Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials

Popplewell, Linda J.; Adkin, Carl; Arechavala-Gomeza, Virginia; Aartsma-Rus, Annemieke; de Winter, Christa L.; Wilton, Steve D.; Morgan, Jennifer E.; Muntoni, Francesco; Graham, Ian R.; Dickson, George

doi:10.1016/j.nmd.2009.10.013

« Previous Next »Neuromuscular Disorders
Volume 20, Issue 2 , Pages 102-110, February 2010

Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials

Linda J. Popplewell
- School of Biological Sciences, Royal Holloway – University of London, Egham, Surrey TW20 0EX, United Kingdom
- These authors contributed equally to this paper.
Carl Adkin
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom
- These authors contributed equally to this paper.
Virginia Arechavala-Gomeza
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom
Annemieke Aartsma-Rus
- Center for Human and Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands
Christa L. de Winter
- Center for Human and Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands
Steve D. Wilton
- Centre for Neurological and Neuromuscular Disorders, Australian Neuromuscular Research Institute, University of Western Australia, Perth, WA 6009, Australia
Jennifer E. Morgan
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom
Francesco Muntoni
- Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom
Ian R. Graham
- School of Biological Sciences, Royal Holloway – University of London, Egham, Surrey TW20 0EX, United Kingdom
George Dickson
- School of Biological Sciences, Royal Holloway – University of London, Egham, Surrey TW20 0EX, United Kingdom
- Corresponding author. Tel.: +44 (0)1784 443870; fax: +44 (0)1784 414224.

Received 13 July 2009; received in revised form 20 October 2009; accepted 27 October 2009.

Abstract

Duchenne muscular dystrophy (DMD) is caused by the lack of functional dystrophin protein, most commonly as a result of a range of out-of-frame mutations in the DMD gene. Modulation of pre-mRNA splicing with antisense oligonucleotides (AOs) to restore the reading frame has been demonstrated in vitro and in vivo, such that truncated but functional dystrophin is expressed. AO-induced skipping of exon 51 of the DMD gene, which could treat 13% of DMD patients, has now progressed to clinical trials. We describe here the methodical, cooperative comparison, in vitro (in DMD cells) and in vivo (in a transgenic mouse expressing human dystrophin), of 24 AOs of the phosphorodiamidate morpholino oligomer (PMO) chemistry designed to target exon 53 of the DMD gene, skipping of which could be potentially applicable to 8% of patients. A number of the PMOs tested should be considered worthy of development for clinical trial.

Keywords: Exon skipping, Duchenne muscular dystrophy, Antisense oligonucleotides, Phosphorodiamidate morpholino oligomer