title: Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa.
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.
authors.affiliation: Department of Genetics, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
authors.forename: Sophia
authors.initials: S
authors.lastname: Millington-Ward
authors.forename: Naomi
authors.initials: N
authors.lastname: Chadderton
authors.forename: Mary
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Arpad
authors.initials: A
authors.lastname: Palfi
authors.forename: Tobias
authors.initials: T
authors.lastname: Goldmann
authors.forename: Claire
authors.initials: C
authors.lastname: Kilty
authors.forename: Marian
authors.initials: M
authors.lastname: Humphries
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kenna
authors.forename: G Jane
authors.initials: GJ
authors.lastname: Farrar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012174:Retinitis Pigmentosa / Q000628:therapy*