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Übersicht

Medical and Semi-surgical Treatments for Fuchs Endothelial


Corneal Dystrophy
Interventionelle und pharmakologische Behandlungsansätze
für Fuchs-Endotheldystrophie

Authors
Katrin Wacker 1, 2, Keith H. Baratz 1, Michael P. Fautsch 1, Sanjay V. Patel 1

Affiliations AB STR AC T
1 Ophthalmology, Mayo Clinic, Rochester, Minnesota, Unraveling the genetic mechanisms of Fuchs endothelial cor-
United States neal dystrophy has opened new possibilities for future tar-
2 Eye Clinic, Faculty of Medicine, University of Freiburg, geted medical therapy of the disease. Until these possibilities
Freiburg, Germany

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mature, regenerative semi-surgical approaches by cell injec-
tion or cell sheet transfer could help expand the donor pool,
Key words and possibly enable autologous transplantation. Descemet
endothelial keratoplasty, Fuchs endothelial corneal dystrophy, membrane stripping alone and acellular Descemet membrane
trinucleotide repeat expansion, TCF4 gene, ROCK inhibitor, transfer are more immediate surgical approaches that could
cell injection be temporary treatments in some patients, though there is a
lack of understanding of the factors that predict success for
Schlüsselwörter these procedures. Regardless of approach, clinical trials will
Endothelzelltransplantation, Fuchs‑Endotheldystrophie, be necessary, and clinicians should therefore try to standard-
Trinukleotid‑Repeat‑Expansion, TCF4‑Gen, ROCK‑Inhibitor, ize their methods of assessing disease severity and the out-
Zellinjektionen comes of intervention.

received 7. 12. 2017


ZU SAM ME N FA SS UN G
accepted 6. 2. 2018
Ein Verständnis der genetischen Grundlagen der Fuchs-Endo-
Bibliography theldystrophie eröffnet die Möglichkeit zukünftiger gezielter,
DOI https://doi.org/10.1055/a-0577-7953 nicht operativer Therapien. Bis diese Therapien ausgereift
Published online | Klin Monatsbl Augenheilkd © Georg sind, könnten neue regenerative therapeutische Ansätze wie
Thieme Verlag KG Stuttgart · New York | ISSN 0023-2165 die Injektion von Endothelzellen oder der Transfer kultivierter
Endothelzellschichten helfen, die Verfügbarkeit von Donor-
Correspondence
gewebe zu verbessern und vielleicht sogar autologe Trans-
Prof. Sanjay V. Patel, MD FRCOphth
plantationen zu ermöglichen. Eher temporäre operative An-
Mayo Clinic, Ophthalmology
sätze für ausgewählte Patienten sind das alleinige Stripping
200 First St SW, Rochester, Minnesota 55905, United States
und der azelluläre Transfer der Descemet-Membran, obgleich
Phone: + 1 50 72 66 49 18, Fax: + 1 50 72 84 46 12
unklar ist, welche Patienten am meisten von diesen Verfahren
patel.sanjay@mayo.edu
profitieren können. Für alle Behandlungsverfahren werden kli-
nische Studien notwendig sein, weshalb Kliniker anstreben
sollten, die Bestimmung des Schweregrads der Fuchs-Endo-
theldystrophie und der postoperativen Erfolgsparameter zu
standardisieren.

the disease. Endothelial keratoplasty has safely lowered the


Introduction threshold for intervention [1], and retention of the host cornea
Advances in research and novel therapies for Fuchs endothelial and its morphologic changes that persist after restoring endothe-
corneal dystrophy (FECD) have been driven by two major factors: lial function by this technique have offered insight into disease
the advent of endothelial keratoplasty, and discovering the genet- chronicity and its relationship to patient symptoms. The discovery
ic basis of and various pathophysiologic mechanisms related to that three-quarters of patients in the U. S. and Europe with FECD

