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Mol Ther. 2014 Feb;22(2):265-277. doi: 10.1038/mt.2013.232. Epub 2013 Oct 4.

Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.

Author information

1
INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
2
CHU-Hôtel Dieu, Service d'Ophtalmologie, Nantes, France.
3
ONIRIS, Nantes-Atlantic College of Veterinary Medicine Food Science and Engineering, Emergency and Critical Care Unit, Nantes, France.
4
CNRS UMR 6061, Université de Rennes 1, Rennes, France.
5
Clinique Vétérinaire Atlantia, Nantes, France.
6
Institut Pasteur, INSERM UMRS 1120, Paris, France.
7
INRA/ONIRIS, Nantes-Atlantic College of Veterinary Medicine Food Science and Engineering, Nantes, France.
8
INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France; Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
9
INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France. Electronic address: fabienne.rolling@inserm.fr.

Abstract

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. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.

PMID:
24091916
PMCID:
PMC3918913
DOI:
10.1038/mt.2013.232
[Indexed for MEDLINE]
Free PMC Article

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