Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Georgiadis, A; Tschernutter, M; Bainbridge, JW; Robbie, SJ; McIntosh, J; Nathwani, AC; Smith, AJ; Ali, RR.
AAV-mediated knockdown of peripherin-2 in vivo using miRNA-based hairpins.
Gene Ther. 2010; 17(4): 486-493.
Doi: 10.1038/gt.2009.162
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- Co-Autor*innen der Med Uni Graz
- Tschernutter Marion
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- Abstract:
- Gene therapy for inherited retinal degeneration in which expression of a mutant allele has a gain-of-function effect on photoreceptor cells is likely to depend on efficient silencing of the mutated allele. Peripherin-2 (Prph2, also known as peripherin/RDS) is an abundantly expressed photoreceptor-specific gene. In humans, gain-of-function mutations in PRPH2 result in both autosomal dominant retinitis pigmentosa and dominant maculopathies. Gene-silencing strategies for these conditions include RNA interference by short hairpin RNAs (shRNAs). Recent evidence suggests that microRNA (miRNA)-based hairpins may offer a safer and more effective alternative. In this study, we used for the first time a virally transferred miRNA-based hairpin to silence Prph2 in the murine retina. The results show that an miRNA-based shRNA can efficiently and specifically silence Prph2 in vivo as early as 3 weeks after AAV2/8-mediated subretinal delivery, leading to a nearly 50% reduction of photoreceptor cells after 5 weeks. We conclude that miRNA-based hairpins can achieve rapid and robust gene silencing after efficient vector-mediated delivery to the retina. The rationale of using an miRNA-based template to improve the silencing efficiency of a hairpin may prove valuable for allele-specific silencing in which the choice for an RNAi target is limited and offers an alternative therapeutic strategy for the treatment of dominant retinopathies.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Base Pairing -
- Base Sequence -
- Blotting, Western -
- DNA Primers - genetics
- Dependovirus -
- Genetic Therapy - methods
- Immunohistochemistry -
- Intermediate Filament Proteins - genetics
- Membrane Glycoproteins - genetics
- Mice -
- MicroRNAs - genetics
- Molecular Sequence Data -
- Nerve Tissue Proteins - genetics
- Peripherins -
- RNA Interference -
- Retinal Degeneration - genetics Retinal Degeneration - therapy
- Reverse Transcriptase Polymerase Chain Reaction -
- Find related publications in this database (Keywords)
- RNAi
- Prph2
- AAV
- miRNA
- rds
- retinal degeneration