January is Glaucoma Awareness Month. Thomas Vincent Johnson III, MD, PhD, of Johns Hopkins, is conducting groundbreaking research into retinal ganglion cell replacement or regeneration to restore vision in patients with glaucoma.
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Thomas Vincent Johnson III, MD, PhD:
Hi, my name is Tom Johnson. I’m an associate professor of ophthalmology at the Johns Hopkins School of Medicine, and I’m a glaucoma specialist and a neuroscientist. Glaucoma is a really difficult disease. It’s an age-related condition that causes degeneration of the optic nerve, the connection between the eye and the brain and by doing so causes progressive vision loss. It tends to be insidious. It occurs very slowly and the vision loss tends to start in the periphery. People tend not to notice it, sometimes until very late stages of the disease. But the key problem with glaucoma and all optic neuropathies is that when vision loss does occur due to that disease, it’s permanent. We, at this point in time, have no treatments that can restore vision that’s been lost to glaucoma. The key for anybody that has or might have glaucoma is to be evaluated thoroughly by an ophthalmologist so that they can diagnose it as early as possible, and then institute therapy to prevent it from getting worse.
The treatments for glaucoma are all aimed at reducing the eye pressure, and this can be done with eye drops or lasers or sometimes incisional surgery. When they’re effective, they work very well and sometimes completely halting the disease to prevent any further vision loss from occurring. But in order for that to take place, the disease has to be recognized and the treatment has to be instituted.
Question:
Your lab is focused on research on retinal ganglion cell (RGC) death in glaucoma and other optic nerve conditions. Can you talk about your interest in this area?
Thomas Vincent Johnson III, MD, PhD:
As a clinician, as a glaucoma specialist, I spend most of my time talking to my patients about things that are happening in the front part of the eye, what’s causing the pressure to go up, what we can do to get the pressure down. But as I alluded to before, the reason people lose vision is actually due to what’s going on in the back of the eye. Retinal ganglion cells, or RGCs, are a type of nerve cell that lives in the retina, which is the light sensitive tissue that lines the back wall of the eyeball. These neurons are special in that they connect to other nerve cells in the retina. They receive information about light entering the eye. Then, they communicate that to the brain by way of these very long fibers called axons that run all the way through the optic nerve and into various vision supporting centers in the middle of the brain.
In order to really understand glaucoma and in order to develop treatments to better help patients preserve or restore their vision, we really need to understand more about these retinal ganglion cells and why they’re dying in glaucoma. I’ve been interested in the fact that glaucoma has been a intense area of research for decades, yet we still don’t really understand why retinal ganglion cells die in the disease. We know it has something to do with the eye pressure, most notably because if people have glaucoma and we reduce their eye pressure, their disease stops getting worse. But we don’t fully understand the link between eye pressure and retinal ganglion cell death. There seems to be some sort of an injury to these nerve cells at the point where they exit the back of the eye and enter the optic nerve, that’s called the optic nerve head.
There’s evidence to suggest that it could be mechanical damage, that these axons are being kinked as they go through the sensitive tissue at the back of the eye. There could be issues with poor blood supply as the pressure goes up. Some people have implicated inflammatory processes, neuroinflammation, and excitotoxicity as contributing factors, but we really don’t have a strong unifying model for what’s causing retinal ganglion cell death. That’s been an interest of our lab for a while because as we better understand the gene pathways or the cellular events that are leading to retinal ganglion cell death, we could then develop targeted therapies that have nothing to do with eye pressure per se, but might act directly on the retinal ganglion cells to enhance their resilience in the disease. That class of treatment that has been under investigation for 20 or 30 years now is called neuroprotection.
We’re very excited now that there are several randomized clinical trials that are being instituted or conducted for potential new neuroprotective therapies for glaucoma that may be heading down the pipeline soon. But beyond that, even if we had a perfect neuroprotective drug that would stop visual loss in all patients, that still would not totally solve the problem of glaucoma because as I said, a lot of people are not diagnosed with the disease until after vision has already been lost. There are people now that are undergoing therapy, and for whatever reason, the eye pressure is just hard to reduce, and they continue to lose vision from the disease. My lab has been particularly interested more recently in retinal ganglion cell replacement, or regeneration, in order to restore vision in glaucoma.
Question:
Can you walk us through the research you’re doing in RGC regeneration and how this research might impact the future of glaucoma treatment and care?
