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Janey L. Wiggs, MD, PhD (Harvard Medical School/Mass Eye and Ear) delivered the Drs. Henry and Frederick Sutro Memorial Lecture at the Glaucoma 360 New Horizons Forum in San Francisco on February 1, 2019.
The keynote, entitled Glaucoma Genetics: Working Toward a Cure, started a full day of presentations and panel discussions on innovations in glaucoma drug delivery, pharmaceuticals, and devices, as well as special sessions focused on vision restoration, telemedicine, working with the FDA, and venture capital funding. New Horizons Forum is presented by Glaucoma Research Foundation (GRF), a national nonprofit based in San Francisco, California, focused on curing glaucoma and restoring vision.
Andrew Iwach, MD: Now it’s my pleasure to introduce the Drs. Henry and Frederick Sutro Memorial Lecture. This originated from a very significant bequest, $3.2 million from Dr. Sutro, who had been one of my patients. I had no idea that this was going to happen. Who was he? He was a faculty member at the Pacific School of Dentistry. He had private practice in Oakland. Later on, I realized that his great-grandfather was Adolph Sutro. He was the former mayor of San Francisco and actually one of the largest landowners in San Francisco in 1898.
We’re pleased that some of our past keynote speakers are here with us, including Bob Weinreb, Paul Lee, Rick Lewis, Joel Schuman, and Ike Ahmed, which brings us to this year, Dr. Janey Wiggs. She is an incredible scientist, clinician. Her studies began here in California at the University of California where she did her biochemistry degree and PhD. She went on to Harvard Medical School, did her residency at Harvard, fellowships at Mass Eye and Ear and also did medical genetics studies at Tufts University.
She is one of only seven ophthalmologists in the world currently board certified in both ophthalmology and medical genetics. She joined the Harvard faculty back in 1992. She’s the Paul Austin Chandler professor of ophthalmology, co-director of the Glaucoma Center of Excellence, also associate director of the Ocular Genomics Institute at Harvard, also interim glaucoma service director at Mass Eye and Ear, associate director of the Howe Laboratory. She is quite busy.
She’s very productive in her publications, over 175 scientific articles, reviews, book chapters. She’s been continuously funded by the NIH for the past 28 years. Last year, congratulations to her for being elected to the National Academy of Medicine, a huge honor. She’s received many awards, including the David Epstein award from ARVO. Her studies, of course, look at genetics, the underpinning of glaucoma and a collaboration and multidisciplinary approach.
She’s also an incredible teacher for residents and fellows and medical students and has won awards for her teaching efforts. She also serves on the Glaucoma Research Foundation’s Shaffer Grant Advisory Committee. With that, I’d like Dr. Wiggs to come up to the podium. [Applause] I’d like to present you this small token of our appreciation, a plaque commemorating your lecture today. Thank you.
Janey L. Wiggs, MD, PhD: Well, thank you Andrew. It is just such a pleasure to be here today. I would also like to acknowledge the generous contribution of Dr. Henry Sutro that is supporting this talk today. I’m honored to acknowledge his memory and also to acknowledge the legacy of Adolph Sutro, who was the 24th mayor of San Francisco and during his time, contributed so much to this great city that we’re fortunate to have the meeting in today.
I don’t need to tell all of you that glaucoma is the leading cause of blindness throughout the world, irreversible blindness throughout the world. It’s been projected that there will be 80 million people affected by glaucoma in 2020, which is next year. Of course, that number is just going to continue to increase with the aging population.
Our current therapies are directed at lowering intraocular pressure, which of course can slow, in some cases very effectively slow the disease, but do not cure the disease, meaning that patients are subject to a lifetime of chronic therapies. We don’t have curative therapies, and we also don’t have therapies that are capable of preventing the disease.
As the population ages and this number of glaucoma patients increases, we have a real need to develop curative and potentially preventative therapies for the disease. A major goal of glaucoma genetics research is to identify genes that code for proteins or define biological pathways that are actually the cause of the disease and therefore could be targets of potentially curative and preventative therapies.
Now, when we think about glaucoma genetics, it’s very helpful to actually divide all the glaucomas into early onset forms like juvenile open-angle glaucoma, congenital glaucoma, the anterior segment development syndromes and the adult onset forms like primary open-angle glaucoma, angle-closure glaucoma, and exfoliation glaucoma.