Wacker K et al. Medical and Semi-surgical … Klin Monatsbl Augenheilkd


Übersicht

harbor a trinucleotide repeat expansion in the third intron of the


▶ Table 1 Genes associated with FECD.
transcription factor 4 (TCF4) gene has stimulated studies to under-
stand the mechanism of the disease and is creating an opportu-
Gene Protein
nity for targeted medical therapy. Coupled with improved under-
AGBL1 ATP/GTP binding protein like 1
standing of various dysregulated downstream processes [2],
COL8a2 Collagen type VIII alpha 2 chain
these clinical and basic science approaches will merge in the fu-
ture, with the likelihood of offering new medical and minimally-in- DMPK Dystrophia myotonica protein kinase or
myotonic dystrophy protein kinase
vasive surgical treatments for the disease.
This overview will highlight current investigational treatments LAMC1 Laminin subunit gamma-1 protein

for FECD that might be of promise in the immediate and distant LINC00970/ Na+, K+ transporting ATPase, beta-1 polypeptide
ATP1B1
future for managing the disease. These treatments will be catego-
rized as genetic, pharmacologic, basement membrane-related, LoxHD1 Lipoxygenase homology domains 1 protein
and cell-based, although many could be combined or fall into KANK4 KN motif and ankyrin repeat domain-
multiple categories. containing protein 4
SLC4a11 Sodium bicarbonate transporter-like protein 11
TCF4 Transcription factor 4
Genetic
ZEB1 Zinc finger E‑box-binding homeobox 1 protein
Over the last two decades, the number of genes associated with
FECD has steadily increased [3 – 8]. Currently, there are 10 genes

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that have been found to be associated with FECD (▶ Table 1) [4,
9]. The majority of these associations appear to be responsible tion include gene editing or deleting the repeat expansion region
for a small proportion of the disease, including early-onset varia- by using endonucleases, and preventing the formation of RNA foci
tions. The strongest genetic linkage to FECD is in the TCF4 gene. to maintain normal RNA splicing activity. Other approaches to
Baratz and colleagues reported that a single nucleotide poly- treating FECD at the gene level might include options that are cur-
morphism, rs613872, in the TCF4 gene (chromosome 18) was sig- rently being studied for DM1, such as oligonucleotides to target
nificantly associated with FECD in more than three-quarters of and disrupt RNA-MBNL interaction. Further studies and in vivo as-
FECD patients compared to controls [3]. Subsequent analysis of sessment of such targeted therapies will require the development
the TCF4 gene in FECD patients found that an expansion of a of animal models of the TCF4 trinucleotide repeat expansion prior
CTG. trinucleotide repeat sequence in the third intron of the to considering delivery to humans in clinical trials.
TCF4 gene was strongly associated with FECD, with repeat lengths
> 50 occurring in 79 % of FECD eyes and only 3 % of controls [10].
Trinucleotide repeat expansion disorders include several neu-
Pharmacologic
rodegenerative diseases, including Huntingtonʼs disease, spino- While drugs that interfere with genetic anomalies are the future,
cerebellar ataxia, and myotonic dystrophy type 1 (DM1). The hall- opportunities to affect corneal endothelial proliferation are the
mark of these diseases is the presence of RNA repeat expansion present. Okumura and colleagues investigated the effect of a
sequences forming hairpin structures that accumulate in the nu- Rho-associated protein kinase (ROCK) inhibitor (Y-27632) on cor-
cleus as RNA foci. For example, in DM1, which is caused by a CTG neal endothelial cells and found it promoted proliferation and ad-
repeat expansion in the myotonic dystrophy protein kinase hesion of the cells in vitro and in animal models [12 – 14]. In a clin-
(DMPK) gene, the presence of RNA foci in skeletal muscle cells ical trial, Koizumi and colleagues assessed the effect of Y-27632
leads to sequestration of the RNA splicing protein Muscleblind- on corneal edema in humans in vivo [15, 16]. This study examined
like protein 1 (MBNL1). The lack of MBNL1 due to sequestration four eyes with FECD treated with topical Y-27632 ROCK inhibitor
impairs normal RNA splicing within the nucleus, resulting in ab- (50 µL of 10 mM applied 6 times daily for 1 week) after a central
normal splice variants and cellular dysfunction. Similar to DM1, transcorneal freeze injury, and three eyes had an improvement in
FECD patients harboring a CTG trinucleotide repeat sequence corneal thickness with one of these eyes attaining visual acuity of
have RNA foci sequestering MBNL1 in the corneal endothelium 20/20 (or 1.0 in decimal notation). In contrast, they also treated
[10]. RNA sequence analysis of corneal endothelium from FECD four eyes with diffuse corneal edema (from argon laser iridotomy)
patients with a CTG trinucleotide repeat expansion sequence and found no improvement in corneal thickness or visual acuity.
identified a signature set of RNAs that are alternatively spliced This was a pilot study and therefore lacked a control group to help
due to the presence of RNA foci and sequestration of MBNL1 understand the true effect of Y-27632. This ROCK inhibitor is com-
[11]. How these changes in RNA splicing and the effect of RNA mercially available in some countries and has been used in corneal
toxicity on the corneal endothelium that leads to the patho- endothelial culture medium for human trials and as a topical treat-
genesis of FECD is currently unknown. However, it is reasonable ment after basement membrane surgery. A limitation of topical
to speculate that cellular impairment will likely involve multiple treatment with ROCK inhibitors or any other pharmacologic agent
downstream processes. is that guttae, which are considered to be visually significant [17,
The current understanding of the genetic basis of FECD has 18], are not removed. In addition, it is unknown if ROCK inhibitor
provided an opportunity to explore targeted therapies, although treatment might result in unwanted endothelial cell proliferation,
to date there are no published studies. Opportunities for interven- glaucoma, or other adverse effects in vivo [19, 20].

