Polymer Nanoparticle-Mediated Delivery of MicroRNA Inhibition and Alternative Splicing

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• 作者：Christopher J. Cheng ; W. Mark Saltzman
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：May 7, 2012
• 年：2012
• 卷：9
• 期：5
• 页码：1481-1488
• 全文大小：409K
• 年卷期：v.9,no.5(May 7, 2012)
• ISSN：1543-8392

文摘

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.

Keywords:

gene therapy; microRNA (miRNA) inhibition; alternative splicing; poly(lactic-co-glycolic acid) (PLGA) polymer nanoparticles; peptide nucleic acids (PNA); phosphorodiamidate morpholinos (PMO)