Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.

Details

Ressource 1Download: 28754419.pdf (4196.32 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_BA0EF611C7C2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.
Journal
Translational research
Author(s)
Matet A., Kostic C., Bemelmans A.P., Moulin A., Rosolen S.G., Martin S., Mavilio F., Amirjanians V., Stieger K., Lorenz B., Behar-Cohen F., Arsenijevic Y.
ISSN
1878-1810 (Electronic)
ISSN-L
1878-1810
Publication state
Published
Issued date
10/2017
Peer-reviewed
Oui
Volume
188
Pages
40-57.e4
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event.

Keywords
Animals, Eye Proteins/administration & dosage, Female, Gene Transfer Techniques, Genetic Vectors/administration & dosage, Genetic Vectors/adverse effects, Lentivirus/genetics, Macaca fascicularis, Receptors, G-Protein-Coupled/administration & dosage, Retina
Pubmed
Web of science
Open Access
Yes
Create date
08/08/2017 12:00
Last modification date
20/08/2019 15:28
Usage data