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Comparative analysis of antisense oligonucleotide sequences for targeted skipping of Exon 51 during dystrophin Pre-mRNA splicing in human muscle

Arechavala-Gomeza, V; Graham, IR; Popplewell, LJ; Adams, AM; Aartsma-Rus, A; Kinali, M; Morgan, JE; ... Muntoni, F; + view all (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. 10.1089/hum.2006.061. Green open access

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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.

Type: Article
Title: Comparative analysis of antisense oligonucleotide sequences for targeted skipping of Exon 51 during dystrophin Pre-mRNA splicing in human muscle
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2006.061
Publisher version: http://dx.doi.org/10.1089/hum.2006.061
Language: English
Additional information: This is a copy of an article published in Human Gene Therapy © 2007 copyright Mary Ann Liebert, Inc.; Human Gene Therapy is available online at: http://online.liebertpub.com
Keywords: DUCHENNE MUSCULAR-DYSTROPHY, MDX MOUSE MUSCLE, NONSENSE MUTATION, SOMATIC REVERSION, SYSTEMIC DELIVERY, REVERTANT FIBERS, GENE TRANSCRIPT, POSITIVE FIBERS, IN-VITRO, EXPRESSION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/140751
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