Abstract
In many human disorders mitochondrial dysfunction is central to degeneration of retinal ganglion cells. As these cells do not regenerate, vision is irreversibly lost. Here we show reversal of visual dysfunction by a mitochondrially targeted adeno associated virus in transgenic mice harboring a G11778A mutation in the ND4 subunit of complex I persists longterm and it is associated with reduced loss of RGCs and their axons, improved oxidative phosphorylation, persistence of transferred ND4 DNA and transcription of ND4 mRNA.
Highlights
G11778A mitomice (n = 14) with low PERG amplitudes were injected with mitochondrially targeted AAV containing the wild-type (WT) human ND4 (MTSAAV-hND4)
In our PERG experiments here we set the stimulus gratings to the largest size (0.05 c/deg = 2.77 logMAR7–9) and most contrast to detect severe visual deficits of our mice, as is characteristic of human LHON, and to demonstrate reversal of them
The PERG amplitude of at least one eye of each transgenic mutant ND4 mouse randomized for treatment was at noise levels (2–3 uV), similar to blind G11778A LHON patients
Summary
G11778A mitomice (n = 14) with low PERG amplitudes were injected with mitochondrially targeted AAV containing the wild-type (WT) human ND4 (MTSAAV-hND4) Both eyes of littermates with low PERG amplitudes (n = 10) were injected with mitochondrially targeted AAV carrying the mCherry gene in the mitochondrial genetic code (MTS-AAV-mCherry) Gene therapy with wild-type ND4 reversed loss of PERG amplitudes with an increase of 17% at one month post injection (p = 0.007) that improved further to 42% at three months post injection (p = 0.007) (Fig. 1A). PERG amplitudes of mCherry injected eyes remained low (Fig. 1B). It is unclear whether initial benefits to visual function return would diminish as seen in Leber Congenital Amaurosis (LCA2), a non-mitochondrial disease caused by recessive mutations in the RPE65 gene, where topographical maps of visual sensitivity in retinal regions treated by AAV delivery of the normal RPE65 cDNA had progressive diminution of the areas of improved vision 4–6 years after treatment[10]
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