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Guy Lenaers, Marie Seveno, Lucie Elzière, Emmanuelle Sarzi, Vasiliki Kalatzis, Christian P. Hamel; Gene therapy for Dominant Optic Atrophy: a first pre-clinical trial on the OPA1delTTAG mouse. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1896.
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© ARVO (1962-2015); The Authors (2016-present)
Dominant Optic Atrophy (DOA) is an inherited mitochondrial disease affecting the Retinal Ganglion Cells (RGCs), caused by mutations in one allele of the OPA1 gene, encoding an intra mitochondrial dynamin. It is now well accepted that in non-syndromic patients, haplo-insufficiency is the primary pathophysiological mechanisms. Our pre-clinical project aims to obtain the proof of principle that the micro-injection of an AAV2 vector expressing OPA1 in an Opa1 mouse model can prevent RGC degeneration and the evolution of the vision deficiency.
We have constructed a new Opa1 mouse model with the c.2708delTTAG mutation in exon27, that reproduces the most frequent mutation found in patients with DOA (30% of all cases), and shown that it progressively looses RGCs. We have constructed an AAV2-pOPA1 vector including the human OPA1 minimal promoter and cDNA, and performed micro-injection in 2 and 9 months old Opa1 and wild-type animals. Vision parameters (Eye fundus, ERG, VEP, Visual acuity) were followed every two months.
Analysis and follow-up of 2 months old animals micro-injected with the AAV2-pOPA1 vector and with a control AAV2-eGFP vector showed that: 1) the surgery is not armful for the animal vision, 2) the expression of the eGFP is easily detectable by fluorescent eye-fundus examination, 3) whereas the specific expression of the human OPA1 protein can difficultly be differentiated from the endogenous Opa1 expression, 4) visual parameters (VEP and visual acuity) were significantly decreased in Opa1 animals, 5) treatment with the AAV2-pOPA1 vector has not yet induced a significant improvement of Opa1 mouse vision, after a 9 months follow-up. Immuno-histological analysis of the retina and optic nerve are in process. 9 months old micro-injected animals are under investigation.
We have developed the concept of gene therapy for Dominant Optic Atrophy and consequently set up the different tools to perform eye surgery and analyse the possible consequences of AAV2 micro-injections on the visual parameters. Although we can expect that the ectopic expression of human OPA1 can rescue the haplo-insufficiency found in Opa1 mouse model, our actual results require further observations to confirm this hypothesis.
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