Corneal diseases afflict millions of people each year, with some 12.7 million people worldwide awaiting corneal transplants for diseases such as Fuchs’ endothelial corneal dystrophy, pseudophakic or aphakic bullous keratopathy, and many others.1
Traditionally, the surgical treatment of corneal endothelial dysfunction has relied on full-thickness corneal transplantation. However, advancements in recent years have ushered in new, safer and less invasive approaches to treatment based on endothelial cell transplantation and other techniques.
There is little question that endothelial keratoplasty stands as a beacon of hope for individuals afflicted by various corneal diseases and injuries, offering these patients a chance at restored vision and improved quality of life.
CURRENT STATE OF CORNEAL TRANSPLANTATION
Recently, pre-loaded Descemet’s stripping automated endothelial keratoplasty (DSAEK) or Descemet’s membrane endothelial keratoplasty (DMEK) tissues have become available. Studies show that both approaches result in quicker vision recovery, better long-term visual outcomes, less surgically-induced astigmatism and fewer intraoperative and postoperative complications than full-thickness corneal transplantation.2,3 However, some studies show that DMEK poses less risk than either DSAEK or penetrating keratoplasty (PK).
In a 2022 retrospective study published in International Ophthalmology, 33 patients who underwent DMEK between 2009 and 2012 for endothelial dysfunction were evaluated for clinical outcomes. The study found that the BCVA improved from 0.55 ± 0.37 logMAR (n = 54) to 0.15 ± 0.11 (n = 47) in eyes without ocular comorbidities 1 year after DMEK (p < 0.001) and remained stable up to 10 years later.4
While these results are promising, especially when using healthy donor corneas, the procedure has a steep learning curve and final visual acuity depends largely on the skill of the surgeon. In addition, more studies are necessary to ascertain the long-term success of DMEK.
(For more, see “Corneal transplantation keeps evolving,” here)
EMERGING TECHNOLOGIES AND TECHNIQUES
Novel approaches based on tissue engineering are emerging that have the potential to create bioengineered corneal tissue with properties similar to native tissue.
One new — some would say radical — approach involves cultured endothelial cells (CECs). Instead of transplanting an actual cornea, a small number of individual endothelial cells are retrieved from a young healthy donor cornea, cultivated in vitro, and then injected into the anterior chamber of the recipient eye. There, they adhere to the Descemet’s membrane to make self-organization of the endothelial cell layer at the posterior corneal surface, resulting in corneal clearing and transparency.
In 2018, along with several colleagues, I conducted a small study using CECs to treat 11 eyes with endothelial corneal disease. Corneal transparency was restored after 24 weeks in all 11 treated eyes. In addition, corneal thickness of less than 630 µm (range, 489 to 640) was attained in 10 of the 11 treated eyes (91%; 95% CI, 59 to 100), and an improvement in BCVA of two lines or more was recorded in nine of the 11 treated eyes (82%; 95% CI, 48 to 98).5 The data obtained from 5 years postoperative showed promising results as well.6
Cornea disease treatment using CECs received the approval of the Japanese Ministry of Health, Labour and Welfare last year and it is awaiting final reimbursement approval by Japan’s national health insurance system. Meanwhile, in the United States, several companies are pursuing clinical trials with treatments based on CECs (see “Cultured endothelial cell treatments in the pipeline”). If this approach proves as successful as many believe, hundreds, perhaps even thousands, of corneal disease patients could benefit from just one donor cornea.
ARTIFICIAL CORNEA IMPLANTATION
Just as IOLs are used to replace the natural lenses of cataract patients, artificial corneas are being explored as alternatives to donor corneas; they have the potential to overcome the limitations associated with donor availability and compatibility. Among artificial corneas, the most commonly used currently is the Boston KPro type 1 (Boston Keratoprosthesis, a not-for-profit entity within Massachusetts Eye and Ear), almost 20,000 of which have been implanted to date.7
In addition, two other companies are in the midst of developing artificial corneas. One, EyeYon Medical, is working on a flexible acrylic polymer used to produce artificial corneal tissue of varying thicknesses as an alternative to DSEK/DMEK procedures. The other is Israel-based CorNeat Vision, which is developing CorNeat KPro. The CorNeat KPro is designed to replace deformed, scarred or opacified corneas. The artificial cornea remains in clinical trials aimed at achieving CE Mark, FDA clearance and China NMPA approval.
LIMITATIONS AND SOCIOECONOMIC FACTORS
Despite these promising advances, artificial cornea transplantation challenges remain. Infection and other complications remain significant issues, and it will be some time before the procedure becomes as widespread as cataract surgery. In addition, the global shortage of donor corneas poses a significant barrier to accessing transplantation services, particularly in low- and middle-income countries.
Efforts are underway to address these challenges through initiatives aimed at increasing awareness about eye donation, improving tissue procurement and distribution networks, and enhancing surgical capacity in underserved regions. Researchers are successfully meeting these challenges, particularly in India and the United States.
Cultured Endothelial Cell Treatments in the Pipeline
1. Eversight and Emmecell. The companies are partnering in a Phase 1 clinical trial of Emmecell’s minimally invasive treatment that injects healthy donor corneal endothelial cells into the eye to repopulate the patient’s diseased cornea with functioning endothelial cells, potentially eliminating the need for transplantation. Safety data from nine subjects treated in this study was presented at the 2022 ARVO meeting.
2. Cellusion. The FDA granted Orphan Drug Designation to Cellusion’s CLS001, an investigational regenerative compound for the treatment of bullous keratopathy. CLS001 is an iPSC-derived corneal endothelial (CE) therapy designed as an alternate solution for longstanding corneal transplantation problems by injecting CE cells from iPSCs. The therapy injects CE cells from iPSCs via a syringe and would require a patient to remain face-down for 3 hours following treatment. No data are yet available.
3. Aurion Biotech. Late last year, Aurion began a Phase 1/2 US clinical trial of AURN001, a combination cell therapy (biologic/drug) comprising neltependocel (allogeneic human corneal endothelial cells) and Y-27632 (an inhibitor of Rho-associated, coiled-coil containing protein kinase, or ROCK). AURN001 is intended to be administered to the eye as a one-time, intracameral injection for the treatment of corneal edema secondary to corneal endothelial dysfunction. Aurion Biotech Japan received an approval of neltependocel (Vyznova), from the Japan Ministry of Health, Labour and Welfare.
FUTURE DIRECTIONS AND BREAKTHROUGHS
The landscape of corneal transplantation is rapidly evolving, driven by advancements in CEC transplantation and research into other innovative techniques such as corneal xenotransplantation, which involves transplanting corneas from non-human donor corneas, and the use of autologous cultivated mucosal epithelial cells to reconstruct severely damaged ocular surfaces, such as those seen in Stevens-Johnson syndrome.8,9
It is worth noting that, prior to this century, PK was our only option for treating patients with corneal diseases and injuries. The number of options now at our disposal have multiplied in just the past two decades. Indeed, we truly are still just at the beginning, and the entire scope and nature of corneal disease treatment is certain to change even more in the next 20 years. OM
REFERENCES
1. Liu S, Wong YL, Walkden A. Current Perspectives on Corneal Transplantation. Clin Ophthalmol. 2022;16:631-646. Published 2022 Mar 4.
2. Lee WB, Jacobs DS, Musch DC, Kaufman SC, Reinhart WJ, Shtein RM. Descemet’s stripping endothelial keratoplasty: safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology. 2009;116(9):1818-1830.
3. Deng SX, Lee WB, Hammersmith KM, et al. Descemet Membrane Endothelial Keratoplasty: Safety and Outcomes: A Report by the American Academy of Ophthalmology. Ophthalmology. 2018;125(2):295-310.
4. Weller JM, Kruse FE, Tourtas T. Descemet membrane endothelial keratoplasty: analysis of clinical outcomes of patients with 8-10 years follow-up. Int Ophthalmol. 2022;42(6):1789-1798.
5. Kinoshita S, Koizumi N, Ueno M, et al. Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy. N Engl J Med. 2018;378(11):995-1003.
6. Numa K, Imai K, Ueno M, et al. Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure. Ophthalmology. 2021;128(4):504-514.
7. Fu L, Hollick EJ. Artificial cornea transplantation. 2023 Apr 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 33760451.
8. Nakamura T, Inatomi T, Sotozono C, Koizumi N, Kinoshita S. Ocular surface reconstruction using stem cell and tissue engineering. Prog Retin Eye Res.51:187-207, 2016.
9. Sotozono C, Inatomi T, Nakamura T, Ueta M, Imai K, Fukuoka H, Komai S, Ishida G, Kitazawa K, Yokoi N, Koizumi N, Kimura Y, Go M, Fukushima M, Kinoshita S. Oral Mucosal Epithelial Transplantation and Limbal-Rigid Contact Lens: A Therapeutic Modality for the Treatment of Severe Ocular Surface Disorders. Cornea. 2020 Nov;39 Suppl 1:S19-S27.
