Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates
In: Transl Res ; https://hal.science/hal-02880996 ; Transl Res, 2017, 188, pp.40-57 e4. ⟨10.1016/j.trsl.2017.06.012⟩, 2017
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Zugriff:
International audience ; 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.
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Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates
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Autor/in / Beteiligte Person: | 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. ; Department of Ophthalmology ; Université de Lausanne = University of Lausanne (UNIL) ; Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN) ; Molecular Imaging Research Center Fontenay-aux-Roses (MIRCEN) ; Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) ; Service de Radiologie et Imagerie Médicale CHU Limoges ; Limoges, CHU ; Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE) ; École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon ; UMR649 ; Institut National de la Santé et de la Recherche Médicale (INSERM) ; Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes) ; Centre de Recherche des Cordeliers (CRC) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
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Zeitschrift: | Transl Res ; https://hal.science/hal-02880996 ; Transl Res, 2017, 188, pp.40-57 e4. ⟨10.1016/j.trsl.2017.06.012⟩, 2017 |
Veröffentlichung: | HAL CCSD, 2017 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.trsl.2017.06.012 |
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