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Intracellular Delivery of Short Interfering RNA in Rat Organ of Corti Using a Cell-penetrating Peptide PepFect6
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-7746-8574
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2012 (English)In: Molecular Therapy - Nucleic Acids, ISSN 2162-2531, Vol. 1, e61- p.Article 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.

Place, publisher, year, edition, pages
2012. Vol. 1, e61- p.
Keyword [en]
cell-penetrating peptide (CPP), cochlea, connexin, FRAP, gap junctions, gene therapy, inner ear, nanoparticles, siRNA
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
URN: urn:nbn:se:su:diva-84941DOI: 10.1038/mtna.2012.50PubMedID: 23232329OAI: diva2:582051
Swedish Research CouncilSwedish Foundation for Strategic Research Swedish Cancer Society
Available from: 2013-01-03 Created: 2013-01-03 Last updated: 2015-04-23Bibliographically approved

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Lindberg, StaffanLangel, Ülo
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