Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_B54F8E1C9922
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis.
Périodique
PLoS Medicine
Auteur(s)
Bemelmans A.P., Kostic C., Crippa S.V., Hauswirth W.W., Lem J., Munier F.L., Seeliger M.W., Wenzel A., Arsenijevic Y.
ISSN
1549-1676
Statut éditorial
Publié
Date de publication
2006
Peer-reviewed
Oui
Volume
3
Numéro
10
Pages
e347
Langue
anglais
Notes
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Oct
Résumé
BACKGROUND: RPE65 is specifically expressed in the retinal pigment epithelium and is essential for the recycling of 11-cis-retinal, the chromophore of rod and cone opsins. In humans, mutations in RPE65 lead to Leber congenital amaurosis or early-onset retinal dystrophy, a severe form of retinitis pigmentosa. The proof of feasibility of gene therapy for RPE65 deficiency has already been established in a dog model of Leber congenital amaurosis, but rescue of the cone function, although crucial for human high-acuity vision, has never been strictly proven. In Rpe65 knockout mice, photoreceptors show a drastically reduced light sensitivity and are subject to degeneration, the cone photoreceptors being lost at early stages of the disease. In the present study, we address the question of whether application of a lentiviral vector expressing the Rpe65 mouse cDNA prevents cone degeneration and restores cone function in Rpe65 knockout mice. METHODS AND FINDINGS: Subretinal injection of the vector in Rpe65-deficient mice led to sustained expression of Rpe65 in the retinal pigment epithelium. Electroretinogram recordings showed that Rpe65 gene transfer restored retinal function to a near-normal pattern. We performed histological analyses using cone-specific markers and demonstrated that Rpe65 gene transfer completely prevented cone degeneration until at least four months, an age at which almost all cones have degenerated in the untreated Rpe65-deficient mouse. We established an algorithm that allows prediction of the cone-rescue area as a function of transgene expression, which should be a useful tool for future clinical trials. Finally, in mice deficient for both RPE65 and rod transducin, Rpe65 gene transfer restored cone function when applied at an early stage of the disease. CONCLUSIONS: By demonstrating that lentivirus-mediated Rpe65 gene transfer protects and restores the function of cones in the Rpe65(-/-) mouse, this study reinforces the therapeutic value of gene therapy for RPE65 deficiencies, suggests a cone-preserving treatment for the retina, and evaluates a potentially effective viral vector for this purpose.
Mots-clé
Animals, Carrier Proteins, Disease Models, Animal, Electroretinography, Eye Proteins, GTP-Binding Protein alpha Subunits, Gene Transfer Techniques, Genetic Vectors, Heterotrimeric GTP-Binding Proteins, Lentivirus, Mice, Mice, Knockout, Molecular Sequence Data, Pigment Epithelium of Eye, Retina, Retinal Cone Photoreceptor Cells, Retinitis Pigmentosa, Rod Opsins, Time Factors, Transducin
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/01/2008 12:53
Dernière modification de la notice
20/08/2019 15:23
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