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Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle.
Hum Gene Ther. 2007 Sep; 18(9):798-810.HG

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in the absence of functional protein. In the majority of cases these are out-of-frame deletions that disrupt the reading frame. Several attempts have been made to restore the dystrophin mRNA reading frame by modulation of pre-mRNA splicing with antisense oligonucleotides (AOs), demonstrating success in cultured cells, muscle explants, and animal models. We are preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 51 into the mature mRNA by the splicing machinery, a process known as exon skipping. Here, we describe a series of systematic experiments to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom. Eight specific AO sequences targeting exon 51 were tested in two different chemical forms and in three different preclinical models: cultured human muscle cells and explants (wild type and DMD), and local in vivo administration in transgenic mice harboring the entire human DMD locus. Data have been validated independently in the different model systems used, and the studies describe a rational collaborative path for the preclinical selection of AOs for evaluation in future clinical trials.

Authors+Show Affiliations

Department of Paediatrics, Imperial College, London W12ONN, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17767400

Citation

Arechavala-Gomeza, V, et al. "Comparative Analysis of Antisense Oligonucleotide Sequences for Targeted Skipping of Exon 51 During Dystrophin pre-mRNA Splicing in Human Muscle." Human Gene Therapy, vol. 18, no. 9, 2007, pp. 798-810.
Arechavala-Gomeza V, Graham IR, Popplewell LJ, et al. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum Gene Ther. 2007;18(9):798-810.
Arechavala-Gomeza, V., Graham, I. R., Popplewell, L. J., Adams, A. M., Aartsma-Rus, A., Kinali, M., Morgan, J. E., van Deutekom, J. C., Wilton, S. D., Dickson, G., & Muntoni, F. (2007). Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Human Gene Therapy, 18(9), 798-810.
Arechavala-Gomeza V, et al. Comparative Analysis of Antisense Oligonucleotide Sequences for Targeted Skipping of Exon 51 During Dystrophin pre-mRNA Splicing in Human Muscle. Hum Gene Ther. 2007;18(9):798-810. PubMed PMID: 17767400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. AU - Arechavala-Gomeza,V, AU - Graham,I R, AU - Popplewell,L J, AU - Adams,A M, AU - Aartsma-Rus,A, AU - Kinali,M, AU - Morgan,J E, AU - van Deutekom,J C, AU - Wilton,S D, AU - Dickson,G, AU - Muntoni,F, PY - 2007/9/5/pubmed PY - 2007/11/10/medline PY - 2007/9/5/entrez SP - 798 EP - 810 JF - Human gene therapy JO - Hum Gene Ther VL - 18 IS - 9 N2 - Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in the absence of functional protein. In the majority of cases these are out-of-frame deletions that disrupt the reading frame. Several attempts have been made to restore the dystrophin mRNA reading frame by modulation of pre-mRNA splicing with antisense oligonucleotides (AOs), demonstrating success in cultured cells, muscle explants, and animal models. We are preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 51 into the mature mRNA by the splicing machinery, a process known as exon skipping. Here, we describe a series of systematic experiments to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom. Eight specific AO sequences targeting exon 51 were tested in two different chemical forms and in three different preclinical models: cultured human muscle cells and explants (wild type and DMD), and local in vivo administration in transgenic mice harboring the entire human DMD locus. Data have been validated independently in the different model systems used, and the studies describe a rational collaborative path for the preclinical selection of AOs for evaluation in future clinical trials. SN - 1043-0342 UR - https://www.unboundmedicine.com/medline/citation/17767400/Comparative_analysis_of_antisense_oligonucleotide_sequences_for_targeted_skipping_of_exon_51_during_dystrophin_pre_mRNA_splicing_in_human_muscle_ L2 - https://www.liebertpub.com/doi/10.1089/hum.2006.061?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -