By Dr Flora Hui, Centre for Eye Research Australia
When a patient is diagnosed with glaucoma, the only currently available evidence-based clinical treatments focus on lowering intraocular pressure (IOP) to prevent further damage to the optic nerve.
But despite the many effective options available to lower IOP – such as eye drops and surgery – many high-risk patients do not respond well to treatment or continue to progress to blindness despite low IOP.
The need for a new approach that goes beyond lowering pressure was the catalyst for a clinical trial at the Centre for Eye Research Australia that examined the role of nicotinamide, a water-soluble form of vitamin B3, in improving visual function and potentially slowing glaucoma progression.
Our research – published in Clinical and Experimental Ophthalmology last year – was the first clinical study to demonstrate the potential of vitamin B3 as a glaucoma therapy.
Our team is now planning a larger, multi-site trial to study vitamin B3’s long-term potential to reduce visual field progression in people with primary open angle glaucoma.
Powering retinal ganglion cells
Glaucoma is a complex disease with a range of risk factors including age, genetics and elevated IOP which lead to the gradual death and dysfunction of the retinal ganglion cells (RGCs) and their axons which make up the optic nerve.
Traditionally, the disease has been considered a one-way ticket to irreversible vision loss but studies like ours are attempting to find new strategies that directly target and protect the health of the retinal ganglion cells.
The retina has a relatively large demand for energy and like all cells, relies on the production of a compound known as adenosine triophosphate (ATP) to maintain regular function.
The majority of ATP used in the retina is produced in a process known as oxidative phosphorylation (See Figure 1) which occurs in the mitochondria, the tiny power-packs that provide energy to our cells.
There have been many studies demonstrating signs of oxidative stress and dysfunctional mitochondria in ageing and glaucoma.
Our labs have previously shown defects in oxidative phosphorylation in cells of people suffering from primary open angle glaucoma.
And a previous study of inherited glaucoma found extensive defects in the structure of function of mitochondria and reduced levels of ATP in the retina in addition to the loss of retinal ganglion cells.
Why nicotinamide?
Nicotinamide adenine dinucleotide (NAD+) plays a vital role in helping our mitochondria produce ATP, and many studies have shown it can slow ageing or neurodegenerative diseases.
Recent research has demonstrated that people with primary open angle glaucoma have reduced serum levels of nicotinamide, indicating that reduced levels in our bodies may be associated with increased susceptibility to glaucoma.
Pre-clinical studies have robustly shown that increasing dietary nicotinamide raised the levels of NAD+ in the retina and provided strong, long-term protection of the optic nerve in a glaucoma-prone mouse model.
In much of medical and scientific literature, nicotinamide has been grouped together with niacin and nicotinic acid as ‘vitamin B3’.
But as niacin and nicotinic acid have known side effects at high doses, our research focused on nicotinamide, a widely commercially available vitamin B3 supplement with a good safety profile.
The widespread availability and cost-effective nature of this supplement makes it an ideal candidate for neuroprotection in glaucoma.
And if it proves effective over the longer term, it can be rapidly introduced into clinical management as an adjunct therapy to current glaucoma treatments.
Trial findings
Our trial, at the Centre for Eye Research Australia in Melbourne, aimed to investigate whether nicotinamide supplements could lead to a detectable improvement in visual function in people with glaucoma.
We studied 57 glaucoma patients in a randomised, placebo-controlled crossover clinical trial.
During the study, all of the participants received either a high dose of 3g/day of nicotinamide or placebo in addition to their usual glaucoma therapy for 12 weeks before crossing over to the other treatment.
Their vision was monitored using electroretinography and visual field testing to determine any changes every 6 weeks.
Electroretinography allowed us to non-invasively and objectively measure the functional activity of the retina and retinal ganglion cells in response to light.
It showed a clear improvement of retinal ganglion cell function, which was measured using the photopic negative response, after 12 weeks of taking nicotinamide supplements (Figure 2).
Our team believes this reflects an improvement in overall retinal ganglion cell health.
It’s also the first time that any therapeutic approach other than lowering IOP has improved visual function in glaucoma patients.
However, we don’t yet know if this short- term improvement can be sustained over the longer term or accurately predict a delay in visual field progression.
Overall, our research participants tolerated the therapy well with an excellent adherence rate – demonstrating the potential of this supplement to be used in conjunction with usual intraocular pressure lowering treatments.
Next steps
While the outcomes of our early research are promising, we now aim to determine conclusively whether nicotinamide can reduce longer-term glaucoma field progression.
I am now working with CERA Managing Director Professor Keith Martin to plan the TAMING (Targeting Metabolic Insufficiency in Glaucoma) Trial.
The two-year trial will involve 150 patients in Melbourne, along with patients from interstate and overseas.
It will investigate the effect of vitamin B3 on visual field progression in patients who are over 60 and have moderate to severe primary open angle glaucoma over 2 years.
Participant recruitment will being to take place in mid-2021. Patients can self-register to be considered for inclusion in this, or any of CERA’s other glaucoma trial.
Optometrists and other eye care professionals are also able to refer patients for our research trials. Register or find out more at cera.org.au/current-trials
More information
Dr Flora Hui BOptom, MPhil, PhD is a Research Fellow at the Centre for Eye Research Australia and the Department of Optometry and Vision Sciences at the University of Melbourne.
Dr Flora Hui has a particular interest in innovative methods to improve patient outcomes in optometry and ophthalmology and neuroprotectants for treating glaucoma.
Read more about Dr Hui’s profile at cera.org.au/people/flora-hui/
Read the full study
Hui F, Tang J, Williams PA, McGuinness MB, Hadoux X, Casson RJ, Coote M, Trounce IA, Martin KR, van Wijngaarden P, Crowston JG Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B3) Supplementation: A Crossover Randomised Clinical Trial at Clinical and Experimental Ophthalmology. DOI https://doi.org/10.1111/ceo.13818
Research supporters
The research was supported by the Jean Miller Foundation, Connie and Craig Kimberley Foundation, the Ophthalmic Research Institute of Australia, Jack Brockhoff Foundation, Marian and EH Flack Trust, Fund and Board of Research Faculty (Karolinska Institutet).The Centre for Eye Research Australia also receives funding under the Victorian Government’s Operational Infrastructure Program.
Dr Hui was the recipient of Glaucoma Australia’s Quinlivan 2020 Research Grant to support her work on the next phase of the research.
