Abstract |
Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.
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Authors | Lolita Petit, Elsa Lhériteau, Michel Weber, Guylène Le Meur, Jack-Yves Deschamps, Nathalie Provost, Alexandra Mendes-Madeira, Lyse Libeau, Caroline Guihal, Marie-Anne Colle, Philippe Moullier, Fabienne Rolling |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 20
Issue 11
Pg. 2019-30
(Nov 2012)
ISSN: 1525-0024 [Electronic] United States |
PMID | 22828504
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Messenger
- Cyclic Nucleotide Phosphodiesterases, Type 6
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Topics |
- Animals
- Cyclic Nucleotide Phosphodiesterases, Type 6
(deficiency, genetics)
- Dependovirus
(genetics)
- Disease Models, Animal
- Dogs
- Electroretinography
- Genetic Therapy
- Genetic Vectors
- Humans
- RNA, Messenger
(genetics, metabolism)
- Recovery of Function
- Retina
(metabolism, pathology, physiopathology)
- Retinal Vessels
(pathology)
- Retinitis Pigmentosa
(physiopathology, therapy)
- Reverse Transcriptase Polymerase Chain Reaction
- Transgenes
- Treatment Outcome
- Vision, Ocular
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