There’s no doubt that virtual conferences have proven to be highly popular and very successful during the COVID-19 pandemic and may change the way the profession does at least some of its learning going forward. Optometry Western Australia (OWA) took the initiative to run its annual conference – WAVE – in several bite sized sessions, beginning with Dr Lauren A yton and Dr Alex Hui on the weekend of 29 March.
Almost 600 optometrists went online to listen to eminent clinician-scientist Dr Lauren Ayton present three live 30-minute sessions on age related macular degeneration (AMD) and gene therapy.
if you have patients with IRD or AMD who are interested in what’s going on, and you think they might benefit from being involved in research… offer them access to clinical trials
Dr Ayton reiterated the importance of the Beckman Classification for AMD, which was devised in 2013 to avoid confusion when communicating disease progression. She said rather than referring to wet and dry AMD, by now all optometrists should be referring to the following stages:
- Normal ageing changes (druplets only)
- Early AMD (medium size drusen, nopigmentary changes)
- Intermediate AMD (large drusen and/orpigmentary changes)
- Late stage AMD (atrophic orneovascular)
Although AMD can exist at different stages in each eye, the Beckman classification is per patient and based on their worst eye. A practitioner’s classification of a patient should be determined based on what they see clinically or in colour fundus photographs.
GENETICS AND THERAPIES
Science has now identified over 35 genes linked to AMD. This knowledge is opening doors for gene therapy, and helping identify people at an earlier stage, who might benefit from early interventions as they become available.
The aim of new AMD treatments is to reduce the burden of anti-VEGF treatment, which is currently significant. Sustained release treatments (e.g. ocular implants and longer lasting anti-VEGF injections), complement inhibitors, neuroprotection, and anti-inflammatory drugs as well as stem cell and gene therapies are all on the way.
Dr Ayton said ocular gene therapy for eye disease is “huge” and optometry would be at the centre of this.
“It’s gone from the sphere of science fiction to reality very quickly… The eye is the perfect place for gene therapy: there is no direct blood supply to the retina, there are no lymphatics within the eye and the eye has immune deviant properties which mean gene therapies delivered to the eye are more likely to last.
“Anything we inject into the eye will not enter the systemic blood stream and the retinal cells do not divide after birth, so if you can treat the retina then the transgene expression may persist indefinitely and will not be diluted.”
Three different forms of gene therapy are being explored. Initially, these will be to treat inherited retinal disease (IRD), and then expanded to more genetically-complex diseases such as AMD and glaucoma:
- Gene augmentation: the defective gene isreplaced, typically using an injected virusas the vector,
- Gene editing: CRISPR/Cas9 technologyis used to edit /change the genome,
- Optogenetics – “a clever way to use genetherapy” which turns healthy inner retinalcells into photoreceptors by making them reactive to light. “This is very exciting, very early, and there are some clinical trials but we are unlikely to see a therapy for a few years,” Dr Ayton said.
Gene therapy was designed to halt disease progression, but in some cases patients are regaining some sight. It is most effective when at least 63% of the photoreceptors are still present, even if they are sick, and cannot be used in patients who are completely blind. This makes gene therapy most suitable for children, or those with relatively early disease.
The first inherited retinal disease patient was treated in 2007 and in November 2017, the first direct-to-human gene therapy in the world (Luxturna) was approved for Leber Congenital Amaurosis (a form of IRD). Luxturna, which delivers the correct version of the mutated RPE65 gene to the retina, is not yet available in Australia but negotiations are underway to get it here by the end of the year. Theoretically, this is a once-off treatment that halts the progression of the disease. It costs US$850,000 to treat a patient with Luxturna, which presents complications for funding.
In May 2020, a phase one/two trial for a CRISPR-based gene editing therapy for Leber Congenital Amaurosis commenced. This is the first time that gene editing has been used in patients, and the therapy was used because, in this group, the gene needed to replace the mutated gene was too big to be fitted into a viral vector.
A 15-year trial is currently underway to determine exactly how long gene therapies will last and while the first-generation therapies have targeted IRDs, the next generation are focussed on increasing neuroprotective factors against more complex but more common eye diseases such as glaucoma and AMD.
“I strongly advise, if you have patients with IRD or AMD who are interested in what’s going on, and you think they might benefit from being involved in research, that you offer them access to clinical trials. This will help us further our knowledge in the research field and give them access to early treatments,” Dr Ayton said.
