Researchers behind a world-first Australian-built registry collating real-world data on current keratoconus treatment and patient outcomes, including quality-of-life markers, are hoping to add a novel stem cell treatment that can restore the cornea to its normal shape and size.
Based on studies in the early 1980s, keratoconus was estimated to affect one in every 2,000 people in the general population, according to Keratoconus Australia. Forty years on, it is thought to be as high as one in 750 people worldwide. A recent Australian study published in 2020 indicates a prevalence of 1 in 84 amongst 20-year-olds.
The variation, Keratoconus Australia notes, more likely reflects improved diagnostic techniques, rather than a rising incidence of this disease that new studies suggest affects quality-of-life more than other eye conditions.
Fortunately, treatment options have also evolved. Surgery, including corneal collagen crosslinking and less commonly intra-corneal rings, are feasible options, as well as the mainstay of treatment rigid contact lenses.
Now, medicine and engineering are combining to forge a multidisciplinary approach to finding a novel treatment that could potentially change the lives of those who are suffering from this progressive disease.
It works in a trial, but what about the real world?
Professor Stephanie Watson OAM is head of the corneal unit at Sydney Eye Hospital, head of corneal research group at Save Sight Institute (SSI) and chair of Australian Vision Research as well as co-Deputy Director of Industry, Innovation and Commercialisation at Sydney Nano.
She was integral in establishing the Save Sight Keratoconus Registry in 2015, a world-first for keratoconus patients and clinicians. The registry enables eyecare practitioners to benchmark their practice as everyday outcomes are tracked. Patients can also provide perspectives on their treatment via patient-reported outcomes questionnaires.
“I run a research program which has a number of facets; one of them is the Keratoconus Registry to immediately improve outcomes through providing clinicians with benchmarking and CPD points,” Watson says.
“We can track which treatments are being given to patients with keratoconus – as current treatments can have variable results, some treatments are good, and the evidence for some is still emerging.”
Corneal crosslinking is one treatment the registry is tracking.
“Generally, crosslinking has good results, but it’s been done in quite a number of different ways; there’s a lot of innovation. For example, surgeons have started using oxygen within the crosslinking procedure. The registry allows us to see if the outcomes in the real world reflect what has been found in clinical trials,” she says.
“The registry is collecting data on the use of oxygen in crosslinking and we’ve just published a review of available evidence, so we can immediately find out what’s going on with the current treatment.”
According to Watson, optometry plays a key role in keratoconus management, so an optometry module was added to the Save Sight Keratoconus Registry, allowing primary eyecare providers to track the outcomes of contact lens wear, considered a mainstay for restoring vision.
Watson says another facet her team is researching is quality-of-life, because a lot of measurements used to evaluate a patient’s condition don’t always directly link to this.
“We’re very much interested in that aspect. And that’s why we work very closely with Keratoconus Australia, and patients with keratoconus, because we want the research to make meaningful changes to patients’ lives.”
Another closely related facet SSI researchers are investigating is the impact of keratoconus on mental health and wellbeing.
“For teenagers with keratoconus, when they’re transitioning into adulthood, it can be distressing for them to know that their vision may decline. So that’s another area that we’ve started to work on with the registry.”
Watson says while the treatments available can stop keratoconus getting worse, there isn’t any treatment that can make the cornea ‘normal’ again, and that’s where research is heading.
“We’ve started to investigate stem cells and cell-based therapies to try to change the cornea back to its normal shape,” she says.
“But to work with cells, we need to be able to harvest and transplant them. And to do that, we’re looking at different materials and technologies, including nanotechnology.”
SSI has developed a preclinical model for keratoconus, which is ready for testing.
“We have pre-clinical models and a clinical trials unit at the Save Sight Institute. So we’ve got the pathway to clinic ready; now we’re refining the technology and hope to be able to bridge the translation gap,” Watson says.
“We want to develop treatments for the future. But we also need to look at current treatments and make sure they’re safe and effective. That’s why we cover both aspects in the corneal research program – tracking outcomes and developing treatments. Hopefully we’ll be adding stem cell treatments to the registry and tracking the outcomes in future.”
Applying nano-bioengineering to keratoconus care
Indian-born academic Dr Yogambha Ramaswamy was awarded a PhD in Biomedical Engineering from the University of Sydney and has been a recipient of the prestigious Vice-Chancellor’s Research Fellowship from UNSW and NHMRC Peter Doherty early career fellowship. She is currently a senior lecturer in the School of Biomedical Engineering at the University of Sydney.
Ramaswamy has a strong research experience in the area of biomaterials and tissue engineering. Her research work has led to the development of materials for tissue engineering applications and has had significant impact in advancing the knowledge in biomaterials and its translational potential.
She describes her involvement in keratoconus clinical research through meeting Professor Watson as serendipitous.
“I knew Stephanie briefly from my time at UNSW, however a chance meeting at the Sydney Nano Health forum last year gave us an opportunity to work together,” Ramaswamy says.
The pair got in touch towards the end of last year and, realising the synergy in their research expertise, conceptualised a project to apply their respective skills towards developing a novel solution for keratoconus treatment. In March, they secured seed funding through Sydney Nano Health, and have applied for further funding opportunities.
“I thought our multidisciplinary project was a novel way of integrating medicine and engineering by bringing together Stephanie’s clinical expertise in keratoconus treatment and my engineering experience in materials and nanotechnology,” Ramaswamy says.
The pair have also engaged other researchers, who are experts in in vivo models, stem cell biology and nanotechnology.
“I lead from engineering, and Stephanie leads from medicine. We feel that our research strengths and strategies can advance research in this area and lead towards clinical translation and potentially improve keratoconus treatment.”
Ramaswamy says there is a lot of global healthcare initiatives looking into nano bioengineering and applying it to various streams in tissue engineering including ophthalmology.
“There has been a lot of funding channelled into the global regenerative medicine and nano bioengineering market – which involves using materials, biomolecules, cells, and nanotechnology, to repair and restore damaged tissue, including ocular tissue – and it keeps increasing,” she says.
“As ophthalmology is dealing with soft tissue, polymer-based materials are considered to be appropriate, and you can integrate these materials with nanotechnology to improve and address diseases like keratoconus.”
She continues: “If you think of keratoconus, it is a progressive thinning and steepening of the cornea. Changes in corneal shape distort vision. When healthy stem cells become deficient, the regenerative capacity of these corneal stem cells is damaged.”
Ramaswamy says cellular therapy of the cornea is considered as a promising advanced therapeutic approach for corneal disease, including keratoconus.
“We want to see whether we can repair damaged corneas using tissue engineering approaches.”
In this project, Ramaswamy says the team will use a combination of stem cells, multi-functional nanomaterials, and polymer-based jelly-like hydrogel constructs that can help in the repair of the cornea.
“For corneal repair we want to increase the stemness of the cells to improve the stem cell quality and functionality, as well as their numbers.”
Watson and Ramaswamy believe that their nano-bioengineering platform comprising of polymers, stem cells and nanotechnology has the potential to achieve it.
“Stephanie led a clinical trial of a stem cell treatment that restored the cornea in limbal stem cell deficiency. But not all patients could be treated. We now want to see whether we can improve on stem cell numbers and quality using our multicomponent platform, and then transplant stem cells to the patient’s eye.”
Their project is currently lab-based but they are working towards a goal of clinical translation.
“We have applied for several funding grants and have a team who are helping us to advance our study. We have good support from scientific community who are really interested to see this work go forward.”
Bringing quality-of-life to the fore
Nepal-trained optometrist Dr Himal Kandel travelled and studied extensively before accepting the position of Kornhauser Research Associate at SSI.
After graduating with a Master’s in Public Health for Eye Care from the London School of Hygiene and Tropical Medicine at the University of London, Kandel then moved to Australia to pursue a PhD at Flinders University, focusing on the impact of refractive error on quality-of-life.
Immediately after completing his PhD, Kandel accepted his current research position at SSI.
Evaluating and improving quality-of-life has been a major focus of the Save Sight Keratoconus Registry.
“I am interested in looking at comprehensive patient outcomes. And here, we have the Save Sight registries, which track outcomes, including quality-of-life as well as other clinical outcomes,” he says.
Although SSI has produced quality-of-life research for eye conditions including age-related macular degeneration and diabetic macular oedema, Kandel is mainly focused on keratoconus. Because keratoconus is often diagnosed in adolescence, and is a progressively worsening condition, it affects patients for a lifetime.
He says the data shows that keratoconus patients have the worst quality-of-life status compared to other eye conditions.
“Usually, people don’t go blind because of keratoconus, meaning they may have quite good visual acuity compared to other eye conditions. But even though their visual acuity can be good, keratoconus can lead to severe quality-of-life impacts. This is the key message from our research because for policymaking or resource allocation, we have the option to consider visual acuity and vision impairment, but we don’t consider quality-of-life impact,” Kandel says.
