Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa
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Sophia Millington-Ward, Naomi Chadderton, Mary O'Reilly, Arpad Palfi, Tobias Goldmann, Claire Kilty, Marian Humphries, Uwe Wolfrum, Jean Bennett, Peter Humphries, Paul F Kenna and G Jane Farrar, Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa, Molecular Therapy, 2011Download Item:
Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa.pdf (Published (publisher's copy) - Peer Reviewed) 1.947Mb
Abstract:
For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect in a mutation-independent manner thereby circumventing the mutational diversity. Separate adeno-associated virus (AAV) vectors were used to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. Viruses were subretinally coinjected into P347S mice, a model of dominant rhodopsin-linked retinitis pigmentosa. Benefit in retinal function and structure detected by electroretinography (ERG) and histology, respectively, was observed for at least 5 months. Notably, the photoreceptor cell layer, absent in 5-month-old untreated retinas, contained 3?4 layers of nuclei, whereas photoreceptor ultrastructure, assessed by transmission electron microscopy (TEM) improved significantly. The study provides compelling evidence that codelivered suppression and replacement is beneficial, representing a significant step toward the clinic. Additionally, dual-vector delivery of combined therapeutics represents an exciting approach, which is potentially applicable to other inherited disorders.
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Enterprise Ireland
Science Foundation Ireland (SFI)
Irish Research Council for Humanities and Social Sciences (IRCHSS)
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http://people.tcd.ie/phumphrshttp://people.tcd.ie/oreillym
http://people.tcd.ie/millins
http://people.tcd.ie/gjfarrar
http://people.tcd.ie/mhumphri
http://people.tcd.ie/palfia
http://people.tcd.ie/chaddern
http://people.tcd.ie/pfkenna
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Author: MILLINGTON-WARD, SOPHIA; O'REILLY, MARY; PALFI, ARPAD; KILTY, CLAIRE; HUMPHRIES, MARIAN; KENNA, PAUL; FARRAR, JANE; HUMPHRIES, PETER; CHADDERTON, NAOMI
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Molecular TherapyAvailability:
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Genetics, Retinitis PigmentosaSubject (TCD):
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