Thomas Vincent Johnson III, MD, PhD:
We believe that if we can repopulate retinal ganglion cells and reestablish their connections to other nerve cells in the retina and the brain that that could actually restore vision for people that have lost it. We are investigating this through a number of pathways, but essentially the idea is that we would take human stem cells and we have methods now to differentiate them or turn them into retinal ganglion cell neurons in a dish. The trick though is figuring out how to get them to integrate appropriately into the visual pathway of eventually people with optic nerve disease. We’re studying this in the laboratory in a number of preclinical glaucoma and other optic nerve degeneration models. Our work so far has been successful in identifying one of the major barriers to these stem cell-derived neurons entering the retina and taking up residence where the former retinal ganglion cells have died.
That barrier is the internal limiting membrane, which is a basement membrane that separates the retina from the vitreous cavity. We’ve determined that if you disrupt that, and we’ve developed a number of ways to do so in the laboratory, that we can get a much, much higher percentage of transplanted retinal ganglion cells to enter the retina. We’re very excited now that in addition to simply structurally existing in the correct part of the retina, they are also growing nerve fibers or dendrites into the retina and forming synaptic connections with the upstream neurons. When we transplant RGCs into a retina, we can then shine light or flash pictures at that retina, and we can see through experimental means that the donor RGCs we’ve transplanted are receiving information about those pictures. They’re appropriately encoding information about light so that that can be transmitted to the brain.
The other half of what needs to happen, and this may be a more formidable challenge, but one that I think there’s precedent for, is we have to get those retinal ganglion cells to grow those long axonal fibers through the optic nerve and the brain. We’ve recently developed evidence that when we transplant RGCs into the retina, they do grow fibers and they know where in the eyeball to go in order to get out of the back of the eye and enter the optic nerve. We’ve found human stem cell-derived donor RGC axons in the optic nerve of these preclinical models. We’re now working to try to figure out how to coax them to grow down the optic nerve and into the brain. Fortunately, there’s a lot of good work that’s been carried out by some brilliant scientists over the last 15 or 20 years that have shown us some of the most important molecular pathways and drug treatments that might promote this process.
That was done originally not by transplanting retinal ganglion cells, but by injuring the optic nerve and then trying to get those surviving retinal ganglion cells to regenerate their axons to the brain. We’re currently leveraging that information to genetically engineer our transplanted RGCs so that they can do the same thing and find those central subcortical nuclei or visual centers in the brain that they need to communicate with in order to restore vision.
This is all preclinical work. I tell my patients that ask me about this in the clinic, this is experimental. We have a long way to go before we’re going to be offering clinical trials or thinking about doing anything like this in human patients. But I think the precedent is there. We’ve made a tremendous amount of progress in the last 4 or 5 years, and I think it’s a matter of time before we’re able to regenerate the visual pathway of models or humans that have optic neuropathy. If we’re successful, I think it will be a game-changer because we’ll actually then have a therapy that can not just prevent vision loss, but actually restore it after it’s been lost.
Question:
Your lab is part of the RReSTORe Consortium. Can you talk about its mission, goals, and ongoing work?
Thomas Vincent Johnson III, MD, PhD:
The RReSTORe Consortium was founded 5 years ago now, based on the idea that retinal ganglion cell replacement and optic nerve regeneration is a really, really complicated problem that is unlikely to be completely solved by one scientist or one lab working in isolation. The glaucoma community and the neuroscience community are wonderfully collaborative. We wanted to leverage that collaboration and get people with diverse areas of expertise and interest talking to and working with each other more directly to address this particular problem. The Consortium now involves more than 300 scientists and clinicians worldwide. We get together for an in-person meeting every other year, and we have virtual discussions a few times a year where we pick 1 or 2 of the main challenges facing retinal ganglion cell replacement and discuss it in detail, trying to brainstorm ideas for experiments and techniques that might help us overcome those challenges.
With the help of some foundations, including the Bright Focus Foundation, the Gilbert Family Foundation, The Glaucoma Foundation, and the Glaucoma Research Foundation, we’re now in our second iteration of collaborative challenge grants where we’ve had RReSTORe Consortium members that have not worked together previously, propose a new collaborative endeavor that specifically addresses one of the major challenges of retinal ganglion cell replacement and optic nerve regeneration. Not just by bringing the community together and brainstorming, but by really promoting calls to action and real experimental work, we’re hoping that we can continue to drive the field forward to the point that we may actually be able to translate this technology to real patients.