Preventing sight loss in glaucoma

The increased pressure inside the eye in glaucoma causes damage to retinal ganglion cells (RGCs), the neurons that connect the photoreceptors in the retina to the brain. Prof James Morgan’s work has been based on the idea that sight loss in glaucoma begins when RGCs start slowly degenerating, rather than at the point the cells die, as some other researchers believe.

During his early research career, James and others did indeed prove in animal studies that the RGCs start to degenerate early in glaucoma. One sign of this can be seen in the RGC dendrites, bits of the cell which stick out like branches of a tree to receive signals from other neurons. Over time, these dendrites are ‘pruned back’, leading to progressive sight loss.

Visualising neuron degeneration

But while the findings from animal models were compelling, James needed to prove this was also happening in humans. To do this, James was awarded a grant from Fight for Sight in 2015 to study RGCs in retina samples donated by people with and without glaucoma after their death.

In painstaking work, using electron microscopy to reconstruct 3D images of individual RGCs, his team at Cardiff University proved that dendrites do start to degenerate early in human glaucoma.

What’s more, the team showed that changes to the RGCs can be objectively measured using standard OCT instruments. These findings suggest there is an opportunity to spot this degeneration early and bring RGCs back to health, and so maybe prevent sight loss in glaucoma.

Bringing neurones back to health

Another feature the team spotted were abnormalities in the mitochondria, the energy-producing structures inside cells. By this point it was already known that nicotinamide – a cheap, widely available form of Vitamin B­₃ – could prevent damage to mitochondria.

After several clinical trials of nicotinamide in glaucoma had begun, James and his team were awarded funding from Fight For Sight to better understand exactly how nicotinamide protected mitochondria, and the timing and dose needed for the optimal effect.

In this project, they confirmed in a rat model of glaucoma that nicotinamide does prevent the loss of RGC dendrites – providing additional evidence that clinical trials were taking the right approach.

Next generation treatments

But importantly, James’s team found that to see a significant effect, you need a dose of nicotinamide much higher than those being tested in patients, suggesting these trials might end with disappointing results. “We should expect a clinical trial to show hopefully, at best, a moderate effect,” says James, “but there’s a compelling argument for going for a higher dose of nicotinamide.”

So James is now working with chemists to develop new drugs that can slowly release nicotinamide at high doses.  

Slowing sight loss in glaucoma

As a clinician, James knows the impact that glaucoma has on people, and how much of a difference it would make to reverse their sight loss. While there’s lots more work to be done, James is cautiously optimistic that nicotinamide could eventually become an ideal treatment to slow or even prevent sight loss in glaucoma.