Wacker K et al. Medical and Semi-surgical … Klin Monatsbl Augenheilkd


It is unknown whether long-term outcomes are influenced by
Basement Membrane Surgery the presence or absence of the Descemet membrane. Removing
Descemet membrane is the natural basement membrane of the central guttae is important for visual rehabilitation and also for
corneal endothelium and is composed predominantly of collagen enabling cell monolayer reformation [40], yet the time taken to
[21]. The realization that the Descemet membrane/endothelial restore endothelial function on bare stroma varies because of un-
cell complex could be bluntly stripped from posterior stroma was determined factors. In a human cell injection model ex vivo, we
paramount in enabling the endothelial keratoplasty techniques found that endothelial cell attachment to bare stroma was often
that we consider to be the standard of care today [1]. Stripping nonuniform, incomplete, and resulted in abnormal cell morphol-
of the Descemet membrane in FECD is important for removing ogy [41]. Bhogal and colleagues showed that the presence of the
guttae from the visual axis because they might contribute to light Descemet membrane promoted endothelial cell healing and phe-
scattering and aberrations that affect vision [22 – 25]. This con- notype compared to its absence (i.e., bare stroma) [42]. As a re-
cept is important when considering new treatment modalities re- sult, the same investigators are currently evaluating the effect of
lated to the basement membrane. Descemet membrane transplantation (without endothelial cells)
Corneal endothelial cells in vivo are known to be capable of at- in a pilot human clinical trial to determine if corneal clearance is
taching to corneal stroma after tears in the Descemet membrane more predictable and faster compared to Descemet stripping
[26] and at the graft-host junction after penetrating keratoplasty alone. Such an approach to treating FECD would not require
[27]. With reports that corneal edema can also clear in cases of high-quality donor tissue, would remove central guttae to aid vi-
prolonged Descemet detachment after cataract surgery [28], in- sion, and might hasten the time to recovery by providing a normal
advertent “descemetorhexis” [29, 30], and with chronic endothe- substrate for the endothelial cells. Although it would be prefera-

