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Journal article
Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers
Molecular therapy, v 14(1)
01 Jul 2006
PMID: 16488666
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Antisense oligonucleotides (AOs) with 2-O-methyl modifications can circumvent dystrophin mutations via exon skipping and, it is hoped, can become drugs for treatment of Duchenne muscular dystrophy (DMD). However, AO-based approaches are hindered by a lack of effective carriers to facilitate delivery of AOs to myonuclei. We examined whether copolymers composed of cationic poly(ethylene imine) (PEI) and polyethylene glycol (PEG) can enhance AO transfection in skeletal muscle of mdx mice. Single intramuscular injections of AO complexed with low M-w PE12000(PEG550) copolymers into TA muscles of mdx mice resulted in widespread distribution of dystrophin-positive fibers at 3 weeks after injection, with no apparent cytotoxicity. Overall, injections of these low MW polyplexes, which formed 250-nm aggregate particles, resulted in about sixfold more dystrophin-positive fibers than AO alone. Western analysis confirmed the dystrophin expression in these muscles. Surprisingly, injections of AO complexed with high MW PE125000(PEG5000) copolymers, which formed smaller nonaggregated particles, produced about threefold fewer dystrophin-positive fibers than injections of the low MW polyplexes. We conclude that low M-w PEI2000(PEG550) copolymers function as high-capacity, nontoxic AO carriers suitable for in vivo transfection of skeletal muscle and are promising compounds for potential use in molecular therapy of DMD.
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Details
- Title
- Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers
- Creators
- Jason H. Williams - Drexel UniversityShashank R. Sirsi - Drexel UniversityDaniel R. Latta - Drexel UniversityGordon J. Lutz - Drexel University
- Publication Details
- Molecular therapy, v 14(1)
- Publisher
- Elsevier
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000238805400014
- Scopus ID
- 2-s2.0-33745289016
- Other Identifier
- 991019169009204721
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- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental