Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 ) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups ( < 0.001), with significant differences among groups ( = 0.023; Control vs. LHON, = 0.008; Control vs. Rescue, = 0.228). Inner retinal thickness and intraocular pressure did not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype exhibited improved retinal visual acuity (0.29 ± 0.1 cy/deg vs. 0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, < 0.001, effect of Group, = 0.004; Interaction Flicker × Group, < 0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, < 0.001, Control vs. LHON, < 0.001, Control vs. Rescue, = 0.106). These results suggest that MTSAAV-delivered wildtype gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease.