Archive des Bibliothèques universitaires de Nantes

Development of rAAV-mediated gene addition therapies in canine models of severe inherited photoreceptor dystrophies

Par : Monnier-Petit, Lolita

Document archivé le : 04/05/2015

Inherited retinal dystrophies are untreatable blinding disorders caused by mutations in genes expressed in photoreceptors or in retinal pigment epithelium (RPE). Over the last decade, gene addition therapy has been used successfully in different animal models of recessive inherited retinopathies. These studies have paved the way to several clinical trials for RPE diseases with encouraging results. The next level of challenge is to initiate treatment of the majority of disorders that primarily involve photoreceptor cells. For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. It is particularly true for primary photoreceptor dystrophies because the distribution, density and proportion of photoreceptors in large models more closely match those of primates. Here, we evaluated the efficacy of gene addition therapy in two canine models of severe photoreceptor dystrophies: (i) the Pde6β-/- dog, a model of rod-cone dystrophy caused by a defect in rods and (ii) the Rpgrip1-/- dog, a model of cone-rod dystrophy caused by a defect in both rods and cones. Using vectors derived from adeno-associated virus, we showed that it is possible to restore retinal function, preserve photoreceptor structure and visually guided behavior in the two canine models, for at least 24 months postinjection. The efficacy of gene addition therapy in these large animal models of photoreceptor dystrophies provides great promise for human treatment. 14NANT06-VS

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