The early onset forms are rare in the population. They are caused by rare mutations that have large biological effects. These mutations typically disrupt protein functions and are generally manifest early in life. For that reason we find families, large families that are affected by these conditions. Traditionally, genes for these conditions were identified through genetic linkage studies and now more commonly using next-generation sequencing approaches like whole exome sequencing.
In contrast, the adult onset glaucomas are common in the population, as you all know. The genetic risk factors that are associated with these conditions are also relatively common genetic risk factors. Individually, these have relatively small effects when compared to the mutations that cause early onset disease. It’s only in aggregate when you have one, two, four, 10 of these variants or perhaps in combination with environmental factors that the disease becomes manifest.
For that reason, we generally study for these adult disease cases. Yes, there’s a strong family history that’s a component of risk for glaucoma, but we don’t typically have the large three-generation families for the adult diseases that we have for early onset diseases. We study cases. We compare genetic risk factors and cases to controls through genome-wide association studies.
Now, a challenge when you’re trying to find genes that have relatively small effects such as the genes that are responsible or contribute to primary open angle glaucoma is that these individually have small effects. To show an association of something with a relatively small effect, you need very large sample sizes to have a statistically significant result.
To form a sample size that would be useful for this kind of approach for primary open-angle glaucoma, in 2012 we formed the Neighborhood Consortium for Glaucoma Genetics. This consortium includes all the sites that you see listed here on this slide.
Currently we have about 47 investigators who are ophthalmologists, geneticists, and bioinformaticists working together to identify genes that contribute to primary open-angle glaucoma. The neighborhood has collected over 5,000 cases for primary open-angle glaucoma and many, many thousand controls. This genetic data has been used for a number of genetic analyses.
In particular, we completed the largest genome-wide association study for primary open angle glaucoma, which we were fortunate to publish in Nature Genetics a couple of years ago. We’ve been able to use the data for a number of other analyses and have actually published over 40 papers since the consortium first formed in 2012.
The work of our consortium and other investigators and consortiums around the world has now identified a number of genes that either cause early onset forms of glaucoma or contribute to adult onset forms of glaucoma, such as POAG, exfoliation syndrome, angle-closure glaucoma, and others.
These genes are now beginning to define important pathways and biological processes that are contributing to disease mechanisms and also are defining potential targets for therapy.
Interestingly, there’s a very wide range of biological processes that have been identified that are contributing to glaucoma, including ocular development, cell division, cell death, TGF beta signaling, membranes, lipid metabolism, vascular and lymph development, extracellular matrix, mitochondrial function, among others.
This great diversity in biological mechanism and pathways, I think, really underscores something that we as clinicians know and that this is a very heterogeneous disease clinically, and now we understand also genetically and biologically.
Some of these pathways are beginning to identify potential targets for novel therapeutic approaches that in fact have the potential to cure disease or have the potential to protect from developing disease, be preventative. I’m going to talk about several of these today.
The first one I’d like to talk about is myocilin. Myocilin actually is the first gene that was ever discovered to be contributing to glaucoma. This was discovered by Ed Stone and Val Sheffield and their group at the University of Iowa. It’s now well known that mutations cause familial juvenile open-angle glaucoma and also early onset adult open-angle glaucoma.
We understand now quite a bit actually about the mechanism that underlies this. Mutant proteins cause an accumulation of protein aggregate in the endoplasmic reticulum. That interferes then with normal protein production by the cell, causing the cell to die.
An approach to remove mutant proteins using gene editing by CRISPR/cas9 has been shown to effectively remove proteins with the myocilin mutation and lower intraocular pressure now in a transgenic mouse that carries the mutation. This was carried out by Val Sheffield at the University of Iowa and published in PNAS in 2017.
Interestingly, he showed that this CRISPR editing technology in the transgenic mouse is effective in young and in older mutant mice, showing that it could be effective at later stages. I think what’s really exciting is that these pre-clinical studies now pave the way for developing similar technology for humans who also carry mutations in myocilin. This, in theory for patients with these mutations, would be curative therapy for these patients.
The second pathway I’d like to talk about is the TEK Angiopoietin signaling pathway. TEK is a membrane receptor, a receptor, the cellular receptor. Angiopoietin 1 and Angiopoietin 2 are ligands for the receptor. This is a very, very well-known pathway in the vascular world. In fact, it’s been very well studied in eye diseases, veneer vascularization. The pathway is known to be important for vascular endothelial cell proliferation and survival and also is important for lymphanogenesis.
