Loss of vision in Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA)

Grant holder: Dr Michael Gilhooley, NIHR Clinical Lecturer
Institution: UCL Institute of Ophthalmology
Grant award: £9,991
Start: February 2021
End: January 2022

Why is this research needed?

Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA) are inherited diseases that cause damage to the retina, resulting in vision loss. The retina is made up of layers containing different types of cells, including a type of cell called retinal ganglion cells. In both diseases, these cells die because their mitochondrial function is diminished. One particular type of retinal ganglion cell, however, known as the intrinsically photosensitive retinal ganglion cell (ipRGC for short), has been shown to be more resilient to poor mitochondrial function than others – surviving late into the course of both LHON and DOA when most others have been lost.

What are retinal ganglion cells?

Ganglion cells are a type of neuron (nerve cell) found in the retina. Ganglion cells allow us to see by processing the light that enters the eye and transmitting it to the brain via the optic nerve (to which they are directly connected).

The human retina has more than a million retinal ganglion cells and they are particularly susceptible to damage caused by loss of normal mitochondrial function, which is what happens in mitochondrial optic neuropathies.

What are mitochondria?

You can think of mitochondria as a cell's power station that produces the energy for it to carry out all its functions properly. They work in a similar way to a digestive system: they take in nutrients and generate energy by breaking them down. This process is called cellular respiration and mitochondria use oxygen to release energy to the cell.

When disease occurs, their ability to perform their digestive function is diminished. In the eye, this can lead to inflammation in the retina and cell death.

What is the aim of the project?

Currently, there is very limited knowledge about what makes ipRGCs cells different. Dr Gilhooley theorises that there are a number of genes active in ipRGCs, which protect them from damage caused by poorly functioning mitochondria. To test this, he will isolate ipRGCs from the eyes of mice that have LHON and DOA. Using a state-of-the-art genetic technique, he will then determine which genes are active in different types of cells within the optic nerve, including ipRGCs. This will allow his team to identify a list of genes that may be responsible for protecting ipRGCs against cell death in these two diseases. The genes identified will then be manipulated in nerve cells grown in the lab from skin cells donated by patients with LHON and DOA.

How will this research help to beat sight loss faster?

This essential pilot work will provide the basis for a larger research programme to develop new gene therapies designed to protect all nerve cells within the optic nerve. Such treatments could also be applicable to other diseases such as glaucoma, Alzheimer’s disease, and Parkinson’s disease, where mitochondrial dysfunction has been implicated as a major driver of nerve cell death.

Further information

You can find more about the causes and symptoms of Leber's Hereditary Optic Neuropathy (LHON) here.

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