Preclinical safety evaluation of lentiviral LV-RPE65 gene therapy after subretinal delivery in non-human primates

Publication date: Available online 8 July 2017
Source:Translational Research
Author(s): Alexandre Matet, Corinne Kostic, Alexis-Pierre Bemelmans, Alexandre Moulin, Serge G. Rosolen, Samia Martin, Fulvio Mavilio, Vazrik Amirjanians, Knut Stieger, Birgit Lorenz, Francine Behar-Cohen, Yvan Arsenijevic
Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, all strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them showed limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restores protein expression and cone function, as established in mouse models of RPE65 deficiency. The aim of this study was to evaluate the ocular and systemic safety of this lentiviral-based therapy (LV-RPE65) on healthy non-human primates.For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days post-injection using multimodal imaging. We revealed prolonged reattachment times in LV-RPE65 injected eyes compared to vehicle-injected eyes. Nonetheless, certain eyes in both the vehicle (control) and the LV-RPE65 injected groups presented a mild reduction of the outer nuclear layer thickness in the macula. All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite mild structural changes, electroretinography indicated that retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial or leucocytes ocular activation between low-dose, high-dose and vehicle-injected eyes. Moreover LV-RPE65-injected animals did not show signs of vector shedding or extra-ocular targeting confirming the safe restriction of the vector in the eye.Our results evidence the favorable ocular tolerance to LV-RPE65 after subretinal injection, with some drawbacks/complications linked to this route of administration necessitating to block this transient inflammatory event.



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