Journal article
Functionalized PEG-PEI copolymers complexed to exon-skipping oligonucleotides improve dystrophin expression in mdx mice
Human gene therapy, v 19(8), pp 795-806
01 Aug 2008
PMID: 18647087
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Exon-skipping oligonucleotides (ESOs) with 2'-O-methyl modifications are promising compounds for the treatment of Duchenne muscular dystrophy (DMD). However, the usefulness of these compounds is limited by their poor delivery profile to muscle tissue in vivo. We previously established that copolymers made of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) enhanced ESO transfection in skeletal muscle of mdx mice, resulting in widespread distribution of dystrophin-positive fibers, but limited dystrophin expression by Western blot. In an attempt to improve ESO delivery and dystrophin expression, a new formulation of PEG-PEI copolymer was used, along with functionalized derivatives containing either the cell-penetrating peptide TAT (trans-activator of transcription), adsorbed colloidal gold (CG), or both TAT and CG. Tibialis anterior muscles were given three intramuscular injections of various PEG-PEI-ESO polyplexes (3 days apart; 5 mu g of ESO per injection) and muscles were harvested 3 weeks after the first injection. Surface modifications of PEG-PEI copolymers with TAT showed the highest level of dystrophin recovery, with a 6-fold increase in dystrophin-positive fibers compared with ESO alone and up to 30% of normal dystrophin expression by Western blot. The adsorption of CG to either PEG-PEI or TAT-PEG-PEI copolymers showed no further improvement in dystrophin expression. Our data indicate that TAT-modified PEG-PEI copolymers are effective carriers for delivery of ESOs to skeletal muscle and are promising compounds for the therapeutic treatment of DMD.
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Details
- Title
- Functionalized PEG-PEI copolymers complexed to exon-skipping oligonucleotides improve dystrophin expression in mdx mice
- Creators
- Shashank R. Sirsi - Drexel UniversityRebecca C. Schray - Drexel UniversityXiangying Guan - Drexel UniversityNicole M. Lykens - Drexel UniversityJason H. Williams - Drexel UniversityMichelle L. Erney - Drexel UniversityGordon J. Lutz - Drexel University
- Publication Details
- Human gene therapy, v 19(8), pp 795-806
- Publisher
- Mary Ann Liebert, Inc
- Number of pages
- 12
- Grant note
- Muscular Dystrophy Association
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000259034300004
- Scopus ID
- 2-s2.0-50649089185
- Other Identifier
- 991019168204104721
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- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental