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Corinne Kostic, Alexandre Matet, Fulvio Mavilio, Samia Martin, Alexis-Pierre Bemelmans, Francine F Behar-Cohen, Yvan Arsenijevic; Ocular and systemic safety of a HIV-1-derived lentiviral vector after subretinal injection in Macaca fascicularis eyes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4026.
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© ARVO (1962-2015); The Authors (2016-present)
We developed a lentiviral-based strategy of RPE65 gene replacement for Leber congenital amaurosis (LV-RPE65) that restores protein expression and cone function in mouse models of RPE65 deficiency. We previously described the short term effect of subretinal injections of a low dose of LV-RPE65 on healthy primates. The aim of this study was to further evaluate the ocular and systemic safety of 2 different doses of this vector in primates. We report here the ocular safety in terms of retinal function and morphology, and the systemic safety in terms of biodistribution and histology in selected body fluids/organs.
Five females Macaca fascicularis received 1 subretinal injection of either LV-RPE65 at low dose (n=2), high dose (n=2), or the vehicle (n=1). Contralateral eyes served as additional controls by receiving either the vehicle (n=3) or no treatment (n=1). Ocular safety was assessed by intraocular pressure levels, anterior chamber and vitreous cell counts, electroretinography and OCT at regular intervals, and finally by immunohistochemistry. Blood, urine and tears were regularly sampled to evaluate LV-RPE65 biodistribution by PCR of a lentiviral sequence. Tissue histology was performed on specific organs after sacrifice (1 month post-injection for the low-dose and 3 months for the high-dose).
Two low-dose-injected and 1 high-dose-injected animals had an initial self-resolving mild anterior chamber/vitreous inflammation. The other high-dose-injected animal had a more intense inflammation possibly due to an accidental intravitreal leak of the injection. All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved within 7 days. Electroretinography showed that retinal function was preserved over time. Immunohistochemistry identified a glial reaction in the detached retina in all animals but no difference in microglial activation (using Iba-1 staining) between low-dose, high-dose and vehicle-injected eyes. The lentiviral genome was not identified in body fluids at any timepoint. Organ histology did not reveal any sign of abnormal inflammation.
Despite an initial transient perivascular inflammation, eyes that received a subretinal injection of LV-RPE65 did not present severe functional defects but some structural changes. Moreover treated animals did not show signs of systemic inflammation in body fluids and organs.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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