Sunrise was too early in the “Land of the Rising Sun” on Day 2 of the ongoing virtual ACS 2020 Scientific Biennial Meeting and Dr. Kathyrn Colby’s plenary lecture titled Fuchs’ Dystrophy: Past, Present and Future served as intravenous caffeine, shooting straight to sleep-laden brain cells.
Fuchs’ endothelial corneal dystrophy (FECD) or Fuchs’ dystrophy is an old disease that’s new again, emphasized Dr. Colby, the Elizabeth J. Cohen professor and chair of the Department of Ophthalmology at NYU Langone Health (USA).
Dr. Colby’s plenary lecture was followed by an interesting symposium session — Fuchs’ Endothelial Corneal Dystrophy and Genetics — comprising a panel of speakers from the U.S., Japan, Singapore and the Philippines.
Fuchs’ dystrophy is the most common cause of corneal transplantation today. “In the United States, it accounts for one-third of corneal transplantation cases every year,” said Dr. Colby, who is also president of the Cornea Society.
A fascinating tissue, the corneal endothelium
Fuchs’ dystrophy is a slowly progressive dysfunction of the corneal endothelium, the monolayer of hexagonal cells derived from the neural crest. Its main function is to control corneal hydration and nutrition.
During his turn at the symposium, Dr. Yoshinori Oie from Osaka University, Japan, discussed how the corneal morphology changes in the progression of Fuchs’ dystrophy affects visual functions in patients. He reported that the forward light scattering index has the strongest influence on distance visual acuity.
When the morphology of the corneal endothelium displays abnormality (i.e. pleomorphism, polymegethism and guttae), Fuchs’ dystrophy happens. We know that now. But in 1910 when Fuchs’ dystrophy was first identified, it took experts a decade more to elucidate the corneal endothelium involvement.
“It’s a complex multifactorial disease and our efforts and understanding [today] of its pathophysiology are hampered by the lack of relevant animal studies,” explained Dr. Colby. Most approaches, added Dr. Colby, rely on explanted human tissue and cultured cells.
While typically diagnosed in patients in their 40s, intervention in Fuchs’ dystrophy is not needed until later in life (60s to 70s), highlighted Dr. Colby. Also, for reasons yet unknown, women are more commonly and severely affected. “There is a hereditary component and over the course of my career, about 30 percent of my patients have a known family history,” shared Dr. Colby.
A concept: Fuchs’ dystrophy is likely a neurodegenerative disease
There are many commonalities between Fuchs’ dystrophy and other neurodegenerative diseases, according to Dr. Colby. Over the years, there are multiple pathways implicated in the pathophysiology of Fuchs’ dystrophy, including ion channel dysfunction, mitochondria dysfunction, oxidative stress, unfolded protein response, apoptosis, endothelial to mesenchymal transition (EMT), and perturbations in extracellular matrix deposition.
The corneal endothelium has huge energy requirements due to the high metabolic energy that it needs to maintain corneal deturgescence. So, does mitochondrial dysfunction, already known to be related to various eye and neurodegenerative diseases, play a role in Fuchs’ dystrophy? The said question, according to Dr. Colby, was first asked back in the 90s and there were preliminary study findings suggesting that there might be.
Dr. Colby then presented examples of cases of mitochondrial diseases with endothelium morphology similar to Fuchs’ dystrophy. Furthermore, she discussed how corneal endothelial cells are especially vulnerable to oxidative stress: they live in a low oxygen environment on the anterior chamber; they have high metabolic energy that generates reactive oxygen species (ROS); they don’t proliferate; and the mitochondrial DNA lacks repair mechanisms that are present in nuclear DNA.
She presented findings from old and recent studies demonstrating multiple lines of evidence supporting the role of mitochondrial dysfunction in Fuchs’ dystrophy. Dr. Sophie X. Deng, professor of ophthalmology at Stein Eye Institute, UCLA, USA, during her symposium presentation agreed: “The pathogenesis is more likely multifactorial, consisting of intrinsic and extrinsic causes leading to a final convergent pathway that is responsible for the identical clinical presentation.”
