and exons 45-59. However, this appeared complicated and may be dependent on cotranscriptional splicing and the size of the flanking introns. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/16753346/Exploring_the_frontiers_of_therapeutic_exon_skipping_for_Duchenne_muscular_dystrophy_by_double_targeting_within_one_or_multiple_exons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(06)00129-8 DB - PRIME DP - Unbound Medicine ER -