title: Cationic polyelectrolyte-mediated delivery of antisense morpholino oligonucleotides for exon-skipping in vitro and in mdx mice.
abstract: In this study, we investigated a series of cationic polyelectrolytes (PEs) with different size and composition for their potential to improve delivery of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that the poly(diallyldimethylammonium chloride) (PDDAC) polymer series, especially PE-3 and PE-4, improves the delivery efficiency of PMO, comparable with Endoporter-mediated PMO delivery in vitro. The enhanced PMO delivery and targeting to dystrophin exon 23 was further observed in mdx mice, up to fourfold with the PE-4, compared with PMO alone. The cytotoxicity of the PEs was lower than that of Endoporter and polyethylenimine 25,000 Da in vitro, and was not clearly detected in muscle in vivo under the tested concentrations. Together, these results demonstrate that optimization of PE molecular size, composition, and distribution of cationic charge are key factors to achieve enhanced PMO exon-skipping efficiency. The increased efficiency and lower toxicity show this PDDAC series to be capable gene/antisense oligonucleotide delivery-enhancing agents for treating muscular dystrophy and other diseases.
authors.affiliation: Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Tucker
authors.affiliation: Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Peijuan
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Neurology, McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D016189:Dystrophin / Q000737:chemistry / Q000187:drug effects; D004566:Electrodes; D005091:Exons; D018014:Gene Transfer Techniques; D051379:Mice; D018101:Mice, Inbred mdx; D046529:Microscopy, Electron, Transmission; D060172:Morpholinos / Q000737:chemistry* / Q000494:pharmacology; D009136:Muscular Dystrophies / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D000071228:Polyelectrolytes; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016189:Dystrophin; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D011073:Polyamines; D000071228:Polyelectrolytes; D011094:Polyethyleneimine
keywords: PMO; antisense delivery; cationic polyelectrolytes; exon-skipping; muscular dystrophy