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. 2018 Feb 6;8(1):2468.
doi: 10.1038/s41598-018-20838-8.

OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Emmanuelle Sarzi  1 , Marie Seveno  2 , Camille Piro-Mégy  2 , Lucie Elzière  2 , Mélanie Quilès  2 , Marie Péquignot  2 , Agnès Müller  2   3 , Christian P Hamel  2   4 , Guy Lenaers  2   5 , Cécile Delettre  2
Affiliations

OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Emmanuelle Sarzi et al. Sci Rep. .

Abstract

Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Gene therapy strategy. pCMV: CMV promotor; HsOPA1:Homo sapiens OPA1; VEP: Visual Evoked Potentials; RGC: retinal ganglion cells. This strategy included 4 female Opa1+/+ controls, 4 untreated and 8 treated female Opa1+/− mice.
Figure 2
Figure 2
Assessment of the vector transduction efficiency. (A) Quantification of murine endogenous Opa1 transcripts as well as GFP transcripts. MmOpa1: Mus musculus Opa1 (B) In vivo funduscopy was performed on untreated and treated Opa1+/− mice in brightfield (upper panel) and using a specific green filter to observe GFP fluorescence (lower panel). (C) Post-mortem immunohistochemistry was done on whole mount retinas using a RGC specific Brn3a labelling (Upper panel). Zoom-in (lower panel) was done to observe Brn3a/GFP double-positive RGCs (double arrow), Brn3a positive (arrow) and GFP negative RGCs.
Figure 3
Figure 3
Efficiency of the AAV2/2 injection on visual function and retinal ganglion cell number. (A and B) In vivo electrophysiological recordings. (A) visual evoked potential (VEP) N-wave latencies, (B) negative scotopic threshold response (nSTR). (C) Assessment of visual acuity using an optokinetic drum. Measurements of frequency thresholds (left) and contrast perception (right). NS: not significant. (D) post-fixed RGC counting using a specific Brn3a immuno-labelling in whole mount retinas. White rectangles: enlargement of whole-mount retinas. Brn3a positive dots were quantified using Imaris and MetaMorph® softwares. Data were expressed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 using one-way ANOVA.
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