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Intracellular Delivery of Short Interfering RNA in Rat Organ of Corti Using a Cell-penetrating Peptide PepFect6
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
Department of Neurochemistry, Stockholm University, Stockholm, Sweden.
Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
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2012 (English)In: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, E-ISSN 2162-2531, Vol. 1Article in journal (Refereed) Published
Abstract [en]

RNA interference (RNAi) using short interfering RNA (siRNA) is an attractive therapeutic approach for treatment of dominant-negative mutations. Some rare missense dominant-negative mutations lead to congenital-hearing impairments. A variety of viral vectors have been tested with variable efficacy for modulating gene expression in inner ear. However, there is concern regarding their safety for clinical use. Here, we report a novel cell-penetrating peptide (CPP)-based nonviral approach for delivering siRNA into inner ear tissue using organotypic cultures as model system. PepFect6 (PF6), a variant of stearyl-TP10, was specially designed for improved delivery of siRNA by facilitating endosomal release. We show that PF6 was internalized by all cells without inducing cytotoxicity in cochlear cultures. PF6/siRNA nanoparticles lead to knockdown of target genes, a housekeeping gene and supporting cell-specific connexin 26. Interestingly, application of PF6/connexin 26 siRNA exhibited knockdown of both connexin 26 and 30 mRNA and their absence led to impaired intercellular communication as demonstrated by reduced transfer of calcein among the PF6/connexin 26-siRNA-treated cells. Thus, we conclude that PF6 is an efficient nonviral vector for delivery of siRNA, which can be applied as a tool for the development of siRNA-based therapeutic applications for hearing impairments.Molecular Therapy - Nucleic Acids (2012) 1, e61; doi:10.1038/mtna.2012.50; published online 11 December 2012.

Place, publisher, year, edition, pages
Nature Publishing Group, 2012. Vol. 1
Keyword [en]
cell-penetrating peptide (CPP); cochlea; connexin; FRAP; gap junctions; gene therapy; inner ear; nanoparticles; siRNA
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URN: urn:nbn:se:liu:diva-101047DOI: 10.1038/mtna.2012.50ISI: 000208876500004PubMedID: 23232329OAI: diva2:665173
Available from: 2013-11-19 Created: 2013-11-19 Last updated: 2015-11-18

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