The RANZCO Congress never fails to attract a high-powered line-up of invited speakers. Part 2 of Insight’s conference coverage features interesting topics, including ocular CRISPR gene editing, arguments for cataract surgery simulation training and the need for true innovations in ophthalmology.
In one of the most intriguing presentations of the congress, Tasmania-based preeminent ocular genetics expert Professor Alex Hewitt delivered a lecture entitled: ‘Dawn of Precision Ophthalmology in the Asia-Pacific’. It focused on adaptation of the CRISPR/Cas system to mammalian cells, a revolution set to reshape inherited retinal disease (IRD) treatments.
Hewitt kicked off his discussion describing his wonder at some of man’s most amazing achievements, including putting astronauts on the moon, and the work of SpaceX to launch and land 15-storey-high rockets, leading him to question why – with all these advances – all blinding eye diseases can’t be cured?
While ophthalmology is doing a great job in treating the major areas that make up 80% of blindness and vision impairment, he said there remained a significant portion with IRDs who have had little hope, until now.
Explaining the challenges of this cohort, he said it comes down to the complexity of the genome. As an analogy, he asked viewers to imagine expanding each of the 3.3 billion nucleotides that make up the genetic code, in each cell, to the size of a matchstick. Stacked end-on-end, it would have the ability to reach from Earth to the moon, back to Earth, then back to the moon again.
“Genetic code is made up of four different bases/colours (A, C, G, and T) and this means each matchstick is one of four different colours. For genetic disease to manifest, only one needs to be a different colour.”
Hewitt said the exciting thing about IRDs is scientists can now readily identify the genetic cause for disease in seven out of 10 unselected patients.
On this front, he said Australia has led the way in many gene discoveries and dissecting genotype and phonotype correlations. With increasing availability of genetic testing, the industry is now rapidly reaching a point where it is possible to diagnose diseases much earlier, opening possibilities for new interventions.
He highlighted the case of young Melbourne boy Harry Feller who was born deaf, despite his family having no known history of deafness. Genetic testing confirmed he had Usher syndrome type 1F. With this early diagnosis, it gives Hewitt and other researchers a 10-15-year window to develop a treatment to prevent retinal degeneration.
Ultimately, where a patient is on the natural history of the disease trajectory will dictate which therapeutic intervention will be most amenable, with a major focus currently on gene editing. This encompasses the famous CRISPR technology, based on the ancient adaptive immune system of bacteria, and is an approach Hewitt is engaged in.
As Tasmanian Eye Institute (TEI) founder Professor Brendan Vote explained to Insight recently, in short, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-based immunity involves bacteria capturing snippets of DNA from invading viruses and uses them to create DNA segments on CRISPR arrays. These DNA spacers between the repeats are like a ‘wanted poster’ for the virus that allows bacteria to ‘remember’ the viruses. If viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use an enzyme (Cas9) to cut the DNA, disabling the virus.
Used as a therapy, the CRISPR system involves an endonuclease and a guide RNA sequence. The complex traverses the genome until it finds a matching corresponding sequence where the enzyme is activated to cut both strands of DNA.
Using this approach, in 2016 Hewitt and his team were first to report the application of CRISPR in a mammalian retina. Using transgenic mouse, they demonstrated up to an 84% reduction in gene expression, and importantly retinal function was maintained.
Hewitt pointed out this was ideal if the aim is to destroy a gene’s function, but if the goal is to correct a disease-causing variant, it’s a different story.
He outlined the ground-breaking work by various overseas researchers, including converting nucleotides from one to another, the engineering of base editors, and breakthrough efforts to overcome inadvertent edits, or off-target effects. The latter eventually led to the work of PhD candidate Peter Tran in Hobart, who was able to ameliorate the off-target effects with his work on base editors (by embedding the base editor inside the CRISPR enzyme), that could also, importantly, fit the construct into an adeno-associated viral (AAV) vector, commonly used to deliver gene-based therapies.
“With the off-target effects of base editors now sorted, this was terribly exciting and we have now gone on to show the technology and endonucleases (enzymes that recognise DNA sequence) that Peter engineered could be used to directly correct Harry Feller’s disease-causing variant,” Hewitt explained.
With more than 220 base editors now described, Hewitt said this could in future lead to a plug-and-play approach in the clinic, where it is possible to select base editors off-the-shelf for specific targets.
Tasmania home to new CRISPR cures lab
With the ability to now diagnose, design and validate the genetic correction therapy, Hewitt points out the next big hurdle is production.
This is something he is addressing in Hobart with Vote and TEI, with what has been described as Australia’s first dedicated Ophthalmic Gene Therapy Centre, involving the refurbishment of a disused water tank and an adjacent derelict heritage building.
This will become a PC-2 laboratory, which will function as a GMP (good manufacturing practice) production facility. With the hope of producing CRISPR blindness cures, it will operate over 840sqm of lab space, with the aim of linking the project with all active clinicians across Australia and New Zealand.
With production capability taken care of, Hewitt said the last pressing issue is the patient. On this front there are two major considerations, with the first being a redesign of the clinical trial framework for rare orphan diseases seeing Phases 1 and 2 condensed, with a greater focus on post-licensing surveillance.
Secondly, there’s a need to ensure patients would want to edit DNA. To explore this issue, Hewitt highlighted a questionnaire involving 12,000 people from 185 countries that found overall firm support for application of somatic gene editing. Interestingly, those who did not agree said they did not fully understand technology, so education could address this issue.
Hewitt concluded his discussion by stating: “The full clinical loop of the translation to gene editing technology is almost complete and we are set to transform the care of patients with well-defined, genetically characterised diseases, if diagnosed early.”
The lecture was rounded off with a Q&A session. The first question related to the pricing of personalised CRISPR therapies, noting that the first approved ophthalmic gene therapy Luxturna costs somewhere between $500,000 and $1 million per patient.
Hewitt said scalability of the technology is essential. A major issue with the current system is that when drugs are purchased, healthcare payers are paying for the failed R&D that has gone into the therapy.
“So there needs to be a shift in the way medicine is subsidised in Australia and around the world. It is clear RNA therapies can be developed economically at scale, the best example is RNA vaccines – it is possible, there just needs to be a broader conversation about funding it equitably.”
Another intriguing question related to how such therapies would ultimately be delivered to the eye.
While the current focus is on AAVs containing the gene therapy, delivered via a subretinal injection, Hewitt anticipates viral like particles or lipid based nanoparticles, ideally as intravitreal injection, is where delivery may head in future.
Dr David Lockington has been a consultant ophthalmologist at the Tennent Institute of Ophthalmology, Glasgow, Scotland, since January 2014, with sub-specialist training in cornea, cataract and anterior segment. He’s also an ophthalmology trainer and the national simulation lead for the UK’s Royal College of Ophthalmologists.
The lecture entitled: ‘Ensuring a safe cataract experience for all through embracing the role of simulation’, considered historic teaching/training methods and their inadequacy. He also discussed simulation equipment, and how they ensure trainees have the knowledge and experience to perform surgical tasks before live surgery.
He initiated the presentation discussing that, as a trainer, he wants to “train without trouble”, which comes down to developing competent trainees first and foremost.
Lockington showed a graph demonstrating that to reduce avoidable harm, the top two criteria were “the presence of an identifiable modifiable cause”, and “reasonable adaptation to a process that will prevent future occurrence”.
He asked the awkward question, is a trainee an identifiable modifiable risk factor? And is simulation an adaption to a (training) process to prevent future avoidable harm?
“I would suggest it is,” he said.
When deciding if a trainee is ready for surgery, Lockington said too often ‘hope’ and ‘trust’ enters the equation. He highlighted the classic example of a hydrodissection when a trainee might miss the pupil snap sign. However, the trainer lets them continue when, suddenly, the nucleus sinks away because they haven’t realised they have split the posterior capsule with their violent hydrodissection.
He said trainee surveys often assess confidence, a notion that is well-meaning but misplaced, with a greater emphasis needed on competence first, then naturally confidence.
He said a safe roadmap to surgical competence includes background knowledge (reading, watching, journals, books, magazine, webinars), practice foundation (simulation, EYESI, dry lab, wet lab), performing (under supervision, independently), review and refine (recorded surgeries).
Lockington said there were many great many simulation methods, and not only for cataract surgery, but barriers often include time concerns and resource costs, but the real resistance comes from a pre-existing culture with a poor understanding of the benefits.
Looking at his own work in Glasgow, Lockington said they were keen to highlight gaps in the trainee experience in terms of managing complications – posterior capsule rupture or vitreous loss – and experience using adjuncts – capsule tension rings – and organise the simulation accordingly.
By using simulators, Lockington said the program allows for mandatory inductions, mandatory laser training, and delivery of sub-specialty training prior to rotation. Trainees are given model eyes to take home, and were also challenged to perform as many procedures as possible in simulation. The winning entry contained more than 50 procedures, saving costs for the training program and maximising training opportunities.
Interestingly, Lockington said the EYESI simulator in Glasgow in 2019 (pre-pandemic), was used an average of 16 times per trainee, with the monthly median duration of actual simulation being 719 minutes. In 2020, during the pandemic, with fewer real-word training opportunities, much higher use was reported, with 29 average occasions and a monthly median duration of 1,246 minutes.
“People are often concerned about cost of simulation, but I would ask what is the cost of a complication? Our project in this area shows prevention rather than management and follow up of a complication will always be much more cost effective, and that is why we engage in simulation,” he said.
Lockington pointed to Dr John Ferris – who designed the Simulated Ocular Surgery website – and his group who looked at trainee complication rates, if they had been trained on the EYESI simulator prior to cataract surgery. There was a 38% reduction find in those who had done simulator training, “which makes sense because … they were familiar with the steps and already well up the learning curve”.
If trainees aren’t prepared for complications like vitreous loss in cataract surgery, Lockington said this can lead to a ‘grief cycle’, including denial, anger and causing more damage, hence the importance of immersive simulation.
“Some people think you need some complications under your belt, but for the patient it matters, they can have higher retinal detachment risk (42 times) increased endophthalmitis risk (eight times) and may not get back to driving standards due to the CMO (cystoid macular oedema) you have induced,” Lockington added.
He rounded off his presentation with a popular quote among US Navy Seals that: “Under pressure you don’t rise to the occasion, you sink to the level of your training. That’s why we train so hard.”
He added: “This is why we want to simulate scenarios so we can take the complex and make it simple, rather than take simple and make it complicated because you don’t know what you are doing.
“There are real time and cost issues associated with ophthalmic simulation, which is often run on goodwill, with minimal/no time or finance allowance, it needs to be resourced properly. In summary, COVID has disrupted medical education and simulation has filled some gaps, but it should have been prominent the whole time. Coming out of the pandemic we have a unique opportunity to enshrine simulation for safer surgical experiences.”
To round off the congress, Associate Professor Catherine Green delivered the popular Fred Hollows Lecture, with a presentation entitled: ‘Disruption and innovation: Challenges and opportunities in ophthalmology’.
Green is a glaucoma specialist and ophthalmic educator based in Melbourne, and is head of the Glaucoma Unit at the Royal Victorian Eye and Ear Hospital (RVEEH), the largest specialist glaucoma service in Australia.
She discussed the potential for innovation brought about by COVID. And while it’s important to promote sustaining innovations that improve on current technology and systems, she said it’s also important to look for truly disruptive innovations that provide opportunities in ways not previously considered.
In a case study, in 2014 Green said RVEEH decided to discontinue general clinics in response to a need to improve cataract surgery throughput. An unintended consequence was that a third of patients attending general clinics had a glaucoma-associated diagnosis. But with nowhere to go, they were referred to the hospital’s glaucoma clinic. Prior to this, the glaucoma clinic was reserved for tertiary speciality care and was essentially keeping pace with demand. However, numbers soared reaching nearly 4,000 on the waitlist, sitting at less than 1,500 more than a year prior, without a real increase in capacity.
Faced with such a problem, Green adopted systems and design thinking.
Previously, the hospital had improved capacity without increasing resourcing with the establishment of a Glaucoma Monitoring Unit. It went from seeing 5,880 patients in 2006/7 to 6,812 in 2009/10, resulting in an almost 16% increased ability to see patients.
This coincided with new RANZCO Glaucoma Referral Guidelines, and an optometry-ophthalmology chronic eye diseases shared care initiative of RVEEH, which had high acceptability and uptake. RVEEH had also collaborated with the Australian College of Optometry (ACO) looking at GP referrals, which found a large proportion of patients did not need to be seen at RVEEH and could be discharged to the community or optometry care.
