Novel therapies emerge for a progressive corneal disease

Fuchs endothelial corneal dystrophy (FECD) is a common corneal disease that affects 4% to 7% of people in the US.¹ FECD is a progressive dysfunction of the corneal endothelium characterised by abnormal endothelial morphology (pleomorphism and polymegethism) with an accumulation of guttae and excrescences on the Descemet membrane. Early-stage disease is not typically symptomatic. Corneal oedema occurs as the condition progresses, and patients may notice blurry vision, often more severe upon awakening.

FECD accounts for approximately one-third of corneal transplants in the US.² Tremendous strides have been made in the surgical management of FECD over the past 25 years. In the past century, full-thickness corneal transplantation (penetrating keratoplasty [PK]) was the mainstay of treatment for FECD. PK could successfully restore vision for patients with FECD but was associated with a lengthy visual recovery (up to 1 year), a high lifelong risk of graft rejection, risk of suture infections and irregular astigmatism requiring hard contact lenses for optimal vision.

Modern-day selective endothelial keratoplasty (EK) was introduced in the late 1990s.³ Over the next decade, modifications of surgical technique and graft preparation led to widespread adoption of EK. Currently, Descemet membrane EK (DMEK), in which donor endothelium and Descemet membrane without corneal stroma are transplanted, is now the most commonly performed EK technique in the US, having surpassed Descemet stripping EK (DSEK), in which donor endothelium, Descemet membrane and 50 to 100 µm of stroma are transplanted.^2,4 EK offered numerous advantages over PK, including rapid visual recovery and reduced rejection rates.

The outcomes of both DMEK and DSEK are excellent. Visual recovery tends to be quicker with DMEK, although the rate of rebubbling can be higher. At the recent meeting of the International Society of Cornea, Stem Cells and Ocular Surface in Grosseto, Italy, I led a session devoted to the endothelium with Natalie Afshari, MD; Deepinder Dhaliwal, MD; Sadeer Hannush, MD; and Marian Macsai, MD, as panelists.

There was agreement that although EK in its current form is a safe and effective therapy for endothelial diseases, future advances might include insertion techniques that allow more consistent graft delivery and unfolding. Additionally, it may be possible to add various agents to the storage media to enhance endothelial cell function and viability after transplantation.

Descemet stripping only (DSO), in which the patient’s central endothelium and Descemet membrane are removed but no corneal transplant is placed, has emerged as a potential surgical option for FECD in the past 10 years.^5,6 DSO clears central guttae that can be visually significant while circumventing the risks of transplantation (for example, rejection and the need for long-term topical steroids with their associated adverse effects). It best suits patients with predominantly central corneal guttae of 5 mm or less with a preserved peripheral endothelium (Figure 1).

Patients have blurry vision from corneal oedema for 2 to 4 weeks after surgery while the peripheral endothelium migrates to cover the stripped area (Figures 2 and 3). Early studies showed a success rate of approximately 75%, whereas the success rate in more recent studies has approached 100%.^5,6 Rho kinase inhibitors appear to enhance endothelial migration speed and reduce DSO failure rates.

This is being studied in randomised, placebo-controlled clinical trials. Patients with advanced FECD, such as those with limbus to limbus guttae, are not candidates for DSO because they do not have enough healthy peripheral endothelium to repopulate the central cornea after removing the endothelium and Descemet membrane. The initial cases have only recently reached 10 years of follow-up, so long-term data regarding DSO remains limited. However, this technique holds promise, especially in combination with therapies that enhance the functioning of the remaining corneal endothelium or inhibit disease progression.

Implanted cultured human endothelial cells effectively restore corneal clarity in various forms of endothelial dysfunction.⁷ Approved for use in Japan in 2023, cultured cells are being investigated in clinical trials in the US. Cultured cells will have broader applicability for endothelial diseases (for example, to treat disorders characterised by endothelial depletion, such as pseudophakic bullous keratopathy) compared with DSO, which primarily applies to FECD and requires remaining relatively healthy peripheral endothelial cells to be successful.

Cultured cells have the advantage of expanding the impact of a corneal donation because numerous patients (perhaps as many as 50-100) can be treated with cultured cells from a single donor. This exciting technology is likely to positively impact the care of patients with FECD, assuming that regulatory and insurance coverage hurdles can be cleared.

In recent decades, strides have been made to unravel the biological and genetic underpinnings of FECD. However, we do not yet understand the pathophysiology of this common disease that was initially described over 100 years ago. Numerous pathways have been implicated in FECD, including oxidative stress, mitochondrial dysfunction, unfolded protein response, and endothelial-mesenchymal transition.

The exact role of each of these pathways is still to be determined. Most cases of FECD in the US are associated with a repeat expansion in the TCF4 gene on chromosome 18, which may cause endothelial dysfunction by RNA toxicity.⁸ The mechanisms that underlie the endothelial dysfunction caused by most other genetic mutations associated with FECD remain unknown. A better understanding of the biology of FECD will aid in developing effective treatments and preventive strategies. This disease has tremendous interest, and medical therapy is likely within 10 to 20 years.

References

1. Sarnicola C, Farooq AV, Colby K. Fuchs endothelial corneal dystrophy: update on pathogenesis and future directions. Eye Contact Lens. 2019;45(1):1-10. doi:10.1097/ICL.0000000000000469

2. 2023 Eye Banking Statistical Report. Eye Bank Association of America. Accessed July 9, 2024. https://restoresight.org/members/publications/statistical-report

3. Melles GR. Posterior lamellar keratoplasty: DLEK to DSEK to DMEK. Cornea. 2006;25(8):879-881. doi:10.1097/01.ico.0000243962.60392.4f

4. Colby K. Update on corneal transplant in 2021. JAMA. 2021;325(18):1886-1887. doi:10.1001/jama.2020.17382

5. Borkar DS, Veldman P, Colby KA. Treatment of Fuchs endothelial dystrophy by Descemet stripping without endothelial keratoplasty. Cornea. 2016;35(10):1267-1273. doi:10.1097/ICO.0000000000000915

6. Moloney G, Petsoglou C, Ball M, et al. Descemetorhexis without grafting for Fuchs endothelial dystrophy—supplementation with topical ripasudil. Cornea. 2017;36(6):642-648. doi:10.1097/ICO.0000000000001209

7. 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. doi:10.1056/NEJMoa1712770

8. Fautsch MP, Wieben ED, Baratz KH, et al. TCF4-mediated Fuchs endothelial corneal dystrophy: insights into a common trinucleotide repeat-associated disease. Prog Retin Eye Res. 2021;81:100883. doi:10.1016/j.preteyeres.2020.100883

Kathryn A. Colby, MD, PhD | E: kathryn.colby@nyulangone.org

Colby is the Elisabeth J. Cohen, M.D. Professor of Ophthalmology and chair of the Department of Ophthalmology at the NYU Grossman School of Medicine in New York, New York. She is an internationally renowned academic corneal specialist with a longstanding interest in Fuchs dystrophy, the most common reason for corneal transplantation in the US. She is pioneering novel, nontransplant treatments for this condition. She has expertise in managing ocular surface tumours, paediatric corneal disease, infectious keratitis and keratoprosthesis.