Cornea and External Disease

Corneal Endothelial Cell Therapy: A Conversation with Dr. Matt Giegengack

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As cell therapy continues to show promise in ophthalmology, researchers and clinicians are discovering that it may potentially improve vision and even change ophthalmology’s approach to corneal eye diseases.

Mark Dlugoss, senior contributing editor for Ophthalmology 360, recently had a wide-ranging, informative discussion with Dr. Matthew Giegengack, associate professor at Wake Forest University in Winston-Salem, North Carolina, and co-director of Wake Forest’s corneal fellowship program. Over the years, he has become one of the busiest corneal transplant surgeons in North America. Dr. Giegengack is also on the medical advisory board of Aurion Biotech, a clinical stage biotech company developing a cell therapy candidate for the treatment of corneal edema secondary to corneal endothelial disease. Dr. Giegengack was part of the team of four US surgeons who has performed Aurion’s cell therapy procedure in its IOTA and Escalon trials in El Salvador.

Dlugoss: Welcome, Dr. Giegengack.

Dr. G: Thank you. Excited to talk about this.

Dlugoss: Let’s start off with your background: what led you to ophthalmology and more specifically to the cornea subspecialty?

Dr. G: I knew I always wanted to be a scientist. In college, I was a physics major but it was isolating and I wanted more human contact. After teaching high school physics, I realized that I liked working with people, and wanted more of the nitty gritty of science. Medicine was a good way to do both. In medical school, the transition from physics into ophthalmology was natural; no other specialty in medicine has more physics than ophthalmology. I love being an ophthalmologist: the amount of people that we can make a profound impact on in a short period of time is unrivaled, I think, compared to other specialties.

There’s an art to ophthalmology: it challenges both your mind and your hands. The cornea is a subspecialty where there’s a huge humanitarian need for global outreach, which is very important to me as well. More recently, it’s been an exciting area of innovation.

Dlugoss: How did you become interested in cell therapy for corneal endothelial disease? Can you fill us in on your clinical research in this area?

Dr. G: The Wake Forest Institute of Regenerative Medicine is at the cutting edge of cell therapy. About six or seven years ago, I started research on trying to regenerate the “backside” or endothelium for transplant. Ophthalmology is a natural fit for cell therapy: the eye is easily accessed and observed, and much of it is immune privileged. The endothelial layer of the cornea is potentially the most promising for cell therapy.

Dlugoss: Tell us more about corneal endothelial disease.

Dr. G: We’re all born with a certain number of corneal endothelial cells, and they do important work: they regulate hydration of the cornea to keep it clear and functioning properly. Over time we lose those cells due to inherited diseases like Fuchs Dystrophy, or surgical trauma, or just plain old age. If you lose enough cells, you can run into trouble: your cornea might swell, which is very painful, and it may become cloudy, which impairs vision. Over time, if left untreated, patients will go blind. This problem is more common than you might think: about half the corneal transplants we do in the U.S. are for endothelial dysfunction. Years ago, the NIH estimated that about 4% of people over the age of 40 will have some sort of endothelial dysfunction in their lifetime, and some percentage of those people will need an intervention.

Dlugoss: Tell us more about current treatment options.

Dr. G: It used to be that if you had endothelial disease, you had to get a full-thickness corneal transplant. But over the last 20 years, there’s been a revolution in how we treat corneal endothelial dysfunction by removing only the diseased layers of the cornea, keeping healthy layers of tissue, and transplanting less donor corneal tissue overall. That first innovation was DSAEK (Descemet’s Stripping Automated Endothelial Keratoplasty), where the transplant consists of healthy donor endothelial cells that are still attached to Descemet’s membrane, and a portion of the corneal stroma. Next, to make the transplant more effective, corneal surgeons began using even thinner tissue, in a procedure called DMEK (Descemet’s Membrane Endothelial Keratoplasty), where the transplanted tissue consists of only the corneal stroma plus the endothelial cells. While both procedures work very well, most surgeons will agree that DMEK offers patients more clarity of vision, but it’s a very complex procedure to perform. You’re dealing with extremely thin, delicate corneal tissue which is not easy to place correctly inside the patient’s eye. So, there are always trade-offs.

