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dc.contributor.authorFARRAR, JANEen
dc.contributor.authorHUMPHRIES, MARIANen
dc.contributor.authorHUMPHRIES, PETERen
dc.contributor.authorCAMPBELL, MATTHEWen
dc.date.accessioned2010-04-07T13:57:22Z
dc.date.available2010-04-07T13:57:22Z
dc.date.issued2008en
dc.date.submitted2008en
dc.identifier.citationTam, LC, Kiang, AS, Kennan, A, Kenna, PF, Chadderton, N, Ader, M, Palfi, A, Aherne, A, Ayuso, C, Campbell, M, Reynolds, A, McKee, A, Humphries, MM, Farrar, GJ, Humphries, P, Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10)., Human Molecular Genetics, 17, 14, 2008, 2084-2100en
dc.identifier.issn0964-6906en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/38880
dc.descriptionPUBLISHEDen
dc.description.abstractMutations within the inosine 5'-monophosphate dehydrogenase 1 (IMPDH1) gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death of photoreceptors. Apart from the prevalence of RP10, estimated to account for 5?10% of cases of adRP in United States and Europe, two observations render this form of RP an attractive target for gene therapy. First, we show that while recombinant adeno-associated viral (AAV)-mediated expression of mutant human IMPDH1 protein in the mouse retina results in an aggressive retinopathy modelling the human counterpart, expression of a normal human IMPDH1 gene under similar conditions has no observable pathological effect on retinal function, indicating that over-expression of a therapeutic replacement gene may be relatively well tolerated. Secondly, complete absence of IMPDH1 protein in mice with a targeted disruption of the gene results in relatively mild retinal dysfunction, suggesting that significant therapeutic benefit may be derived even from the suppression-only component of an RNAi-based gene therapy. We show that AAV-mediated co-expression in the murine retina of a mutant human IMPDH1 gene together with short hairpin RNAs (shRNA) validated in vitro and in vivo, targeting both human and mouse IMPDH1, substantially suppresses the negative pathological effects of mutant IMPDH1, at a point where, in the absence of shRNA, expression of mutant protein in the RP10 model essentially ablates all photoreceptors in transfected areas of the retina. These data strongly suggest that an RNAi-mediated approach to therapy for RP10 holds considerable promise for human subjects.en
dc.format.extent2084-2100en
dc.language.isoenen
dc.relation.ispartofseriesHuman Molecular Geneticsen
dc.relation.ispartofseries17en
dc.relation.ispartofseries14en
dc.rightsYen
dc.subjectGenetics
dc.titleTherapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10).en
dc.typeJournal Articleen
dc.contributor.sponsorScience Foundation Ireland (SFI)en
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/phumphrsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/gjfarraren
dc.identifier.peoplefinderurlhttp://people.tcd.ie/mhumphrien
dc.identifier.peoplefinderurlhttp://people.tcd.ie/campbem2en
dc.identifier.rssinternalid58207en
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddn107en
dc.identifier.rssurihttp://dx.doi.org/10.1093/hmg/ddn107en


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