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- W2730366947 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. 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. Matet et al. 2017At a Glance CommentaryBackgroundLeber congenital amaurosis, a severe and early-onset form of retinitis pigmentosa is historically the first eye disease to benefit from gene therapy, with several groups worldwide developing AAV-based gene replacement approaches for RPE65, one of the causative genes. However, some clinical trials showed limited safety and only partial recovery which could be linked to the subretinal surgical route, or to subtherapeutic protein levels. Simultaneously, our group has developed a HIV-1–derived lentivirus-based strategy (LV-RPE65), using the high transduction capability of this vector to target epithelia such as the retinal pigment epithelium, which expresses the RPE65 enzyme. LV-RPE65 can restore photoreceptor integrity and function, as previously demonstrated by our group in 2 rodent models of RPE65 deficiency. In this study, we have pursued the translational development of LV-RPE65, to evaluate the ocular and systemic tolerance to LV-RPE65 after subretinal injection in 5 nonhuman primates without antiinflammatory prophylaxis.Translational SignificanceIn the present study, the absence of systemic LV-RPE65 vector particle shedding after subretinal injection in body fluids, or of vector genome integration in various organs is promising for the ocular use of lentiviral vector. Nevertheless, a transient perivascular retinal reaction occurred at very early stages (2 days) following vector administration, and a thinning of the photoreceptor layer at the macula level was observed in all groups, including vehicle-treated animals. No other major ocular adverse event was recorded, except in one eye that inadvertently received intraocular doses due to a leak into the vitreous cavity. Importantly, we were not able to find any other preclinical study in the literature reporting ocular and retinal monitoring at early time points after subretinal gene therapy administration. Our report is thus the first to give insight into these early events and may contribute to elucidate several limitations of the subretinal route approach. These observations contribute to optimizing the translational process of retinal gene therapy, from both the surgical and the gene transfer perspectives, and highlight the necessity to improve lentiviral vector tolerance by antiinflammatory pretreatment. Leber congenital amaurosis, a severe and early-onset form of retinitis pigmentosa is historically the first eye disease to benefit from gene therapy, with several groups worldwide developing AAV-based gene replacement approaches for RPE65, one of the causative genes. However, some clinical trials showed limited safety and only partial recovery which could be linked to the subretinal surgical route, or to subtherapeutic protein levels. Simultaneously, our group has developed a HIV-1–derived lentivirus-based strategy (LV-RPE65), using the high transduction capability of this vector to target epithelia such as the retinal pigment epithelium, which expresses the RPE65 enzyme. LV-RPE65 can restore photoreceptor integrity and function, as previously demonstrated by our group in 2 rodent models of RPE65 deficiency. In this study, we have pursued the translational development of LV-RPE65, to evaluate the ocular and systemic tolerance to LV-RPE65 after subretinal injection in 5 nonhuman primates without antiinflammatory prophylaxis. In the present study, the absence of systemic LV-RPE65 vector particle shedding after subretinal injection in body fluids, or of vector genome integration in various organs is promising for the ocular use of lentiviral vector. Nevertheless, a transient perivascular retinal reaction occurred at very early stages (2 days) following vector administration, and a thinning of the photoreceptor layer at the macula level was observed in all groups, including vehicle-treated animals. No other major ocular adverse event was recorded, except in one eye that inadvertently received intraocular doses due to a leak into the vitreous cavity. Importantly, we were not able to find any other preclinical study in the literature reporting ocular and retinal monitoring at early time points after subretinal gene therapy administration. Our report is thus the first to give insight into these early events and may contribute to elucidate several limitations of the subretinal route approach. These observations contribute to optimizing the translational process of retinal gene therapy, from both the surgical and the gene transfer perspectives, and highlight the necessity to improve lentiviral vector tolerance by antiinflammatory pretreatment." @default.
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- W2730366947 date "2017-10-01" @default.
- W2730366947 modified "2023-10-18" @default.
- W2730366947 title "Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates" @default.
- W2730366947 cites W1587435244 @default.
- W2730366947 cites W1966666501 @default.
- W2730366947 cites W1970654757 @default.
- W2730366947 cites W1972583115 @default.
- W2730366947 cites W1976599692 @default.
- W2730366947 cites W1983421509 @default.
- W2730366947 cites W1987960089 @default.
- W2730366947 cites W1991157268 @default.
- W2730366947 cites W1992009563 @default.
- W2730366947 cites W1995140705 @default.
- W2730366947 cites W1995813245 @default.
- W2730366947 cites W1996875707 @default.
- W2730366947 cites W1998460907 @default.
- W2730366947 cites W2001880844 @default.
- W2730366947 cites W2008512248 @default.
- W2730366947 cites W2019718689 @default.
- W2730366947 cites W2023339971 @default.
- W2730366947 cites W2023962213 @default.
- W2730366947 cites W2025037460 @default.
- W2730366947 cites W2031303778 @default.
- W2730366947 cites W2035101755 @default.
- W2730366947 cites W2035534672 @default.
- W2730366947 cites W2036952474 @default.
- W2730366947 cites W2042328038 @default.
- W2730366947 cites W2045387396 @default.
- W2730366947 cites W2047747556 @default.
- W2730366947 cites W2048251169 @default.
- W2730366947 cites W2050774731 @default.
- W2730366947 cites W2054158396 @default.
- W2730366947 cites W2064199560 @default.
- W2730366947 cites W2069494011 @default.
- W2730366947 cites W2070726099 @default.
- W2730366947 cites W2077204087 @default.
- W2730366947 cites W2081023310 @default.
- W2730366947 cites W2081764664 @default.
- W2730366947 cites W2081826673 @default.
- W2730366947 cites W2086498377 @default.
- W2730366947 cites W2093664801 @default.
- W2730366947 cites W2102131183 @default.
- W2730366947 cites W2114830150 @default.
- W2730366947 cites W2123640323 @default.
- W2730366947 cites W2137222303 @default.
- W2730366947 cites W2140092254 @default.
- W2730366947 cites W2141575938 @default.
- W2730366947 cites W2147540865 @default.
- W2730366947 cites W2151235295 @default.
- W2730366947 cites W2151809142 @default.
- W2730366947 cites W2152853777 @default.
- W2730366947 cites W2160294802 @default.
- W2730366947 cites W2162290849 @default.
- W2730366947 cites W2167845957 @default.
- W2730366947 cites W2175546026 @default.
- W2730366947 cites W2330980141 @default.
- W2730366947 cites W2502954326 @default.
- W2730366947 cites W2518899983 @default.
- W2730366947 cites W2522513651 @default.
- W2730366947 cites W265142245 @default.
- W2730366947 cites W51163154 @default.
- W2730366947 cites W79963072 @default.
- W2730366947 doi "https://doi.org/10.1016/j.trsl.2017.06.012" @default.
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