Glaucoma – New genetic research set to prevent ‘silent thief of sight’ 

Professor Stuart MacGregor (00:41):

Glaucoma is a progressive disease where the retina is damaged, usually through pressure in the eye, but it’s a really slow to develop disease in most cases. People with glaucoma lose their peripheral vision first. The retina is slowly damaged over a period of months and years. Because you lose your peripheral vision first, it’s quite easy to not notice one eye covers for the fact that the other eye has a small gap in the vision. That’s why about half of all Australians are undiagnosed with glaucoma even though they already have the early stages of the disease. That’s a big problem clinically and as the Australian population ages, it becomes a bigger problem as more and more Australians are older and at risk.

Clare Blake (01:20):

How do you find it?

Professor Stuart MacGregor (00:42):

Sometimes by optometrists, sometimes through referral to ophthalmologists. It’s a big problem actually in Australia managing the burden of glaucoma as the population ages. In one sense, if money were no object, it would be to just screen everyone regularly, make sure that everyone got eye checks regularly, and that happens to a degree. It’s just not realistic on a big scale. There’s maybe 10% of the population might be at risk of glaucoma amongst the older generation, but maybe only a third of those people would actually get disease. So, you’d have to screen so many people. That’s not feasible.
(01:52):
It’s more of an ad hoc process of people notice they’ve got a bit of vision damage or you go to the optometrist to get glasses because most people, when you turn about 50, you need reading glasses, which has nothing to do with glaucoma, but sometimes glaucoma might be diagnosed then. But often even at that point, it’s undiagnosed because that’s not the thing that they’re always looking for. So, to fix some of those things about how we could screen the disease more effectively, how we could develop better treatments. There are treatments, but sometimes they’re not applied soon enough and sometimes those treatments just don’t work and we need alternative ones. Understanding the genetics of glaucoma is an exciting opportunity for us to better understand who will be at high risk early on and apply treatments in a more timely fashion, and also potentially to develop new treatments based on an improved biological understanding of the disease.

Clare Blake (02:47):

I want to talk more about that in a moment. What is glaucoma? Is it painful? What do people go through with the disease?

Professor Stuart MacGregor (02:47):

About 300,000 Australians have glaucoma. Only about half of those are diagnosed. The other half have the early stages of the disease where they just lose a little bit of their peripheral vision. There’s no pain involved in the disease and it happens over a long period of time, over months and years in some cases. So, that’s why it’s quite easy to not realize you have the disease and if you’re not getting your eyes checked regularly, there can be no way of knowing that you could be in the early stages where you’re losing your peripheral vision, which is obviously dangerous in terms of everyday activities like driving, potentially dangerous. Crucially, that damage which occurs early on, even if you just lose a little bit of your peripheral vision that happens slowly, that damage is irreversible. So, all current treatments basically just stop the retinal degeneration from getting worse. They can’t magically roll back time. You can’t get retinal ganglion cells back once they’re dead. So, that’s-

Clare Blake (03:31):

But you can treat before the symptoms appear and avoid that blindness?

Professor Stuart MacGregor (03:35):

Yes. In an ideal world, we would treat everyone the minute there was any sign of glaucoma. In about half of cases, that diagnosis don’t come early enough. So, the treatments which work pretty well are not applied in time.

Clare Blake (03:46):

We’ve known for a while that it is a highly genetic disease. So, there were limitations with that and this is where your research has really blown it wide open. Can you tell us more about that?

Professor Stuart MacGregor (03:55):

Yes. We’ve known for decades that glaucoma is a genetic condition. It runs in families. If you have a parent or a brother or sister with the disease, your risk is a lot higher. But we didn’t know the specific genes which caused the disease. In fact, when I started about 15 or 20 years ago, we knew one or two of the genes and knowledge of those helped in a small number of cases, maybe one in a hundred cases, to actually help those people. It wasn’t going to have a big population impact knowing those small amount of genetics.
(04:22):
Over the last 15 years, we’ve built up an increasingly complete picture of what the genes are, how it is that they cause glaucoma. For example, some of those genes increased the pressure in your eye. Some of them increased the robustness of your retinal ganglion cells to damage. So, we’re building a more complete picture about the biology of the disease and also we’re building a more complete picture of how you can predict a person’s risk from your genetics, which in practical terms actually means something pretty simple. It means doing a saliva test.
(04:49):
We work out which genes you inherited from your parents and use that to predict glaucoma risk. For example, in 2015, we had about a dozen loci. 2021, we got up to just over a hundred and in work we’ve just published this year, we’ve taken the number of genes to over 300. This is really exciting I guess for two main reasons. One is better understanding of the biology and new drugs and better prediction of who’s going to be at risk, so we can get early diagnosis to the right people.

Clare Blake (05:14):

Can you predict it earlier? How earlier would you have such a test?

Professor Stuart MacGregor (05:19):

Most people that have glaucoma in Australia get it over the age of 50. There are some cases where it’s earlier than that and there’s some unusual cases, maybe less than 1% of cases, would be before 50, sometimes even a juvenile onset. Really, the burden of Australians showing glaucoma is in older people, people over the age of 50. In terms of the potential for using genetics to get early diagnosis, it’s not practical to screen everyone aggressively for glaucoma. The aggressive treatment might be getting someone to go and get their eyes checked every six months. That’s not feasible for everyone over the age of 50. That would waste a lot of people’s time. It wouldn’t really deliver that many cases or early diagnoses.
(05:57):
What we’re interested in doing is, well, what about if we could find out which 50-year olds were at highest risk or which 55 or even 60-year olds? So, people earlier than you might usually consider screening for the disease. What about if we could identify those people ahead of time and say, “Well, you should go and get tailored treatment every six months”? Other people might be at normal risk, and in fact it might even be that some people are particularly low risk. So, those people can perhaps spend more time worrying about other things than-

Clare Blake (06:21):

There’s plenty.

Professor Stuart MacGregor (06:23):

The dream is to take our knowledge of genetics to build up a risk stratification tool. So, that would be something that would allow people to do a simple saliva test, a simple DNA test, and work out, “Well, is my risk high enough at age 50 that I should be getting treatment regularly or perhaps age 55 or 60?” In some cases in some people, their risk would be lower and so it could be managed differently. The practical steps are basically taking our genetic discoveries and translating those into a test that people can use. We’ve got this knowledge of these hundreds of genes. We need to take the practical steps to get this test into the community.
(06:58):
We have a research use version of the test. I guess, going beyond the work that I do at QIMR Berghofer, we’re also interested in doing commercialization. So, we have a startup company which is developing the test and will soon be able to offer it in an academic context to build the case for a practical implementation of glaucoma screening. We’re starting a new study soon, which is getting people who have family history of the disease and getting them to do a genetic test. Those people are probably at unusually high risk, and those people might be the people who’d benefit in the near term for this DNA test being particularly useful in terms of them getting early diagnoses. So, that’s just-

Clare Blake (07:32):

I think you’ve just got a lot more compliance by saying a saliva test. Would that be the genetic test as well?

Professor Stuart MacGregor (07:36):

The genetics we’re talking about, to be completely clear, is the genes that you’re born with. They’re sometimes called germline DNA rather than your somatic DNA, which would be DNA which was damaged through the process of tumorgenesis and cancer, for example. So, we’re just talking about the genes you’re born with. Actually, the genetic test for glaucoma, which in most cases would be applied when someone’s about 50 or 55 when they’re starting to get into the period of risk as you age, that genetic test could be done at any time between birth and age 50. Obviously, in practical terms, now we’re going to be offering these tests soon to people and they get it done at the right time.
(08:11):
In the not too distant future, we will just have that in your health record. For a few people, when they get to the age of 50, that information pops up in your record and says, “Actually, this person is in a really unusually high risk category. We should start screening them earlier,” and they get better screening. In some cases, those people get glaucoma. We get them the right treatment at the right time, so they don’t have irreversible blindness. Not everyone’s like that. There’s still an element of randomness, but at least we can apply the treatments in general to the right groups of people, so that most people would benefit whilst others are not worried.

Clare Blake (08:41):

Just because you’re high risk doesn’t mean you’re going to get it.

Professor Stuart MacGregor (08:44):

Yeah. Australians over the age of 50, they have about a 3% risk. So, about one in 30 Australians over the age of 50 have glaucoma. If you have a family history of disease, it’s about five or six times higher than that. So, maybe 15 or 18% risk. That’s an average risk. People who are lucky, instead of having a 15% risk, they just have a 3% risk or the normal risk. Some people with family history when they do the simple saliva test could actually not worry too much about their glaucoma.
(09:11):
But unfortunately, some people who have family history and also are unlucky with the genes that they’re born with, their risk maybe 30, 40, 50%. We’d like to make sure that those people are getting their eyes checked early on. Even amongst those people, only maybe a third or a half of those people are affected. But that’s high enough that those people I think really want the health system to know to make sure those people get the right screening.

Clare Blake (09:33):

Well, at the moment, we’re treating the pressure that builds up and that causes the problem with the retina, but your research is really going to open up for actually treating the retina, which might be better in terms of overall treatment.

Professor Stuart MacGregor (09:46):

All existing treatments for glaucoma just lower the pressure within the eye, and in many cases that works very well. Sometimes, there are issues because you get someone who’s diagnosed with glaucoma, unfortunately, particularly older men who are perhaps not so keen on taking medications or going to the doctor. Sometimes, what happens is those people are given pressure lowering medication. They take eye drops. The eye drops don’t feel like they do anything, but what they actually do is control the pressure, but you can’t feel yourself. So, sometimes they stop taking the eyedrops because they feel like it’s not doing anything, and then the glaucoma initially stopped through the eyedrops. But if you stop taking the eyedrops, it gets worse. Pressure lowering medication in theory works, but in practice, not always, because some people stop taking the medication because it feels like it doesn’t do anything.
(10:27):
This also happens in cardiovascular disease as well. You’re given medicine. You take it for the first few months and you think, “Oh, well, it’s not working. Things aren’t different.” But actually, it is working. The existing treatments focus on the pressure in the eye. The retinal damage is really secondary to that pressure effect. Really, the holy grail of treatments for glaucoma would be to not just change the pressure, but would be to change the retina to make it robust to the pressure increase. There’ve been trials of what are called neuroprotection drugs. So, drugs for protecting the retina from damage and making it more robust. But so far, those haven’t worked. What’s exciting about the genetic research is when we found a few genes for glaucoma, most of them affected the pressure in the eye. Particularly now, we have over 300 genes for glaucoma. About a third of those genes affect the retina of the person who has those genes, and they influence how robust the retina is to damage.

Clare Blake (11:23):

So, even if the pressure builds up, some people have got a strong enough retina to cope with it.

Professor Stuart MacGregor (11:27):

Yeah, exactly. By having a better understanding of why certain people’s retina are more robust to damage than others, we can harness existing drugs which work in the same pathways as the ones that we are implicating through our genetic studies. Basically, we’ll get a drug which will mimic and make everyone be naturally more robust in terms of their retina to glaucoma.

Clare Blake (11:48):

That’s extraordinary. You want hundreds of thousands of more people to continue this research. Who do you need to participate?

Professor Stuart MacGregor (11:58):

We’ve had over 5,000 people in the last three years sign up for our studies of the genetics of glaucoma. So, that’s been terrific. That’s helped us in two ways. One of them is building a better genetic test. We have a genetic test, which does a pretty good job of stratifying who’s at low, medium, and high risk, but we know that there’s room for improvement there. There’s more genes we can fine tune, so we can get more effective tests. Just the basic test works pretty well, but we think there’s room for improvement there. So, we want more people with glaucoma to sign up for our study. That process is pretty simple. They fill out a simple questionnaire about their health. We mail them a saliva kit, which they spit into, send it back to us, and then we can do the DNA test.

Clare Blake (12:34):

It’s way better than the poo kit I have to say

Professor Stuart MacGregor (12:35):

Yeah, it’s a lot cleaner. The implications of the tests are most impactful for people who have a family history of disease because those people are at an elevated baseline risk, and then if they’re unfortunate with the genes they’re born, those people might be the people we really want to grab and say, “You’re 50. You wouldn’t normally be at risk of glaucoma, but actually we think you are,” and we’ll get those people in early. We want to trial the testing of the genetic test in people with family history. So, we’re really encouraging Australians between the age of 50 and 65. We can use ones outside that range, but we’re really interested in that group. That’s the period when most Australians go from negligible risk to potentially moderate risk of glaucoma, people between the age of 50 and 65 who have a brother or a sister or a parent who already has glaucoma. More distant relatives doesn’t increase your risk enough. It’s no use for this particular arm of the study, and those people’s risk is really not as high.

Clare Blake (13:26):

When you do the eye test, the little puff of wind, is that the one that’s looking for pressure in the lens?

Professor Stuart MacGregor (13:33):

Yeah, that’s usually done with a simple puff test that can be done at the optometrist’s or an ophthalmologist. That just basically measures the pressure in the front of the eye. That’s usually a good sign, but not always a good sign. Part of the issue with the under-diagnosis of glaucoma is that some people still get retinal damage even with normal levels of pressure. Hopefully, the genetic test would help with those people too because as I mentioned, we’re finding some of the genes increase your pressure, some of the genes affect your retina and how robust your retina is. So, the genetic test would potentially help in terms of diagnosing people in that way.

Clare Blake (14:05):

When we go right to the end of this research and you get exactly what you want, does it mean that everybody will know their risk, if they choose to participate, and nobody will lose sight?

Professor Stuart MacGregor (14:19):

Currently, about 10% of Australians who have glaucoma reach legal blindness. I guess, the dream would be that people will still get glaucoma, but they’ll have it managed from the early stage of the disease before there’s any vision loss. I’m not a clinician. I’m interested in the epidemiological public health space. I’m particularly interested in how we can prevent the disease, prevent the early stages. The genetic test that we’ve developed is also potentially useful in how aggressively a person might need to be treated if they’re at the moderate or late stage of the disease. So, there’s a potential there for that to prevent blindness as well, because someone who is, say, diagnosed unfortunately too late, they might have lost quite a lot of their vision, but we want to maintain what they’ve got. The genetic test has shown some promise in terms of tailoring their treatment, for example, to whether they continue drops or whether they get laser surgery, which is a more aggressive but potentially more effective treatment. So, there’s scope at each of the stages of the disease to try and make improvements.

Clare Blake (15:16):

You’re not a clinician. So, you don’t want to get into the treatment too much, but I think a lot of people would avoid knowing about glaucoma thinking that to relieve the pressure on the lens, they’d have to have an needle. But that’s only in serious cases, I guess.

Professor Stuart MacGregor (15:29):

Yeah. In the majority of cases, eyedrops are effective. The most commonly used ones are called minimally invasive treatments. Those ones, they have essentially a laser which changes some of the cells within the eye and the trabecular meshwork in the eye to make the flow be accelerated out of the [inaudible 00:15:48] to basically lower the pressure. So, there is a relatively simple laser treatment. It’s still a surgery, but it’s not as scary as you might think.

Clare Blake (15:54):

Right.

Professor Stuart MacGregor (15:55):

In most cases, eyedrops are effective as long as people take them in time and as long as they keep taking them. If that doesn’t work for whatever reason, the laser treatment is usually pretty good. If the latest treatment also fails, there are more invasive treatments which can be done.

Clare Blake (16:10):

How do you go about it if you’d like to participate in this trial? Because we need lots and lots of people.

Professor Stuart MacGregor (16:15):

Participating in this trial is very simple. We have a genetics of glaucoma webpage, which you can find on the QIMR Berghofer website. You click on the link, you fill out a simple survey about either your own history of glaucoma, if you have glaucoma yourself, or your family history of the disease, if you have a parent or a sibling with the disease. We send you a spit kit in the mail. In most cases, you send that back to us in a reply-paid envelope, and if you’re eligible for the trial, we’ll ask you to go to a local optometrist and get your eyes checked, and we’ll marry that up with your genetic profile and make sure that the right people get the right glaucoma diagnoses at the right time.

Clare Blake (16:50):

This research is so incredible, you also found a link to other diseases. What does that mean?

Professor Stuart MacGregor (16:55):

Because we’ve now found so many genes, which explain why some people get glaucoma and some people don’t, interestingly, some of those genes are actually linked to other complex diseases. So, there’s a link with diabetes, and that link may actually be over and above the link which exists where people with diabetes, sometimes their glaucoma is found opportunistically because they’re screened for diabetic retinopathy. The genetic links that we found with glaucoma, some of those turn out to be shared with diseases like diabetes, but also interestingly, some immune-related diseases such as multiple sclerosis.
(17:31):
I guess ultimately, one of the big things that’s come out a lot of the genetic studies is that there’s a relatively limited number of genes in the human genome, but it seems like many of those genes do so many different things. So, we’re actually finding unexpected links between diseases which weren’t previously thought to be linked. That’s one of the really exciting new things that we’re still trying to work out how to harness, but it’s certainly fascinating getting so many genetic discoveries and working out what the implications of those are, both for glaucoma and for other diseases.

Clare Blake (17:59):

If you get thousands of people that you need to continue research, there might be more surprises.

Professor Stuart MacGregor (18:06):

Yeah, I’m pretty confident in the next few years, rather than having 300 genes for glaucoma, we will have 500, 700, and each of those will help with predicting risk. They’ll provide exciting new insights into the biology of the disease, and they may help with further development of new treatments for the disease.

Clare Blake (18:24):

If you’d like to donate, if you’d like to find out more, or if you’d like to participate in this really exciting research, there’s one place to go and that is qimrberghofer.edu.au. Thank you so much, Stuart.

Professor Stuart MacGregor (18:40):

That’s great. Thank you very much.

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