It’s become clear in the last few years from work done by ourselves and also our collaborators, Terry Young at the University of Wisconsin, Susan Quaggin at Northwestern University, that rare mutations in the gene coding for TEK, the receptor, cause a congenital glaucoma and also juvenile glaucoma and in some cases actually even young adult glaucoma for the TEK mutations.
We’ve also shown that rare mutations in Angiopoietin 1, the ligand for the receptor, can cause congenital glaucoma and adult glaucoma. We’ve also shown recently that common variants in the Angiopoietin 1 gene, the kinds of variants that you would see in adult onset glaucoma, are associated with elevated intraocular pressure in population studies and also associated with primary open-angle glaucoma.
Studies of the TEK knockout mouse showed that, in fact, the reason for this is when you disrupt this TEK Angiopoietin signaling pathway, Schlemm’s canal does not form properly. The knockout mouse is shown on the left panel. You can see that the cornea is quite enlarged because the pressure is quite high.
Then on the adjacent panel are confocal microscope images of Schlemm’s canal for the knockout mouse, a heterozygous knockout and the wild type. I think it’s relatively clear to see that Schlemm’s canal has not developed normally in the knockout mouse.
The TEK Angiopoietin genetic factors, we hypothesize, cause elevation of intraocular pressure by interfering with Schlemm’s canal formation or function. Restoring TEK signaling could reduce intraocular pressure, especially in those patients who carry defects in this signaling pathway. I think it’s also interesting to speculate that delivery of agents that could restore TEK signaling to Schlemm’s canal could be particularly beneficial since that’s where the defects are located.
I want to turn now to cholesterol. Three genes associated with primary open-angle glaucoma and also elevated intraocular pressure in population studies are known to be associated with cholesterol metabolism. What’s interesting about this is that these three genes interact with each other in a membrane complex called caveolae. They interact to promote efflux of cholesterol from cells.
There's also evidence of a role for cholesterol in glaucoma development from a study that we did several years ago looking at pathways including the acetylcholine pathway that is necessary for production of cholesterol. Then of course work done by Josh Stein and now others showing that statins which inhibit this pathway could reduce primary open-angle glaucoma risk.
Interestingly this past year, there has been additional data published on another gene, DKGK, which is diacylglycerol kinase gamma, which is a gene that also is involved in lipid and cholesterol metabolism. What’s going on here with lipid metabolism, cholesterol, IOP and glaucoma?
It’s interesting that there are now four genes associated with both traits, first of all suggesting that the cholesterol metabolism may influence glaucoma development by elevating intraocular pressure. What underlies this effect, I don’t think we know yet, but one thing that does come to mind is that we can begin to hypothesize that by treating or targeting this pathway, we may able to develop some effective treatment.
Specifically, would the statin effect be more effective in glaucoma patients who in fact are the carriers of these glaucoma related genetic risk factors?
I want to finish this section with talking about mitochondria and glaucoma. We all know, of course, that mitochondria are very important for energy production in the eye. We know that mitochondria densely populate the metabolically active unmyelinated pre-laminar optic nerve. There’s been great work done to show, in fact, that mitochondria are very important for ganglion cell function, particularly Nick Marsh-Armstrong with funding from the GRF showed an important role for mitophagy in glaucoma.
It’s important to remember that mitochondria produce ATP through the electron transport chain. This involves, of course, transfer of electrons through the cytochromes. It’s important to remember that during electron transfer, it’s not 100 percent efficient and that leaked electrons can cause formation of reactive oxygen species and free radicals, which ultimately are damaging to the mitochondria and damaging to the surrounding tissues.
Mitochondria are prepared to address this. There are free radical and reactive oxygen species scavenging systems located in mitochondria. One of those is the thioredoxin system where thioredoxin is an important reactive oxygen species scavenger. There’s another protein involved in this, thioredoxin reductase 2, which is necessary to maintain the thioredoxin in its reduced state so that it’s free to accept these free radicals.
In our neighborhood genome-wide association study, we showed that there is a strong association between thioredoxin reductase 2 and primary open angle glaucoma. What’s interesting is that the risk variants associated with disease are correlated with decreased gene expression.
In this graph here, you can see that the general expression of the gene is reduced in individuals who carry these risk variants. The decreased gene expression then in primary open angle glaucoma patients could lead to an increase in damaging reactive oxygen species. This would suggest that restoring anti-oxygen function could be important for these patients.
Now, what’s interesting is that I think for a long time we have thought about mitochondria as primarily affecting ganglion cell function or retinal function, optic nerve function, but there is also a potential role, I think, for mitochondria in intraocular pressure.
