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

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.

Towards a therapy for mitochondrial disease: an update

“…AAVs have been used to deliver therapeutic genes in several mouse models of mitochondria disorders, including the models for ADOA [ 52 ], MNGIE [ 53 ], and EE [ 54 ].…”

Idebenone increases chance of stabilization/recovery of visual acuity in OPA1‐dominant optic atrophy

“…The possibility to transfer idebenone therapy from LHON to OPA1 ‐related DOA would represent a very relevant option to fight blindness in the largest categories of inherited optic neuropathies. This is an important opportunity for this rare and currently untreatable disease while waiting for other therapeutic options such as gene therapy 15 or other strategies under scrutiny 16 but possibly needing a long way to reach translation into patients.…”

Validating the RedMIT/GFP-LC3 Mouse Model by Studying Mitophagy in Autosomal Dominant Optic Atrophy Due to the OPA1Q285STOP Mutation

“…Given that OXPHOS deficiency also results in AMPK-dependent mitochondrial fragmentation (Toyama et al, 2016 ), mitochondrial dynamics could contribute to the lysosomal response. In the case of OPA1 (Sarzi et al, 2018 ), mitochondrial fragmentation is apparent before loss of dendrites in RGCs while MMP is maintained (Williams et al, 2010 ). Hence delivery of mitochondria to the regions of the cell requiring energy may be as important as mitochondrial quality.…”