Titre
Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Matet, A.
Auteure/Auteur
Kostic, C.
Auteure/Auteur
Bemelmans, A.P.
Auteure/Auteur
Moulin, A.
Auteure/Auteur
Rosolen, S.G.
Auteure/Auteur
Martin, S.
Auteure/Auteur
Mavilio, F.
Auteure/Auteur
Amirjanians, V.
Auteure/Auteur
Stieger, K.
Auteure/Auteur
Lorenz, B.
Auteure/Auteur
Behar-Cohen, F.
Auteure/Auteur
Arsenijevic, Y.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1878-1810
Statut éditorial
Publié
Date de publication
2017-10
Volume
188
Première page
40
Dernière page/numéro d’article
57.e4
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
PID Serval
serval:BIB_BA0EF611C7C2
PMID
Open Access
Oui
Date de création
2017-08-08T11:00:46.338Z
Date de création dans IRIS
2025-05-20T22:44:10Z
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Nom
28754419.pdf
Version du manuscrit
published
Taille
4.1 MB
Format
Adobe PDF
PID Serval
serval:BIB_BA0EF611C7C2.P001
URN
urn:nbn:ch:serval-BIB_BA0EF611C7C28
Somme de contrôle
(MD5):4b123b96e0b8d14b8db9aadade38242a