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Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers.
Mol Ther. 2006 Jul; 14(1):88-96.MT

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 Mw PEI2000(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 PEI25000(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 Mw 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.

Authors+Show Affiliations

Department of Pharmacology and Physiology, Drexel University College of Medicine, Mailstop 488, NCB 8302, Philadelphia, PA 19102, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16488666

Citation

Williams, Jason H., et al. "Induction of Dystrophin Expression By Exon Skipping in Mdx Mice Following Intramuscular Injection of Antisense Oligonucleotides Complexed With PEG-PEI Copolymers." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 14, no. 1, 2006, pp. 88-96.
Williams JH, Sirsi SR, Latta DR, et al. Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. Mol Ther. 2006;14(1):88-96.
Williams, J. H., Sirsi, S. R., Latta, D. R., & Lutz, G. J. (2006). Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. Molecular Therapy : the Journal of the American Society of Gene Therapy, 14(1), 88-96.
Williams JH, et al. Induction of Dystrophin Expression By Exon Skipping in Mdx Mice Following Intramuscular Injection of Antisense Oligonucleotides Complexed With PEG-PEI Copolymers. Mol Ther. 2006;14(1):88-96. PubMed PMID: 16488666.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. AU - Williams,Jason H, AU - Sirsi,Shashank R, AU - Latta,Daniel R, AU - Lutz,Gordon J, Y1 - 2006/02/20/ PY - 2005/07/29/received PY - 2005/11/19/revised PY - 2005/11/25/accepted PY - 2006/2/21/pubmed PY - 2006/9/6/medline PY - 2006/2/21/entrez SP - 88 EP - 96 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol Ther VL - 14 IS - 1 N2 - 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 Mw PEI2000(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 PEI25000(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 Mw 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. SN - 1525-0016 UR - https://www.unboundmedicine.com/medline/citation/16488666/Induction_of_dystrophin_expression_by_exon_skipping_in_mdx_mice_following_intramuscular_injection_of_antisense_oligonucleotides_complexed_with_PEG_PEI_copolymers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(06)00010-4 DB - PRIME DP - Unbound Medicine ER -