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Intracellular Deliv...
Intracellular Delivery of Short Interfering RNA in Rat Organ of Corti Using a Cell-penetrating Peptide PepFect6
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- Dash-Wagh, Suvarna (author)
- Karolinska Institutet,Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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- Jacob, Stefan (author)
- Karolinska Institutet,Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
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- Lindberg, Staffan (author)
- Stockholms universitet,Institutionen för neurokemi,Department of Neurochemistry, Stockholm University, Stockholm, Sweden
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- Fridberger, Anders, 1966- (author)
- Karolinska Institutet,Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
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- Langel, Ülo (author)
- Stockholms universitet,Institutionen för neurokemi,Department of Neurochemistry, Stockholm University, Stockholm, Sweden
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- Ulfendahl, Mats (author)
- Karolinska Institutet,Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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(creator_code:org_t)
- Elsevier BV, 2012
- 2012
- English.
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In: Molecular Therapy Nucleic Acids. - : Elsevier BV. - 2162-2531. ; 1:e61
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- cell-penetrating peptide (CPP)
- cochlea
- connexin
- FRAP
- gap junctions
- gene therapy
- inner ear
- nanoparticles
- siRNA
- neurokemi med molekylär neurobiologi
- Neurochemistry with Molecular Neurobiology
Publication and Content Type
- ref (subject category)
- art (subject category)
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