The genetic connection, a disease of aging
The genetics of Fuchs’ is challenging to study not only because it is a commonly late-onset disease and mild cases may not be diagnosed. However, based on published findings on Fuchs’ dystrophy genetics, multiple genes have already been implicated: from the COL8A2 in 2001 to the KANK4 and others in 2017.
Since then multiple gene defects have been identified. In his presentation, Dr. Naoki Okumura of Doshisha University, Kyoto, Japan, delivered a comprehensive review of the genetic study findings related to Fuchs’ dystrophy. There are many genotypes that contribute to the one clinical phenotype of Fuchs’ dystrophy.
“Although we don’t know the exact contribution of these genetic defects to the pathophysiology of Fuchs’, the major finding was the determination that trinucleotide repeats expansion in the TCF4 gene underlies a great percentage (60 to 75 percent) of Fuchs’ dystrophy cases especially in Caucasians,” reported Dr. Colby.
On the other hand, Dr. Keith H. Baratz from the Mayo Clinic in the United States, talked about the genetics and inheritance patterns of Fuchs’ dystrophy. “The CTG repeat expansion of the TCF4 gene is by far the strongest risk factor identified with Fuchs’ dystrophy in the majority of U.S. and Europe cases,” said Dr. Baratz.
“The findings on CTG repeat expansion has opened to new treatment options. CTG sequencing has an effect on patient prognosis, but there are ethnic variations,” said Dr. Jodhbir S. Mehta of Singapore National Eye Centre.
Toward a unified theory of Fuchs’ dystrophy
“But we need to have one final common pathway,” said Dr. Colby. Is mitochondrial function it?
“It [the mitochondria] is central to the pathophysiology of Fuchs’ dystrophy. However, it is complex teasing out relevant pathways for therapeutic interventions. This will keep us busy for a while. But I do think that medical therapy is likely in our lifetime, such as mitochondrial stabilizers, gene editing, intervening in downstream effects from repeat expansion, preventing extracellular matrix deposition, and endothelial to mesenchymal transition,” she added.
“Strategies involving DNA/RNA therapeutics offer an upstream approach to the treatment instead of cadaver transplantation,” added Dr. Mehta.
“Additionally, we will likely gain insights by the study of other neurodegenerative diseases (i.e. Alzheimer’s, Parkinson’s, Huntington’s, myotonic dystrophy, ALS) and we in turn can help our neurology colleagues. They need brain tissues, we only need the affected layer, the corneal endothelium, to study the cellular mechanisms,” explained Dr. Colby.
A 25-year clinical revolution
In the past, the only intervention that surgeons could offer patients with Fuchs’ dystrophy is penetrating keratoplasty (PK). A relatively quick operation, it was associated with multiple problems, from multiple clinic visits to high astigmatism, as well as rejection/failure, suture related issues and others.
The last 20 to 25 years have seen tremendous surgical advances in Fuchs’ dystrophy. There was a gradual transition to a more anatomical replacement, from PK to EK (endothelial keratoplasty): DSEK and DMEK. “Gone are the PK days. Today, we can do a selective replacement of just the deceased layer(s),” said Dr. Colby.
The availability of pre-cut tissue from the bank, according to Dr. Colby has become the tipping point for acceptance of DSEK and DMEK. “While DSEK is still the most commonly performed procedure, DMEK is catching up … more so since eyebanks are now preparing and pre-loading tissue for transplant clinics,” she said.
Implantation of cultured endothelial cells: The future?
It would be amiss, said Dr. Colby, if the work of Prof. Shigeru Kinoshita and colleagues was not mentioned in this section. The group, from the Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine in Kyoto, Japan, has developed a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions which have successfully restored corneal clarity in patients.
The investigators’ five-year findings on the follow-up of those first 11 patients has recently been published in the journal Ophthalmology.*
“This is groundbreaking work and it holds real promise for the care of patients with endothelial dysfunction, not just Fuchs’ dystrophy patients,” said Dr. Colby.
*Numa K, Ima 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.
Editor’s Note: The Asia Cornea Society (ACS) 2020 Biennial Scientific Meeting was held online from April 28-29, 2021. Reporting for this story took place during the event.
