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AAV-mediated knockdown of peripherin-2 in vivo using miRNA-based hairpins

Georgiadis, A; Tschernutter, M; Bainbridge, JW; Robbie, SJ; McIntosh, J; Nathwani, AC; Smith, AJ; (2010) AAV-mediated knockdown of peripherin-2 in vivo using miRNA-based hairpins. Gene Ther. , 17 (4) pp. 486-493. 10.1038/gt.2009.162.

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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

Type: Article
Title: AAV-mediated knockdown of peripherin-2 in vivo using miRNA-based hairpins
DOI: 10.1038/gt.2009.162
Additional information: DA - 20100408 IS - 1476-5462 (Electronic) IS - 0969-7128 (Linking) LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't RN - 0 (DNA Primers) RN - 0 (Intermediate Filament Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (MicroRNAs) RN - 0 (Nerve Tissue Proteins) RN - 0 (peripherin) SB - IM
Keywords: Animals, Base Pairing, Base Sequence, Blotting,Western, Dependovirus, DNA Primers, Gene Therapy, genetics, Humans, Immunohistochemistry, Intermediate Filament Proteins, Membrane Glycoproteins, methods, Mice, MicroRNAs, Molecular Sequence Data, Nerve Tissue Proteins, Retinal Degeneration, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, therapy
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1330956
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