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Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide.
J Gene Med. 2006 Feb; 8(2):207-16.JG

Abstract

BACKGROUND

Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterised by an absence of functional protein, while Becker muscular dystrophy is usually caused by in-frame deletions allowing synthesis of some functional protein. Treatment options are limited, and we are investigating the potential of transcript manipulation to overcome disease-causing mutations. Antisense oligonucleotides have been used to induce specific exon removal during processing of the dystrophin primary transcript and thereby by-pass protein-truncating mutations. The antisense oligonucleotide chemistry most widely used to alter pre-mRNA processing is 2'-O-methyl-modified bases on a phosphorothioate backbone.

METHODS

The present studies evaluate 2'-O-methylphosphorothioate, peptide nucleic acid and morpholino antisense oligonucleotides in the mdx mouse model of muscular dystrophy, which has a nonsense mutation in exon 23 of the dystrophin gene.

RESULTS

We demonstrate dystrophin expression in mdx mouse tissues after localised and systemic delivery of a morpholino antisense oligonucleotide designed to target the dystrophin exon 23 donor splice site.

CONCLUSIONS

The stability of the morpholino structural type, and the fact that it can be delivered to muscle in the absence of a delivery reagent, render this compound eminently suitable for consideration for therapeutic exon skipping to address dystrophin mutations.

Authors+Show Affiliations

Experimental Molecular Medicine Group, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Perth, Western Australia, 6097. sfletch@cyllene.uwa.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16285002

Citation

Fletcher, Susan, et al. "Dystrophin Expression in the Mdx Mouse After Localised and Systemic Administration of a Morpholino Antisense Oligonucleotide." The Journal of Gene Medicine, vol. 8, no. 2, 2006, pp. 207-16.
Fletcher S, Honeyman K, Fall AM, et al. Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide. J Gene Med. 2006;8(2):207-16.
Fletcher, S., Honeyman, K., Fall, A. M., Harding, P. L., Johnsen, R. D., & Wilton, S. D. (2006). Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide. The Journal of Gene Medicine, 8(2), 207-16.
Fletcher S, et al. Dystrophin Expression in the Mdx Mouse After Localised and Systemic Administration of a Morpholino Antisense Oligonucleotide. J Gene Med. 2006;8(2):207-16. PubMed PMID: 16285002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide. AU - Fletcher,Susan, AU - Honeyman,Kaite, AU - Fall,Abbie M, AU - Harding,Penny L, AU - Johnsen,Russell D, AU - Wilton,Steve D, PY - 2005/11/15/pubmed PY - 2006/3/25/medline PY - 2005/11/15/entrez SP - 207 EP - 16 JF - The journal of gene medicine JO - J Gene Med VL - 8 IS - 2 N2 - BACKGROUND: Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterised by an absence of functional protein, while Becker muscular dystrophy is usually caused by in-frame deletions allowing synthesis of some functional protein. Treatment options are limited, and we are investigating the potential of transcript manipulation to overcome disease-causing mutations. Antisense oligonucleotides have been used to induce specific exon removal during processing of the dystrophin primary transcript and thereby by-pass protein-truncating mutations. The antisense oligonucleotide chemistry most widely used to alter pre-mRNA processing is 2'-O-methyl-modified bases on a phosphorothioate backbone. METHODS: The present studies evaluate 2'-O-methylphosphorothioate, peptide nucleic acid and morpholino antisense oligonucleotides in the mdx mouse model of muscular dystrophy, which has a nonsense mutation in exon 23 of the dystrophin gene. RESULTS: We demonstrate dystrophin expression in mdx mouse tissues after localised and systemic delivery of a morpholino antisense oligonucleotide designed to target the dystrophin exon 23 donor splice site. CONCLUSIONS: The stability of the morpholino structural type, and the fact that it can be delivered to muscle in the absence of a delivery reagent, render this compound eminently suitable for consideration for therapeutic exon skipping to address dystrophin mutations. SN - 1099-498X UR - https://www.unboundmedicine.com/medline/citation/16285002/Dystrophin_expression_in_the_mdx_mouse_after_localised_and_systemic_administration_of_a_morpholino_antisense_oligonucleotide_ L2 - https://doi.org/10.1002/jgm.838 DB - PRIME DP - Unbound Medicine ER -