"It is not currently possible to regenerate a damaged optic nerve in glaucoma and recover vision. Our approach is therefore to keep the nerve healthy as long as possible," says Pete Williams, an Assistant Professor and Research Group Leader at Karolinska Institutet, and responsible for the new glaucoma laboratory at St. Erik Eye Hospital.
Glaucoma is characterised by progressive visual dysfunction often leading to irreversible blindness. The major risk factors are age, elevated intraocular pressure, and familial risk.
Current clinical interventions for glaucoma focus on managing intraocular pressure, a major risk factor, rather than the neurodegenerative changes in the retina and optic nerve that result in blindness.
"By the time a patient starts to experience a significant loss of vision, it is usually already too late. At present it is not possible to regenerate the damaged cells," says Pete Williams.
The changes occur in nerve cells in the innermost layer of the retina, retinal ganglion cells. The nerve cell fibres, axons, which conduct visual impulses to the brain via the optic nerve degenerate leading to visual impairment.
Focusing on cell metabolism
Extensive research studies in glaucoma-prone rats and mice have revealed that metabolic dysfunction in the retinal ganglion cells may be a key initiating factor for glaucomatous neurodegeneration. This occurs prior to a loss of functional vision.
The use of new technology (RNA-sequencing) to map changes in retinal ganglion cells has enabled researchers to determine that the level of NAD, an essential metabolite, is crucial to neuronal cell health. If the level is too low, cells are more susceptible to stress caused by age or intraocular pressure.
Pete William’s group has since gone further by enhancing cell resilience in two ways. The first involves the administration of nicotinamide, a form of vitamin B3 and a precursor for NAD production, as a dietary supplement. The subsequent increase in NAD levels helps increase cell resilience even during periods of age- or intraocular pressure-induced stress.
The second method involves using gene therapy. Researchers found that a single injection of a gene therapy construct encoding Nmnat1 (an enzyme that makes NAD from nicotinamide) prevented the onset of glaucoma.
Clinical studies in humans
Pete Williams' group now wants to push on by creating tangible benefits for patients.
"We are initiating clinical trials in humans. I strategically set up this laboratory at St. Erik Eye Hospital, where we can collaborate with clinicians in addition to getting access to human samples, which we can use to better understand glaucoma pathogenesis and identify novel biomarkers for disease."
One problem associated with clinical glaucoma studies is the length of time they take, normally five to ten years. However, new methods can be employee to study electrophysiological function and visual function allowing researchers to accelerate the time taken to see degenerative changes in glaucoma.
"The interest in our project has grown, which is gratifying. We now have new technology and new methods to draw on in glaucoma research as we head into the next decade," concludes Pete Williams.
Text: Henrik Möller
Facts about glaucoma
Glaucoma is a complex disease that occurs in two forms: one where loss of vision comes on slowly, and a rarer acute form. St. Erik Eye Hospital conducts intensive research into better treatment for glaucoma patients.
- Approximately 100,000 people in Sweden have been diagnosed with glaucoma.
- Another 100,000 or so are undiagnosed.
- Elevated intraocular pressure, age, and genetics are the predominant risk factors.
- Cells contain sequences of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid).
- The DNA sequence makes up the inherited genetic information in cells, while RNA sequences translate the information in the DNA that determines how the genes will be expressed.
- RNA sequencing is a modern technique that is used to map and describe which genes are active and how active they are in a certain tissue at a certain point in time.