Based on this, the department was able to advocate for Glaucoma Collaborative Care (GCC) project, which commenced in 2016. Based at ACO, it included a multidisciplinary team of orthoptists, optometrists and ophthalmologists. It was vital the right patients were sent to the clinic, so it involved a consultant triage. Initially, it looked at new referrals and then took in patients on the waiting list. Continuing education was important for involved health professionals, and patients had a full glaucoma work up.
Green said the promising 17-month evaluation data showed 65% of the 1,024 clinic attendees had no glaucoma or were low risk with ocular hypertension or glaucoma suspect. The majority were safely seen in the community by optometrists or private ophthalmologists. This had a positive impact on the RVEEH wait list, with a 48% drop in those overdue for review and a 92% drop on the new patient wait list.
“This meant that patients we needed to be seeing with advanced glaucoma and adverse effects due to not being seen were being adequately looked after,” she said.
“But this still wasn’t enough, we still had a backlog of patients and oversubscription for our services, so what about patients who can’t be discharged? The RANZCO guidelines indicate patients with early stable or moderate stable glaucoma need to be monitored, but not necessarily at each visit by an ophthalmologist.”
This led to the establishment of another initiative in 2019, the Glaucoma Community Collaborative Care Project (G3CP). This involved engagement of community optometrists in areas of high geographical demand, with patients recruited in the clinic. Underpinning this was education sessions for optometrists where they could interact with glaucoma consultants. A structured protocol was also followed and clinical outcomes sent to the hospital and reviewed by a glaucoma specialist.
After a year, G3CP had 70% uptake from patients offered participation, with the most common reason for non-participation being the RVEEH was more convenient. There was also high patient satisfaction, and it had excellent optometry engagement and satisfaction.
“So, we now have a proof-of-concept where we can now safely monitor lower risk glaucoma patients, and the other positive is we now have an established network of optometrists with whom we can collaborate,” Green said.
But there were challenges, including lower than projected recruitment (91 patients) due to it being done opportunistically in the clinic instead of systemically. However, a major issue was the exchange of information and the need for a digital solution critical to long-term sustainability and scalability, highlighting the issue of electronic health records and the management of clinical information. Another unanticipated issue was optometry workforce turnover, which Green said is a manageable problem and will have less impact if scaled up.
In early 2020, COVID-19 resulted in reduction of the RVEEH Glaucoma Clinic with the need to see only the most urgent patients initially. Monthly wait lists grew from around 2,000 pre-pandemic peaking to around 3,800, while the number of patients seen reduced from around 1,500 to around 1,000, dipping below 500 at one point.
However, triaging processes used during the pandemic has allowed the hospital to see all high risk and most moderate risk patients, but there is a growing backlog of overdue reviews. There’s also a likely backlog of new referrals with optometry also affected by lockdowns.
In terms of next steps, Green said with G3CP now established and the concept proven, there is a network of optometrists that need to be operationalised, with the program potentially expanded.
“It’s also a great opportunity to demonstrate the need for an improved digital health solution and we are certainly exploring options,” Green added.
She pointed to a 2020 JAMA Ophthalmology article showing that an existing health record with adequate clinical information was able to triage patients in a less labour-intensive way. Other examples of innovation include technological enablement, such as smartphone-based vision screening (PEEK, successful in Africa), rapid assessment and avoidable blindness (RAAB) eye health surveys, real time data reporting and analytics, training and support, and program design and planning tools.
But Green said it was important to consider innovation vs evidence and the need for robust data (Scott’s parabola, the rise and fall of a surgical technique). There’s also the need to consider cost effectiveness of new approaches (microshunt vs trabeculectomy).
“Innovation is needed now more than ever; sustaining innovation is possible, even without enabling tools – for example our rather non-digital, manual way of improving our glaucoma service was possible, if not completely efficient,” Green said.
“Improvements can be slow, and we need to persist, we also need to employ design and systems thinking when solving problems. And there is a need to strive for disruptive innovation in eyecare. Enabling technology does exist, we just need to work out how to apply it in a systemic way. And finally, as a profession, we need to consider how we might be disrupted, especially if we don’t innovate.”