Overview
Leber hereditary optic neuropathy and autosomal dominant optic atrophy are both inherited conditions that affect the optic nerve. This is the specialised cable that connects the eye to the brain.
Both conditions are due to problems with the power stations inside cells (mitochondria) and they share many signs and symptoms. Mitochondria produce the energy that cells in the body need to function.
The optic nerve is bundle of connections from nerve cells in the retina, called retinal ganglion cells. Blindness in both conditions happens because these cells (and their connections) die off.
There is no treatment for either condition at the moment. But in this project the research team is testing a potential therapy that uses a certain wavelength of red light.
The genetic faults that cause both conditions make it hard for mitochondria in the retina to make enough energy. But the task is made even harder by the fact that the retina is very active. This means it is always being exposed to toxic by-products from cell activity that could damage the cells even further.
The red light the team is studying undoes the effect of one of these toxic by-products.
Results from the study should tell us whether the red light therapy can help prevent retinal ganglion cell death in an animal version of optic neuropathy. We should also know more about how it works.
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Scientific summary
Light therapy for mitochondrial optic neuropathy
Autosomal dominant optic atrophy is the commonest inherited optic neuropathy, due to mutations in the mitochondrial pro-fusion OPA1 gene, and it leads to visual failure secondary to retinal ganglion cell loss. We have developed a mouse model in which Opa1 mutant mice manifest visual defects and pruning of retinal ganglion cell dendrites. There are deficits in retinal mitochondrial fusion and morphology, increased production of reactive oxygen species and reduced complex I and IV activity in the mitochondrial electron transport chain, with reduced generation of ATP.
The retina is continuously exposed to reactive oxygen and nitrogen species, which may further impair mitochondrial function. One of the effects of nitric oxide (NO) is inhibition of complex IV by binding to cytochrome c oxidase (COX). Absorption of 670nm light by the NO-COX complex results in photo-dissociation of NO and thus releases the enzyme from its inhibitory effect.
The research group hypothesises that by employing 670nm red light LED therapy we can increase COX activity in Opa1 mutant mice resulting in enhanced electron transport chain and production of ATP. Improvement of mitochondrial function is expected to improve retinal ganglion cell health, preventing degeneration. It may also permit early damage to neurons to recover.
To test this hypothesis, the Opa1 mutant mice will be exposed to 670nm light or to sham treatments. The progress of retinal ganglion cell morbidity will be monitored by immuno-confocal on retinal flat mounts with analysis of RGC dendrites labelled with fluorophores, retinal and optic nerve histology and measurement of activities of Complexes I and IV and the production of ATP.