This past year we were fortunate to work with our colleagues in the U.K. on a large IOP genome-wide association study from the UK Biobank. This was analyzing over 100,000 individuals. We discovered 68 novel genes or novel loci for intraocular pressure.
Interestingly and maybe even a little bit surprisingly, what we found is that thioredoxin reductase 2, a gene that we really had been thinking mostly of the retinal ganglion cell protein, we found that it was also associated with elevated intraocular pressure in this study.
Perhaps what was even more surprising is that we found four additional loci that are also associated with mitochondrial function and IOP. Together I think this raises the real possibility of a role for mitochondria in outflow, trabecular meshwork outflow function, and that this is an area now for additional exploration to determine whether or not restoring mitochondrial function to outflow cells and processes could be beneficial in terms of regulating intraocular pressure.
I’d like to take a few minutes then to summarize what I've told you so far. Genetic studies have identified glaucoma genes and biological pathways that are defining disease mechanisms and that could be targets of new, potentially curative and potentially preventative therapies.
I've given you four examples today. The first is using CRISPR/cas9 gene editing for patients who carry mutations in myocilin. This, in principle, would be truly curative therapy for these patients. The second is augmenting tech signaling in patients who carry defects in TEK and Angiopoietin 1 or 2. Again, these patients likely have disease as a result of these genetic defects and could benefit specifically from these therapies.
I've also presented cholesterol and lipid metabolism as a risk factor for elevated intraocular pressure and primary open-angle glaucoma, suggesting that statins could potentially be curative or at least preventative in some of those patients.
Then finally, mitochondrial function and the potential here for addressing redox homeostatic and mitochondrial support could be beneficial for regulating intraocular pressure and potentially also for retinal ganglion cell function.
Where do we go from here? What are our future goals in the future studies for glaucoma genetics that will identify new areas for therapy and prevention? Well, first of all, I think we need more genes. You may say we already have a lot of genes, but compared to other complex disorders, for example even age-related macular degeneration, glaucoma is really lagging behind in terms of the number of genetic elements that we know can contribute to the disease.
We’re addressing this in a couple of ways. First of all, we’re completing this year a multi-ethnic primary open-angle glaucoma meta-analysis with our colleagues in the International Glaucoma Genetics Consortium. It’s over 10,000 cases and many thousands of controls, which will have the power to find additional genes that contribute to disease.
I think it’s also very important to do analysis of early onset glaucoma families. We have a very few number of genes that contribute to these diseases, which we know are very devastating and important. If you compare there are nine currently known genes to over 250 genes that contribute to inherited retinal degenerations, we certainly have more to discover here.
We have the tools now to do this. We have next-generation sequencing that makes it possible to use to more efficiently identify genes contributing to these diseases.
I also think we really need to think about functional studies. I think probably at every glaucoma meeting we have, we talk about the need for animal models, but we really do need good animal models for the disease. We’ve made great progress here. The bead model that David Calkins and others have supported has been a great advance, but we need models that can more rapidly screen genetic defects.
We’ve been working in our lab on zebra fish. I think that’s a possibility, but it’s an area that really needs additional development. I also listed here relevant cell biology. I think one of the challenges, we understand something about the retina and the cell composition of the retina. We know ganglion cells are important.
I think there are cell types that we don’t understand as much about what’s the contribution of astrocytes, what’s the contribution of glial cells, and of course when we get to the anterior segment, there is such a complex cellular milieu, we’re not really sure how those cells interact with each other. Knowing now that there are cells, for example, in Schlemm’s canal that are important targets for therapy, that’s an important aspect of functional work that needs to be done.
Finally, I think it’s very important in the future that we consider adding a genetic component to clinical trials testing new therapies. In particular, to address the question, “Are specific therapies more effective in patients with the related genetic defects?”
If you consider primary open-angle glaucoma as a big gemisch, a therapy that targets just one mechanism within that complex composition is not going to be overall as effective as it would be if you were able to use that therapy on the selected group that truly has that disease mechanism that that particular therapy is addressing.
With that, I’d like to thank you for your attention. I’d like to acknowledge the Ocular Genomics Institute at Mass Eye and Ear where I do most of my work, my laboratory, important collaborators, the Neighborhood Consortium, which has just been fantastic to work with and really important for the field and the International Glaucoma Genetics Consortium as well in our funding. Thank you very much.
Last reviewed on May 17, 2019