“The keratoconus patients may experience glare, distorted vision, dry eyes and tired eyes leading to poor quality vision. Similarly, they may have issues driving during the night, and difficulty working on the computer. The early age of onset and progressive and chronic nature of the disease may cause emotional stress. These issues may be more important in determining their quality of life than the ability to read letters in a visual acuity chart in a clinic.”
He continues: “Keratoconus patients may be considered to be doing well when we assess their vision only, I think our research highlights that we need to consider quality-of-life more comprehensively and how keratoconus is affecting day-to-day visual function along with other symptoms, and emotional well-being.”
Kandel says other studies performed at SSI using data from the registries have found that the quality-of-life scores are weakly correlated with clinical measures.
“That means it’s really important to monitor how patients are doing with respect to quality-of-life, visual function and symptoms.”
He says gathering data on quality-of-life can be complex.
“If we don’t use quality tools and methods, then we will not get quality results. We collect patient reported quality-of-life outcome data using validated questionnaires. When a patient comes to the clinic, they fill out the questionnaire during their waiting time and the data is uploaded automatically into the registry. We are then able to track quality-of-life outcomes with the registry. During the clinic, eyecare practitioners can look at the questionnaire scores, how it has improved or gotten worse, and researchers can study and compare the data,” Kandel explains.
Kandel presented the latest keratoconus quality-of-life research (see Side Bar) at KeraClub in August.
He says one of the questions he received from the audience – predominantly keratoconus patients – was regarding the mental health impact of keratoconus.
“We have recently started collecting data on the mental health of keratoconus patients. It is our next project – evaluating the mental health impact of keratoconus. We have added validated questions on mental health to the Save Sight Keratoconus Registry. We hope that our registry data will enable the mental health impacts of keratoconus to be understood, as the published evidence is conflicting,” Kandel says.
Kandel anticipates the study will support evidence that although keratoconus patients may have good visual acuity, they shouldn’t be prioritised lower than other eye conditions because of the quality-of-life and mental health impact.
“Our team is the largest contributor in this area of research. The Keratoconus Registry data is really helping us to understand more about the impact of keratoconus. It is highlighting the importance of monitoring quality-of-life by eyecare practitioners in routine clinical practice. With the registry we can identify specific issues for a patient so that we can manage them, such as difficulty with computer work. Our research is really useful in finding out how patients’ lives can be improved.”
The need for evaluating patient-reported outcomes in routine clinical practice
The Save Sight Registries at The University of Sydney found that visual acuity may not be the main factor in determining quality-oflife for people with keratoconus.
Using data from the world’s largest keratoconus registry, vision and quality-of-life were found to be only weakly connected.
The ground-breaking research has been published in the May/June issue of the Clinical and Experimental Ophthalmology journal, the official journal of RANZCO.
“Our research findings have important implications for everyday clinical practice as they show the need to measure the patient’s experience of the disease, not just visual acuity, in keratoconus. The patient experience (patient reported outcome) is needed to understand the impacts of keratoconus and its treatment as well as to make decisions on which treatments are needed,” Dr Himal Kandel, the paper’s lead author, said.
“Using patient reported outcomes in everyday practice can also improve communication between patients and clinicians with the end result being shared clinical decision making and improved quality of care.”
In this world-first large study, the researchers compared qualityof- life outcomes from 1,557 patients with keratoconus to those with retinal diseases – specifically age-related macular degeneration, retinal vein occlusion and diabetic macular oedema – in the Save Sight Registries international patient database.
The patients were recruited from 44 sites in Australia, Singapore, Italy, Bosnia and Herzegovina, Spain, and France.
The quality-of-life scores were collected using a validated questionnaire known as the Impact of Vision Impairment questionnaire which had questions on two domains: visual functioning and emotional.
Patients with keratoconus had lower quality-of-life scores, particularly emotional scores, than retinal diseases. Emotional issues had the greatest impact on keratoconus patients with severe disease.
Overall, quality-of-life scores were lower in females with keratoconus than males.
Encouragingly, keratoconus patients who had undergone corneal crosslinking had better quality-of-life scores. This highlights the need for early diagnosis and treatment.
“Every day in the clinic, assessing quality-of-life in patients with keratoconus can guide treatment decisions. Our research shows that treatment should be aimed at optimising visual functioning and emotional wellbeing to improve quality-of-life and informs evidencebased resource allocations at the planning level,” Professor Watson, the senior author of the paper, said.
“Using the Save Sight Keratoconus Registry, patient reported outcomes collection can be easily incorporated into everyday clinical care. Patients with keratoconus can be reassured that clinicians have been made aware of the impact of their condition on their quality-of-life,” she said.
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