The patient’s recovery for both DSAEK and DMEK is challenging. Post-op, patients must lie flat on their back, fully horizontal, for several days in order for the transplanted tissue to adhere to the cornea. That’s a hardship for a lot of patients.

All that being said, DSAEK and DMEK are truly remarkable procedures. So, any cell therapy under development must have very good results to replace the current standard of care.

Dlugoss: Given all these options, is there a need for more innovation?

Dr. G: Well, there’s a bunch of good reasons for more innovation. First, not everybody is a good candidate for the corneal transplant options available right now. And today, due to surgical complexity, current treatments are only performed by corneal specialists. A general ophthalmologist will almost always refer their patient to one of us, so we might guess that patients are perhaps waiting a while for a referral, even when it’s clear they need a transplant. Fortunately, in the United States there’s not really a shortage of donor cornea tissue, but globally, unfortunately, there is both a shortage of donor corneal tissue and fewer trained corneal specialists to treat patients in need. And that’s a problem with our current treatments: they require one donor cornea per one treated eye.

Dlugoss: So, let’s start talking about Aurion Biotech’s cell therapy. It was developed by Professor Shigeru Kinoshita, MD, from Kyoto Prefecture University of Medicine in Japan. Tell us about it.

Dr. G: Sure. Prof. Kinoshita has been working on it for a long time. He’s had publications on this subject dating back to the 1970s and has given many lectures on his groundbreaking innovations. His core achievement was to take healthy endothelial cells out of the eye and get them to reproduce in the lab. They don’t naturally reproduce in the eye, so this was an incredible breakthrough.

Dlugoss: How did Aurion Biotech acquire the rights to develop this treatment?

Dr. G:  That’s a long history with many different threads. At a certain point, I think Prof. Kinoshita recognized that clinical development of this amazing cell therapy would be a full-time occupation and require a lot of resources. So, it was natural that he reached out to industry colleagues to take it to the next level.

Dlugoss: Okay, great. Let’s talk about the mechanism of action. How does this cell therapy work?

Dr. G: Well, there are really two parts to your question: how are the cells produced and how are they delivered to the patient? Regarding cell manufacture, Aurion harvests endothelial cells from a donor cornea and cultivates them in the lab in a proprietary culture. The cells reproduce over multiple passages. What’s exciting is that today, cells from a single donor can be “expanded” to produce more than 100 cell therapy treatments. Remember that existing ratio for the current standard of care? One donor cornea for each diseased eye. So, this cell manufacture process can potentially provide 100 times the supply of our current treatment methods.

Part two of your question is: how are the cells delivered to the patient? It’s a very elegant procedure. First, we remove the patient’s diseased endothelium. Next, we inject the cultured endothelial cells into the anterior chamber of the eye. The patient lies face down for several hours in order to help the cells settle in place and re-form a monolayer. Within a few weeks, the patient’s vision begins to return and improves thereafter.

Dlugoss: What role does the Rho-kinase inhibitor play?

Dr. G: I’m not sure we fully understand the contributions of the Rho-kinase inhibitor. We know it’s part of the cell manufacture process and it’s also part of the drug product.

Dlugoss: Tell us about the IOTA study in El Salvador. This was a proof-of-concept study, right?

Dr. G: Correct. Yes, we – and by “we” I mean myself and three other US corneal surgeons – have treated over 65 patients in several different cohorts of the study in El Salvador. The simple takeaway is that this therapy works, even in patients where the level of pathology was worse than what I normally treat in the United States. El Salvador doesn’t have an eye banking system and so these folks had very diseased, swollen corneas, which is what happens when your endothelium fails to function properly.

When I compare cell therapy to the results that we get with corneal transplants at home, it’s a little bit of “apples and oranges” because the starting pathology levels in the IOTA trial were substantially greater. But outcomes have been favorable nonetheless, and we feel very optimistic about the potential of this cell therapy treatment.

Dlugoss: What is the safety, tolerability, and efficacy of the cell therapy?