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lial graft detachment [31], it became apparent that corneal endo- ble to transplant the Descemet membrane with donor endothelial
thelial cells could also resume their function after migrating onto cells for the fastest corneal and visual recovery, Descemet mem-
and adhering to bare posterior stroma. This generated interest in brane transplant alone could offer a treatment for patients where
the concept of treating FECD by removing the Descemet mem- eye banking and donor tissue are not readily available. Future ad-
brane centrally and allowing repopulation of the central stripped juvant therapies could include a ROCK inhibitor or cell injection.
area by peripheral endothelial cell migration [32 – 34]. The results
of these studies have been variable, indicating that not all corneas
with FECD clear with this treatment and raising questions as to
Cell-Based Therapy
what factors predict improvement with this method [35, 36]. The anatomy of the anterior chamber and ability to examine the
Borkar and colleagues treated 13 eyes by Descemet stripping cornea in vivo render regenerative cell-based therapies ideal for
alone and found resolution of corneal edema in 4 eyes by 1 month, the treatment of FECD, either as cell injection therapy or cell sheet
in another 4 eyes by 3 months, and in 2 more eyes by 6 months; transfer. Both depend on ex vivo expansion of human corneal en-
the other 3 eyes required endothelial keratoplasty [37]. Although dothelial cells in culture. Culture methods have undergone contin-
all successfully treated eyes had excellent visual outcomes, they uous improvement [43, 44] since the initial protocols were de-
also had a central endothelial cell density less than 900 cells/ scribed [45 – 47], introducing the possibility of one donor treating
mm2. It is likely that corneal clearance results from peripheral en- multiple recipients with high-quality cells or even the ex vivo ex-
dothelial cell migration, and not from cell regeneration, resulting pansion and reinjection of autologous endothelial cells.
in a low central endothelial cell density and depletion of cells from Early cell-based studies investigated transferring regenerated
the periphery. While the repopulating cells have adequate func- endothelial cell sheets onto membranous carriers [48 – 50], akin
tion and vision is not affected by the presence of guttae, the to cadaveric endothelial keratoplasty. The advantage of cell sheet
long-term success of this procedure and the secondary effects of transfer is that the cell monolayer is already established. However,
prolonged corneal edema [38], if any, are currently unknown. the technique is invasive (though similar to endothelial kerato-
With preliminary evidence that the Y-27632 ROCK inhibitor plasty) and visual outcomes could be affected by light scattering
might improve endothelial function, some investigators have or posterior surface aberrations [51]. Ideally, the carrier mem-
treated eyes with topical ripasudil hydrochloride 0.4 % (another brane would be as thin and uniform as the normal Descemet
ROCK inhibitor approved for the treatment of high intraocular membrane or degradable in vivo to allow cell transfer only, fol-
pressure in some countries) 6 times daily for 2 weeks after Desce- lowed by deposition of a new Descemet membrane. Because
met stripping alone and suggested that it stimulates corneal there are potential advantages of maintaining a basement mem-
wound healing in vivo. Moloney and colleagues stripped Descemet brane, cell sheet transfer could still be a reasonable future regen-
membrane in 12 eyes with FECD [39]. In 9 eyes, corneal edema erative treatment for FECD.
resolved by 6 months without adjuvant ROCK inhibitor; the other More recently, cell injection therapy has become more attrac-
3 eyes were treated with either topical Y-27632 or topical ripasu- tive because of its relative simplicity as a procedure. Koizumi and
dil because of slow endothelial healing, and the 2 eyes treated colleagues have performed several studies of the technique in an-
with ripasudil cleared. While the current evidence for ROCK inhib- imal models with successful corneal clearance [15, 52]. In these
itors as a treatment for FECD is limited to small and uncontrolled studies, the Descemet membrane was mechanically scraped to
series, further investigation is warranted to determine the safety remove the cells while retaining the natural basement membrane
and efficacy of this medical treatment. for cell adhesion. Their work has progressed to a human clinical
trial of cell injection therapy, which is ongoing and has enrolled

Wacker K et al. Medical and Semi-surgical … Klin Monatsbl Augenheilkd


Übersicht

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Conflict of Interest
26113
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