title: Polymer nanoparticle-mediated delivery of microRNA inhibition and alternative splicing.
abstract: The crux of current RNA-based therapeutics relies on association of synthetic nucleic acids with cellular RNA targets. Antisense oligonucleotide binding to mature microRNA and splicing junctions on pre-mRNA represent methods of gene therapy that respectively inhibit microRNA-mediated gene regulation and induce alternative splicing. We have developed biodegradable polymer nanoparticles, which are coated with cell-penetrating peptides, that can effectively deliver chemically modified oligonucleotide analogues to achieve these forms of gene regulation. We found that this nanoparticle system could block the activity of the oncogenic microRNA, miR-155, as well as modulate splicing to attenuate the expression of the proto-oncogene, Mcl-1. Regulation of these genes in human cancer cells reduced cell viability and produced pro-apoptotic effects. These findings establish polymer nanoparticles as delivery vectors for nonconventional forms of gene therapy activated by cellular delivery of RNA-targeted molecules, which have strong therapeutic implications.
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 414, New Haven, Connecticut 06511, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cheng
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009025:Morpholines; D053758:Nanoparticles / Q000737:chemistry*; D020135:Peptide Nucleic Acids; D011108:Polymers / Q000737:chemistry*; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000715470:MAS1 protein, human; D035683:MicroRNAs; D009025:Morpholines; D020135:Peptide Nucleic Acids; D011108:Polymers; D000090063:Proto-Oncogene Mas