Optometrists who are interested in pursuing this should contact their local research institution, such as the Centre for Eye Research Australia (Melbourne; www. cera.org.au), Lions Eye Institute (Perth; www.lei.org.au), Save Sight Institute (Sydney; www.savesightinstitute.org.au) or an academic within their local University School of Optometry. “
We are working collaboratively across Australia and the globe and are actively searching for people with AMD and inherited retinal diseases for research,” she concluded.
PAIN AND INFECTION IN EYECARE
Dr Alex Hui (UNSW Sydney) presented three sessions on antibiotic selection, infection management and pain management.
Among several topics, Dr Hui spoke about prescribing antibiotics for ‘special populations’ – namely women who are pregnant or lactating and the young – babies and neonates.
Ratings have been developed by the US Food and Drug Administration and Therapeutic Goods Administration (TGA) for each drug in terms of their use during pregnancy to help clinicians when making decisions about prescribing. These ratings take into account the potential for developing birth defects, unwanted pharmacological effects, and developments that may occur after the baby’s birth. Additionally, they consider the systemic exposure to the foetus, and dose, dosing regimen and route of administration – a cream applied to the toe vs a drug injected into the uterus, for example, will have a different impact and potentially a different rating, even for the same active ingredient.
Dr Hui said it is important to note that the ratings only consider drugs used as directed – they do not cover rare reactions, overdoses, or other cases in which the drugs are not used as designed.
Category A drugs are considered safest for use in pregnancy and for women of childbearing age – no increase in frequency of malformations or direct or harmful effects to the foetus have been reported after these drugs have been used by a large number of women. In terms of eye drops, chloramphenicol is a category A drug – it has a long history of use and has been found to be safe.
Category B is the category into which the majority of eye drops fall. Category B comprises three sub categories and there is currently insufficient evidence to show whether drugs that fall into this category increase the occurrence of foetal damage in humans, but there may be some positive or negative evidence from animal studies. Examples of category B drugs include Acyclovir eye ointment and Ciprofloxacin eye drops.
Category C drugs cause, or are suspected to cause, harmful effects on the human foetus without causing malformations, making it important to consult the accompanying texts before considering prescribing for women who are or may be pregnant.
Category D drugs, which include Gentamicin eye drops, have caused, are suspected to have caused, or may be expected to cause an increase in incidence of human foetal malformations or irreversible damage. Accompanying texts should be consulted and other drugs considered before they are prescribed.
Category X drugs, which include Isotretinoin, have such a high risk of causing permanent damage or malformation to the foetus that they should not be used in pregnancy or where there is a possibility of pregnancy.
Dr Hui reminded optometrists that the TGA classification of drugs is not hierarchical – they merely communicate the levels of certainty that the drugs can cause issues during pregnancy or harm to the foetus in humans. For example, the ranking for Category B drugs is based on animal data and a lack of widespread human data, and there is no implication that these are necessarily less safe than those in Category A.
We can really only be certain about drugs in Categories A and X, however there are grey areas around drugs in Categories B, C and D. Optometrists and their patients need to use the ranking and product information available when considering potential risks.
Dr Hui said while the majority of topical ocular antibiotics are ranked in Categories A to B3, other formulations using the same active ingredient in a different way, for example as an oral and injection, may differ in their pregnancy category.
PRESCRIBING FOR CHILDREN
Children have less developed organ systems so their ability to metabolise and clear drugs is different to adults. This affects dosage; it’s not simply a case of giving a nine year old half the dose you’d given an 18 year old for example. Age, weight, and possibly total surface area of the patient all need to be taken into account.
“These children are still developing and anything we do may have an effect on this. For example, tetracyclines are not recommended for those under 18 as it will deposit on developing bones and teeth. There are children who have discoloured teeth because they have been prescribed this drug.”
Dr Hui said optometrists may be uncomfortable prescribing drugs for children because it is necessary to prescribe off-label and outside what the drug’s sponsor used to get the drug approved for the market. The product information sheets may not give you all the information you want – you may have to refer to studies published by the pharmaceutical developer or other resources such as the Australian Medicines Handbook to see what the experiences of using these drugs in children have been.
“So we might need to modify the dose, use drugs in age groups that we might not have information about (as long as not contraindicated) and we might also need to use them for other indications than what has been noted in the product information sheet,” he said.
BROADER AUDIENCE REACHED
Evan McRae, Executive Officer of OWA, said feedback from the WAVE online sessions was exceptionally positive. “It was a shame to have to cancel our annual conference at the Esplanade Hotel in Fremantle as registrations were looking stronger than 2019, however our livestreamed presentations definitely reached a broader audience than those who had registered for the conference.”
Recorded presentations can be viewed and points acquired until 30 November by visiting www.optometry.org.au.