From the lab to the clinic, researchers at the Centre for Eye Research Australia (CERA) are approaching glaucoma from many different perspectives. This article reviews the organisation’s clinical research projects that aim to improve treatments for glaucoma. It’s followed by an article written by CERA researchers, Dr Jennifer C. Fan Gaskin, and Associate Professor Zhichao Wu, who describe the clinical studies underway, why they’re important, and how your patients can become involved.
While research has already had a significant impact on improving treatments for glaucoma, Dr Luis Alarcon-Martinez, Principal Investigator and Head of the Visual Neurovascular Research Unit at CERA, acknowledges there is still more work that can be done to save sight.
A problem we face in glaucoma research is that we don’t have imaging techniques to visualise the optic nerve at very high resolution,” he explained.
Thanks to a grant from Australian Vision Research, Dr Alarcon-Martinez and his team will use cutting-edge two-photon microscopy techniques to investigate the optic nerve at a scale not previously possible.
“It’s very exciting because this novel microscope’s setup will enable us to see the damaged nerve fibres in the optic nerve caused by glaucoma in extremely high detail,” said Dr Alarcon-Martinez. “This will hopefully provide insights into why glaucoma causes this damage in the optic nerve.”
While not all patients with glaucoma have high intraocular pressure (IOP), many show irregularities in the blood vessels of their eyes – something Dr Alarcon-Martinez and his team are keen to investigate.
“One thing we do know is that blood vessels and axons communicate with each other – but we don’t know how or why.”
The group recently developed a world-first two-photon microscopy image set up to take a high-resolution look at the blood flow in the retina of living organisms.
This allowed them to see the retina down to the very small scale of single nerve cells and capillaries, leading to the discovery of previously unseen structures.
Using the same two-photon technology, Dr Alarcon-Martinez’s team has now developed special microsurgery techniques so they can access the optic nerve at the back of an eye in a living organism.
Using this imaging setup, they will attempt to compare the blood flow in a healthy optic nerve with that of a glaucoma-affected optic nerve.
“Two-photon technology has been around for a long time. However, we are the first to adapt it for these purposes,” he said.
If this experimental research is successful, the imaging setup could be applied to gene therapy trials such as that led by Professor Keith Martin, CERA Managing Director and Head of Glaucoma Research.
Dr Alarcon-Martinez said this could have a significant impact on glaucoma and other diseases related to the optic nerve, including macular degeneration, as well as many neurodegenerative diseases such as Alzheimer’s and amyotrophic lateral sclerosis.
REDUCING SCARRING
Other projects at CERA look at improving how current approaches to manage glaucoma can be improved.
Dr Jennifer Fan Gaskin, Head of Ocular Fibrosis research at CERA and Consultant Ophthalmologist at the Royal Victorian Eye and Ear Hospital, says while filtration surgery is highly effective, it comes with a significant risk of scar tissue blocking the drain and causing the surgery to fail.
“We have to use very strong anti-scarring medication that is quite toxic and not specific to the cells we are targeting,” said Dr Fan Gaskin. “At worst, this can lead to a total loss of eyesight.”
She is looking for ways to make the operation last longer by providing a treatment that effectively stops scarring, as well as being safer and more specifically targeting the surgical site.
“We want to go straight to the source of scarring and find ways to stop the affected cells from working or reduce their function.”
To further understand how scarring forms in glaucoma surgery patients, Dr Fan Gaskin is collaborating with Assoc Prof Raymond C.B. Wong, Head of Cellular Reprogramming at CERA, to better understand how scarring forms in glaucoma surgery patients.
Assoc Prof Wong and his team will take healthy cells from glaucoma patients before they undergo filtration surgery.
“We take a biopsy of healthy tissue that typically goes on to scar after surgery and sequence the genes to identify the specific genes involved in the scarring process,” explained Dr Fan Gaskin. “Then we manipulate the cells to encourage scarring and then see what happens to the genes.”
As a cellular and stem cell biologist, Assoc Prof Wong will interpret the results from genetically sequencing the cells.
These insights will inform the work Dr Fan Gaskin is doing with Assoc Prof Rick Guei-Sheung Liu, Head of the Genetic Engineering Research Unit, to develop a gene therapy for scarring.
Assoc Prof Liu says this is a pioneering study, with gene therapy having never been applied to ocular fibrosis.
Using CRISPR gene editing technology, his team plans to edit the gene that promotes the scarring process to prevent fibrotic tissue formation in the eye.
“This could potentially result in a more effective, targeted, and longer-lasting treatment than the currently used drug,” he said.
While the research is in its early stages, Assoc Prof Liu is cautiously optimistic, with gene therapy having successfully been applied to other eye diseases in the past.
Dr Fan Gaskin hopes the treatment could eventually also be applied to other eye diseases, “because scarring is not just a problem with glaucoma surgery, it is a source of disease for almost every part of the eye”.
MITOCHONDRIA MODELS
The role that mitochondria can play in glaucoma is another target of CERA research.
“By examining blood cells, we’ve established that mitochondria have some impairment in glaucoma patients,” says Assoc Prof Ian Trounce, Principal Investigator and Head of Mitochondria and Neurodegeneration Research.
Funded by the NHMRC, Assoc Prof Trounce aims to define mitochondrial DNA variants that may partly contribute to glaucoma.
Once these variants are defined, his team, including Dr Sushma Anand, will investigate why retinal ganglion cells (RGCs) are “particularly susceptible to this modest mitochondrial impairment”.
While taking a sample of RGCs from patients would not be possible, funded by the Cass Foundation, Dr Anand is developing a model to grow RGCs in the lab through direct programming.
“Through this method, we hope to find out why RGCs are affected in glaucoma and other eye diseases, such as Leber’s Hereditary Optic Neuropathy,” he said.
Dr Anand uses skin cells called ‘fibroblasts’ and then puts mitochondria from other mitochondrial DNA variations into them.
From here, he encourages the fibroblasts to become retinal ganglion cells.
“Direct reprogramming takes two weeks to one month, so we have already completed an experiment. At this stage, the cells are showing neuron-like properties, which is the first step.”
If Dr Anand’s cellular model is successful and the team produce RGCs in the lab, the next step will be testing their susceptibility to mitochondrial defects.
