 So our next speaker is our invited guest, and this is Dr. Maureen Knight, and she's here from the University of Washington. She got her PhD at UC Santa Barbara and made her way to Wisconsin for a number of years where she was in ophthalmology there, and now she's been at University of Washington for about the last 10 years. Her lab investigates the genetic basis of normal vision as well as vision disorders, and she's here today to talk about some work in myopia and particularly testing some eye glasses to try to slow down the progression, so very interesting. Thank you. Dr. Knight. Thank you. Good morning, everyone. Okay, so the title of my talk, can everybody hear me? The title of my talk is Myopia, a major worldwide problem that can be solved, and I will start with my disclosure. So I'm a co-founder of a company called Waveshift that has the mission of putting an end to the worldwide myopia epidemic, and I'm also a co-author on patents that are assigned to the Medical College of Wisconsin and to the University of Washington that have been licensed to Waveshift, so these are my significant financial interests in the whole deal. So when I was growing up, you can see I'm nearsighted, and everybody made fun of me calling me four eyes, but since I was a child there has been a huge increase in the prevalence of myopia, and it is predicted that by 2050 there will be five billion people who are myopic, and so that's just basically one generation from now. So the wave of the future is that I will be normal and the people that don't wear glasses will be made fun of instead. But not only is there a huge increase in myopia in general, but it's predicted that a billion people will have high-grade myopia. So one of the things that's happening now is not only are more people myopic, but the agent onset is much earlier than it used to be, and the earlier you start overgrowing your eye, the greater the degree of overall myopia you can achieve by the time you're an adult, and so there are going to be one billion people that have high myopia, and these are the people you'll see in your clinics because they're at higher risk for cataracts, glaucoma, and retinal detachments. I'm a minus nine, and so every time the ophthalmologist looks into my eye they go, oh, I see the stress. So I'm going to tell you our unconventional hypothesis and our unconventional approach to trying to see if we can't stop the progression of myopia, and it all is based on the fact that cone photoreceptors are contrast detectors, and the difference between sharply focused versus blurred images, and we didn't start by being interested in myopia. We got interested in myopia when Terri Young and her colleagues published this paper in 2004 where they did genetic linkage analysis and linked the very first high myopia gene called MYP1. They linked that to XQ28, and XQ28 is the chromosomal location of the red and green cone photopigment genes, and I had spent at this point probably 25 years studying those cone photopigment genes. I'm very in tune to them, so I was really interested in this study. So this study what they showed is that the people that they were studying had this thing called Born Home Eye Disease, so it's a syndromic form of high grade myopia. These are people, by the time they're six years old, they can be minus 11, minus 16 diopters of refractive error, so it's a very aggressive myopia, but they also for the most part all have color blindness, and in this study what they were trying to do was figure out whether the cone ops and genes were the cause of the myopia as well as the color blindness, and it turned out that in this disorder, Born Home Eye Disease, the color blindness is a bit of a red herring, and they got caught in this, so they said, oh no, we ruled out the cone ops and genes as the cause of myopia because everybody that has Born Home Eye Disease, if the cone ops and genes were the problem, then everybody would have the same color vision phenotype, but they don't. So I know more about color vision genetics than anyone else on earth, I claim, I'm a self-proclaimed expert on this, and so I went and looked at the genetics that they had described in the paper, and it's very clear that the people are color blind for the standard reasons that people are color blind. You can see it in the genetics, so it did not rule out the cone ops and genes as being the cause of the myopia. So we ultimately collaborated with Terry Young, and what we did is we showed that there is a specific haplotype of one of the cone ops and gene exons that is the cause of the myopia, and this particular haplotype is in the title of some of these papers. Oops, okay, better not. I'm not good at my mouse. Is there a traditional kind of pointer, or is this just used to us? Okay, so what this, so the initial Terry Young study, we showed that those people had a particular haplotype, which I will refer to as LVAVA, and that haplotype, the average myopic or refractive error in her subjects was minus 12.5. Several other people have now gone on to show, and in her study we later show that they had this particular haplotype. These three other studies that I've listed here independently showed that this haplotype LVAVA is associated with myopia, very high myopia, and the average refractive error in the men that have this haplotype is given over here. So one study, it's minus 10.8, another minus 30.4, another minus 11.4. So it's very high grade myopia that people have. So the way that we, so we discovered that the cone ops and genes are involved in this unusual form of very high grade myopia, made us begin to think about how it might work and what the solutions to this, the cone ops and function in myopia going awry, or cone ops and function in eye growth going awry so that you get myopia. And so we, I'm going to tell it, I'm trying to get to the point where I tell you about the eyeglasses that we have developed in our clinical trials on that. So when an ametrope is accommodated, they're looking at, they're focused on things near and that's in focus, but everything in the periphery, in the peripheral retina, that's out of focus. And that's what's shown here. So when you're a kid and you're playing with your little friends, you're looking here when you're accommodated, so everything in the periphery would be in focus. But once you become ametropic, everything in the periphery becomes out of focus. I'm sorry. Yes. Okay. So, but the question is where are we looking all the time? And are we accommodated and looking at far distance or are we looking near? So there was a study done at Berkeley where they use this special device to try to figure out really where people are looking in the scene. So we can understand what people are actually looking at. And what this shows here is the dashed brown line is showing the scene points of interest. So when the person is looking around, these are a plot of where the scene points of interest are. And here it's showing the distance of those image points in diopters and up top it's showing it in centimeters. And the black curve is showing the fixation points of the person wearing that device. And what this shows is that very rarely are people ever looking at infinity. Mostly they're looking on average at some place it's about a diopter or a meter out there. So they're accommodated to one diopter. So they're very rarely looking out at infinity. So when kids are young, they're farsighted. So the distance scenery produces very high contrast in the periphery. And when the hyperrope is accommodated, the distance scenery is still relatively in focus because they have a very great depth of field. But as the eye grows and the person becomes hematropic, the distance scenery grows out of focus for the accommodated eye. And so that would be the signal for the eye to stop growing when it gets to this place where things go out of focus that knows to stop growing. So the way, theoretically, we evolved to be running in the woods listening to iPods, not sitting around looking at computer screens. And so when you're out in the world, what these two circles show is the foveal vision that you're accommodated to, for example, the face of this young lady who's running. And then this is what's happening in your peripheral vision. So where you're accommodated, it's very highly in focus because you're an hematrope. And everything in the distance is out of focus. But now, in our modern world, what we're doing is we're sitting in front of computer screens all the time. So if you map these places, the same circles of what you're looking at when you're out in the world onto your MacBook Pro, what you find is that not only is the visual stimulus that you're looking at in the center very highly in focus, but now everything in the peripheral retina is also very highly in focus. And this would be the stimulus for the eye to grow. And so because of our lifestyle in the modern world, we are stimulating our eyes to grow. And we would also argue that by constantly updating kids' prescriptions so that they're never with blurry vision, so their vision is always perfectly crisp everywhere in the lenses, that the standard care is also contributing to the progression of myopia. So what is the solution? So we think that the solution would be to blur the image in the periphery. So this is what the idea would be, is that if you could just keep the center in focus and then reduce contrast in the periphery so that you can still see it and read it if you need to. But it's now not so highly in focus that it would now not be the stimulus for the eye to grow. And so we have devised a eyeglasses approach to try and stimulate this reduced contrast in the peripheral retina. And that's illustrated here. So here would be a typical standard of care correction. And then here would be our idea of what a lowered contrast would be. So we did a clinical, a mini clinical trial on our reduced contrast lenses when we were at the Medical College of Wisconsin. And what we did was a, okay, so this is the results of the study, I'm going to tell you what we did. So we did within subjects control so that the kids wore a standard of care lens essentially on one eye. And on the other eye they wore a lens that reduced the contrast of the image. We had them come into the lab for two weeks before they started wearing the eyeglasses. And we only enrolled kids that were progressing at least a diopter per year in the previous year. So we measured their axial lengths and corneal curvature using the IOL master. Then we started them wearing the eyeglasses and they wore them for three months. All the IRB would give us. And they came into the lab every two weeks during the time that they were wearing the glasses. And we measured their axial lengths and corneal curvature. And so the data is shown here. So we have the normal which would be the control eyes and then the reduced contrast eyes there. Every single data point here or every individual person is a different color line. And then the solid black line shows the average of all of the treated eyes and with the standard deviations. And then the experimental lens are over here. We had 20 eyes in this study that wore the experimental lens and 20 that wore the control lens. And then this is our every two weeks measurements in months. And so you can see that the eyes that wore the standard of care continue to progress in their myopia over that short period of time. And the reason why we use the IOL master is we can make very small measurements or measure very small changes in axial length very reliably. And you can see that in the treated eyes or the eyes that wore the low contrast lens, there was a flattening out. This point here where the eye shrinks, that's real. Initially we thought that that was an artifact. And we said, boy, if we were ever to do this again, we would have the kids practice at the IOL master because that first data point is really terrible. But it turns out which we, because we have redone this study, what is happening in that first two week period is there's a corroyal thickening that gives a shorter axial length measurement. So the outcome of this study is that there was a huge reduction in the axial growth of the eyes that wore the reduced contrast lens compared the eyes that wore the normal lens with a very highly statistic significance. RP was .0019. Okay, so we used the data from this trial to justify doing a larger trial. And this was a randomized subject massed multi-center trial. And we had kids that were seven to 10 years old with the history of myopic progression. And the plan was to enroll 45 kids, kids per group. Here we had not within subjects study, we actually had a control arm and a treatment arm. There were 14 sites across the United States that enrolled kids. And the test product were lenses that reduce the contrast. And there were 40 kids that completed the experimental arm. We, five of the kids just didn't pick up their glasses. And then the control product was just standard of care glasses. The duration of this study was six months. And then they, you know, came on this time schedule to have their axial lengths and corneal caravatures measured using the IOL master at these different study points. And here is the results. So our outcome measure was a change in axial length and measured in millimeters over the days of the treatment. And as I say, it was a six-month trial. So this line is our control subjects that have wore the standard care lenses. And what you can see is that they continue to progress in the increase in axial length over the six months of the study. Whereas the kids that were wearing the reduced contrast lens, they had a very much slower progression in their myopia or the increase in axial length. So we were very encouraged by this. And so what this adds up to is a 61% reduction in the progression of myopia in the kids that were wearing the experimental lenses. So Lawrence Peter says, all science is concerned with the relationship of cause and effect. And each scientific discovery increases man's ability to predict. Thank you. To predict the consequences of his actions and thus the ability to control future events. And so we thought, okay, based on the results that we had so far with the eyeglasses reduction of contrast, we think that maybe reducing contrast even more is going to improve the reduction in the progression of myopia. And I want to make a point here first that there's a big difference between blurring the image and reducing the contrast. And what we're doing is we're reducing the contrast with our lens design. If you blur the image, it's very hard to see what the heck is going on. But if you reduce the contrast, you can still read this very easily. It's just reduced contrast. So in trying to reduce the contrast even more, we have done smaller studies. And so this is a study where we only had six subjects. The mean age was 10.67 years. And the mean refractive error in the subjects was minus 4.33. And the test product here were lenses that reduced the contrast twofold compared to the two previous trials that I've already told you about. And the duration of this study was one year. So I'm going to give you the results of that relative to the results of our randomized multi-site trial, which is here. So this is what I just showed you here as the control eyes in our previous study in the, excuse me, experimental lens group in that previous study. And then here we're just, I'm just extrapolating this out to what we would predict their myopia would be at one year if they continued wearing this lens. And then now we had our six kids wear this double reduction in contrast compared to those for one year. And their data points are shown here. And what you see is it flattens out. And this, what I'm showing you right here, these are the 95% competence limits for this endpoint here. And it does not overlap at all the other group. And this corresponds to a 75% reduction in myopia progression. So, of course, my collaborator in all of this, of course, is J. Knights. And J. Knights is the king of if some is good, more is better. So he said, okay, let's make a four times reduction in contrast lens. So then we had three kids wear on one eye a two X reduction in contrast and the other eye a four X reduction in contrast lens. And we measured them over time. And so I've got the color coding wrong on here. I'm sorry. But I'll explain it to you. And then hopefully, you won't need the color coding. So again, the outcome measure is the change in axial length as a function of the days of wear. And so, so this blue line right here goes with this black dotted line right here. So there, this is the increase in axial length for the eye that was wearing the two X reduced contrast. And on the same person, this is the eye that was wearing the lenses that had the forex reduction. And you can see that they're progressed that I that was wearing the four X reduction and contrast progress much slower in the in myopia. This person again, this is the two X contrast lens compared to the axial growth with the forex contrast lens. And again, the forex contrast lens is reducing the growth. And then finally, this person right here goes with this, the forex contrast lens really reduced the progression of myopia. So with this forex reduction in contrast, we're achieving on a small number of people given, but 9% reduction in myopia progression. So this is just lets you see what the difference between two X and forex reduction in contrast looks like. And here you can see up close that this is the forex reduction in contrast. It's really it's you can still read it. And then our present are the original glasses that we did that we did in our Wisconsin study and in the in the randomized clinical trial, the larger study with 45 kids per group. We just had the reduction of contrast across the entire lens. And since then, what we have been doing is we create a clear spot in the center. I don't remember the diameter of that clear spot, but we have it. So there's no reduction of contrast in the very center. So kids can just use that to to see anything that they really need to see super clearly. And we're just blurring the periphery. And we've asked the kids if they have if they have problems with the lenses, because we're worried about tolerability, right? I mean, you can have the best myopia progression, reducing glasses on earth. And if nobody will wear them, it won't do you any good. So we're really concerned about whether or not the kids will wear the glasses. And so this is one of our studies subjects who agreed to let us show her picture around the world. She's wearing the forest reduction of contrast lenses on both eyes. And so you can kind of see it has a foggy appearance. And when the light shines on in a particular way. And so the kids tell us that they that they do notice it at first when they start wearing the glasses, but that they get that they get used to it. And so and they say that other people don't tend to notice that there's a problem. I guess kids walk around with 30 glasses a lot. So it looks like 30 glasses. So it seems to be pretty well tolerated. So right now we have our company that you know this one my financial disclosure that company has a pivotal trial that's underway. And the goal is to enroll a total of 220 children. There's going to be a control arm and then there are two different dose arms. One is going to be forex reduction or is forex reduction in contrast and the other is 2x reduction in contrast. It is the goal is to be fully enrolled by the end of this month. And then it's a three year trial. This is an FDA. We went and talked to the FDA about what what we need to label this as a myopia control product. And so they're requiring a three year trial. They're requiring a 75% reduction in contrast. Sorry in myopia progression. But we're going to look at the data after one year and if it looks good we can begin to market the glasses in other countries. So so now I'm going to so that's what we're doing in terms of our trying to solve the myopia problem. But other people have ideas about things that you might do to to solve the problem of myopia. And and a lot of people thought that just prescribing eyeglasses to correct the refractive error so that people could see solve the problem not realizing that the eye is continuing to grow and that that is the real problem. So the Chinese government their approach is to just ban video games because their idea is okay having kids play video games all day long and sitting at screens is is causing myopia. So now we're not going to let them do that. Here in this country we are taking a different approach. So there was a recent study that was published by the International Pediatric Ophthalmology Strovismus Council where they asked people what they do to treat myopia if they do any sort of treatment for their myopic patients. And most 59% of the respondents say that they do something to try to stop the progression of myopia. And the most common thing people do is to use low dose atropine. There are other approaches but low dose atropine is super popular. And the reason why it is so popular is basically based on this study right here at all that came out in 2016 which is a five year clinical trial results report on atropine for the treatment of myopia. It's the low dose atropine trial. And the unfortunate thing about this particular study is that there's no control group. There's just three treatment groups. There's the low dose atropine 0.01% and then two higher doses of atropine. And what they did here their outcome measure was spherical equivalent refraction in diopters and they did it over five years. And so what they did is each of the kids had their dosage of atropine daily dose over the first two years and at the two year mark they stopped treatment. But they continued to monitor the change in refractive error and that's shown here. And you can see the two higher dose groups plummeted so their refractive error just got much worse. But the low dose atropine seems to also they have continued to progress in their myopia. Then at the end of the third year what they did is everyone who was still continuing to progress in their myopia they put all of those kids onto low dose atropine for the next two years. And so it's plotted here according to their original atropine group. But in these last two years everybody's on the low dose atropine. And you can see that first of all there's this huge rebound for the two higher dose atropine. So it just makes it worse. They just you know they just it's like having no effect at all. And it's hard to argue here that the .01% atropine is having any effect. And particularly with with the two distractor plots there. So if you just look at the low dose atropine group and you look you go really looks more like these these kids are just progressing as they would have if they had no low dose atropine. And since there's no control group you can't argue whether there's really any effect at all. And I argue that there's really no effect of that low dose atropine. More recently in 2018 there was a study published by Yamadol. And this is the lamp study or the low concentration atropine for myopia progression study. And in this study it was a one-year study. And they used change in axial length as their outcome measure. But they did do a control group. So the top line is the progression of myopia in the placebo or you know no treatment group versus low dose atropine and two higher doses of atropine. And at the end of the study there was not a statistically significant difference between the placebo and the low dose atropine group. Which is not to say there's not some difference but there's not a statistically significant difference. And it looks like these two groups are having effect. But we know from earlier studies that the higher doses of atropine actually have a bigger problem is that when you go off of the atropine your eye really begins to progress much faster. So the other things that people do, they based on this keep myopia away, go outdoors and play study. So they encourage kids to go outside and play and spend less time watching TV, reading and doing all kinds of these close work high contrast activities. And so there was a clinical trial on this. The intervention was 80 minutes of outdoor play versus a control group which weren't encouraged to go outside and play. And after one year what they found is that they could reduce the mean progression in myopia by about 1.13 diopters in the group that played outdoors more. So over the lifetime of the kids in school if you go from first to 12th grade and every day play outside for 80 minutes you can add up to a total reduction of myopia by 1.5 diopters. Which if you look if that's not going to be a huge reduction for someone who's going to be a minus six now they're going to be a minus you know 4.5. There is a contact lens product that's not available through in the United States that is a myopia control product. It's a Cooper vision product. It's called MySight. And they did a 48-month trial on theirs. Again their outcome measure was change in axial length and they ran it over four years. And they say that they were able to reduce myopia progression by about 1 diopter over that four years. The problem with contact lenses you can't really put them on little kids. The kids aren't good about washing their hands. So very contact lenses are not that great. So what we argue is that going forward with our eyeglasses that you should be able to treat myopia even before it starts and then you can have a really big overall effect if the eyeglasses work. And the deal is this is that this study shows that the progression of myopia is very highly predictable. So you know if you look at the agent onset then you see that you know someone who starts when they're eight years old or here an eight year old is minus 1.15 and they achieve by the time they're 11 years old their mind is 3.21. So if you if that person right here which could be me because that's when I was diagnosed or what had my agent onset a person that onsets here by the time they're 17 years old they're going to be minus six and a half. And so if you put the contact lenses on when they're 12 years old and achieve an overall reduction of 1 diopter over every four years then when they're 17 years old instead of being minus six and a half they're going to be minus five and a half. I'm currently minus nine. We also know that one of the one of the greatest predictors of who's going to become myopic are the number of myopic parents. So our older daughter asked us when she was little you know when am I going to have to wear glasses and we said yes she said when. Well you know third grade and then our younger one same thing well am I going to have to wear glasses yes and of course it's all true they've had to wear glasses. So we as myopic parents we could have said okay you're going to start by the time you're eight years old so what we'll do is before your eye ever grows too long we'll start you wearing the eyeglasses our contrast reduction eyeglasses here and then continue it until they say look I'm tired of wearing glasses and at that point when they're 12 years old say okay you can have contacts if you really want which would reduce the overall benefit but not that much they'll still only be minus one or two minus one or two compared to just continue to wear the glasses. So we are where this is we're hoping that this will be a way of truly preventing the growth of the eye by having kids wear glasses which are fairly non-invasive and on that note I'm going to stop and take your questions. Randy. So you know fascinating and I think that your case you make is is very strong that this is important but I also point out that there's also a lot of good studies to point out that loss of contrast sensitivity is not totally benign. Contrast sensitivity is particularly important under mesopic conditions driving seeing objects and there's a lot of work showing that that that some loss of that contrast sensitivity can indeed have an impact on things you do a lot of athletics so I think it's going to be important for you to measure not just how these patients think but but some of these driving tests that they have out there they have this the virtual reality and others to see what impact because we we often fight hard in regards to counter exertion other to enhance the contrast all we can to to increase the function with some very real studies showing that it does indeed do that. Well I agree completely with that so I would argue however that the young children aren't driving so until they're driving we don't have to worry about the driving issue. Athletics though is also. Athletics but and so but a lot of times with athletics just wearing glasses in general is not necessarily a safe thing to do so what it so our protocol has the the kids are required to wear the glasses except when it would not be safe to wear the glasses such as when they're playing athletics so they are allowed to take the eyeglasses off. We don't we don't know how many hours a day is the minimum requirement to wear the glasses to have the effect that would be an important piece of information that we'd like to have but you do make a very good point that you do have to be careful that we do need the contrast. There's also a very nearsighted person I've had laser guy I was a minus eight when I had laser you need you glasses to play yeah I mean I was already by fourth grade I was like a minus three and I'm minus four there's no way I was playing baseball without having glasses couldn't see the ball. Right well yeah there is that so yeah. So they probably need two pair they need this pair.