Dr. G. We didn’t have any major complications related to safety. It’s a less invasive procedure than DSAEK / DMEK. On top of that, without getting into all the details, there are some complications with DSAEK and DMEK surgery that don’t occur with cell therapy. For example: the air bubble that we have to inject into the anterior chamber after DSAEK/DMEK, to help the transplanted tissue attach to the cornea. Occasionally, we have to bring the patients back into the operating room and re-inject the air bubble to help re-attach a graft that has moved out of place. Cell therapy doesn’t require an air bubble.

One of the neat things about the El Salvador trial is observing this technology working well, that’s number one. Number two concerns refinements around the procedure: there were four of us surgeons, each taking turns performing the procedure while the others watched and assisted. It made our learning curve very productive. Our hope is that when we open this up to a larger bunch of surgeons, we can say, “these are the techniques we recommend to make it work seamlessly.” Flawlessly is what we want for any surgery.

Dlugoss: Aurion Biotech continues to follow these patients from the IOTA trial. How are they doing?

Dr. G: It looks really promising. I’ve been surprised at how well patients are doing. Many have been able to achieve remarkable clarity of vision, even though some of them had a higher level of pathology than the patients I’m treating at home here in the US. We’ll continue to follow these patients, but my gut feeling is that their improvement will last a long time.

Dlugoss: What are the potential advantages of corneal endothelial cell therapy compared to the current standard?

Dr. G: We’ve already mentioned some of the benefits. First, the cell manufacture technology means that we can solve the shortage of global supply of donor corneas. Perhaps a less obvious benefit is that I think we can serve more patients. For example, patients who have loss of endothelial cells from glaucoma, or people treated with glaucoma surgery encounter challenges with DSAEK and DMEK. But I think they’d be ideal candidates for corneal endothelial cell therapy. And perhaps this is looking down the road, but we know that corneal transplants don’t last forever. Every time we have to repeat a corneal transplant procedure, it’s more risky than the previous time. So, it’s my hope that cell therapy will have more “longevity” for patients; and if the cell therapy does need repeating, I think it could be repeated more safely. Finally, I believe we can introduce this cell therapy to a broader group of surgeons, beyond corneal specialists.

Dlugoss:  Have you experienced any cons or setbacks associated with the cell therapy platform?

Dr. G:  I thought you might ask a question like that. The short answer is, in my experience, no. As with any new procedure, there is a learning curve: the more you do something, the better you get at it. But cell therapy is a very accessible procedure. We continue to make minor refinements on surgical technique and that’s to be expected.

Dlugoss: Where does Aurion Biotech stand, regarding clinical trials – both here in the U.S. and in other global markets?

Dr. G: Here in the U.S., the Aurion team is preparing to submit an IND to the FDA. If they get the green light, that means they can initiate a clinical trial here in the U.S. Their colleagues in Japan are further along; Aurion Japan has completed clinical trials and submitted an application for regulatory approval to the PMDA, the Japanese regulatory authorities, and are awaiting a response. It’s exciting.

Dlugoss: Do you see the potential to expand cell therapy into other segments of ophthalmology?

Dr. G: Yes. Cell therapy is a natural fit for the eye. From a research standpoint, it’s an organ that is easily accessed, which makes innovation more productive. Second, over many years, we know that therapies that work in the eye are generally well tolerated systemically throughout the body. The cornea and endothelial cells are ideal because they are immune privileged and there is no blood supply, so no need for blood type matching. There are other places in the eye that are not quite as ideal, but still pretty good. For example, the trabecular meshwork has very specialized cells that get their nutrition from the fluid circulating inside of the eye. There are also parts of the retina that are being explored for cell therapies.

Dlugoss: We’ve covered a lot. Is there anything you’d like to add before we conclude?

Dr. G: Yes. I do a lot of global outreach as part of my affiliation with Wake Forest. Corneal endothelial cell therapy presents an incredible opportunity to reach underserved parts of the world and make a huge impact on the people that live there, by solving the donor cornea supply shortage with a procedure that I believe will have a high success rate and a low complication rate, and a low need for follow up.

Dlugoss: Thank you for taking time to speak to me today.

Dr. G: Thank you. Thanks for having me.