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Update On Cenegermin Eye Drops In The Treatment Of Neurotrophic Keratitis

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Neurotrophic keratitis is an underdiagnosed degenerative condition induced by impairment to the corneal nerves which may lead to persistent epithelial defects and corneal blindness. Current medical and surgical treatments are only supportive and poorly tackle the underlying problem of corneal anesthesia; hence, fail to provide a permanent cure. Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF) that may address this issue. Preliminary clinical trials have demonstrated the safety and efficacy of topical cenegermin in patients with moderate to severe neurotrophic keratitis; however, the clinical experience with this drug is still limited. This review summarizes the pathogenesis and management of neurotrophic keratitis as well as the mechanism of action, uses, and limitations of cenegermin eye drops in the treatment of neurotrophic keratitis.
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REVIEW
Update On Cenegermin Eye Drops In The Treatment
Of Neurotrophic Keratitis
This article was published in the following Dove Press journal:
Clinical Ophthalmology
Hosam Sheha
13
Sean Tighe
2
Omar Hashem
3
Yasu t a k a H ayashida
4
1
Department of Ophthalmology,
Manhattan Eye, Ear & Throat Hospital,
Northwell Health, New York, NY, USA;
2
Department of Ophthalmology, Florida
International University Herbert
Wertheim College of Medicine, Miami,
FL, USA;
3
Department of Ophthalmology,
Research Institute of Ophthalmology,
Cairo, Egypt;
4
Department of
Ophthalmology, Osaka University
Graduate School of Medicine, Suita, Japan
Abstract: Neurotrophic keratitis is an underdiagnosed degenerative condition induced by
impairment to the corneal nerves which may lead to persistent epithelial defects and corneal
blindness. Current medical and surgical treatments are only supportive and poorly tackle the
underlying problem of corneal anesthesia; hence, fail to provide a permanent cure.
Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF) that
may address this issue. Preliminary clinical trials have demonstrated the safety and efcacy
of topical cenegermin in patients with moderate to severe neurotrophic keratitis; however, the
clinical experience with this drug is still limited. This review summarizes the pathogenesis
and management of neurotrophic keratitis as well as the mechanism of action, uses, and
limitations of cenegermin eye drops in the treatment of neurotrophic keratitis.
Keyword s: cenegermin, corneal nerves, neurotrophic keratitis, nerve growth factors,
persistent epithelial defect
Background
The cornea is the most densely innervated tissue in the human body and is supplied by
the ophthalmic branch of the trigeminal nerve and autonomic nerves (Figure 1). Nerve
bers penetrate the corneal periphery at the limbus and approach toward the central
cornea at the level of the anterior stroma while penetrating the Bowmansmembraneto
create the sub-basal nerve plexus, beneath the basement membrane of the epithelium.
Terminal branches from the sub-basal plexus pass anteriorly into the epithelial cell
layers, terminating within or in between epithelial cells. (Figure 2).
13
These nerves are
essential for maintaining the integrity and clarity of the cornea including the limbal
stem cell niche by mediating protective blinking and tearing reexes as well as other
trophic functions.
1,4,5
Corneal nerves release neuropeptides, such as substance P and
calcitonin gene-related peptide, that promote epithelial cell proliferation, migration,
adhesion, and differentiation. In turn, corneal epithelial cells release neurotrophic
factors, such as nerve growth factor (NGF) and epidermal growth factor, which
promote neuronal extension and survival.
1,6
This balance is vital for corneal healing
and maintenance. Corneal nerve damage results in loss of corneal sensation and trophic
functions which consequently leads to epithelial breakdown and poor healing;
a condition known as neurotrophic keratitis or neurotrophic keratopathy.
68
Cenegermin is a newly introduced recombinant human nerve growth factor (rhNGF)
to promote healing in neurotrophic keratitis. Preliminary clinical trials have demon-
strated the safety and efcacy of topical cenegermin in patients with moderate to severe
neurotrophic keratitis; however, the clinical experience with this drug is still limited.
Correspondence: Hosam Sheha
Department of Ophthalmology,
Manhattan Eye, Ear & Throat Hospital,
210 E 64th Street, New York, NY 10065,
USA
Tel +1 305-710-4709
Email hoss88@gmail.com
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This review summarizes the pathogenesis and management
of neurotrophic keratitis as well as the mechanism of action,
uses, and limitations of cenegermin eye drops in the treat-
ment of neurotrophic keratitis.
Etiology Of Neurotrophic Keratitis
The most common causes of corneal nerves damage include
herpetic keratitis, chemical burns, physical injuries, corneal
surgery, long-term use of contact lenses, and prolonged use
of topical medications.
79
Intracranial mass such as neuroma,
meningioma, and aneurysms may compress the trigeminal
nerve or ganglion and produce impairment of corneal
sensitivity.
10
Systemic diseases such as diabetes, and multi-
ple sclerosis may damage sensory bers leading to corneal
hypoesthesia.
11
More recently, it has been determined dry
eye can also cause corneal nerve damage, as well as corneal
degenerative disorders such as keratoconus and dystrophies.
Stages Of Neurotrophic Keratitis
Based on the severity, neurotrophic keratitis is classied into
three overlapping stages (Figure 3): epithelial alterations
(stage 1), persistent epithelial defects (stage 2), and corneal
ulcers (stage 3).
69,12
Due to decreased corneal sensation,
patients rarely complain of ocular symptoms, and there is a
signicant discrepancy between clinical ndings and subjec-
tive symptoms.
9
Therefore, disease progression is often
asymptomatic and may lead to profound vision loss resulting
from scarring and corneal perforation.
Diagnosis Of Neurotrophic Keratitis
The diagnosis of neurotrophic keratitis is mainly based on
clinical history and clinical signs such as presence of persis-
tent epithelial defects or ulcers and decreased corneal sensi-
tivity. According to the literature, the estimated prevalence of
neurotrophic keratitis is less than 5/10,000 individuals, being
classied as a rare orphan disease (ORPHA137596).
12
With
the evolution of the diagnostic imaging and the quantitative
analysis of corneal innervation,
1316
the prevalence and clas-
sication should be reevaluated to include the correlations
between corneal innervation, clinical ndings, and patients
symptoms. Coexisting ocular surface disorders such as dry
eye and exposure keratitis should also be considered.
Figure 1 Nerve supply of the cornea. The cornea is innervated by the ophthalmic branch of the trigeminal nerve (V1) and by sympathetic and parasympathetic autonomic
nerves.
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Management Of Neurotrophic
Keratitis
Management of neurotrophic keratitis can be divided into
medical management, non-surgical intervention, and surgical
management.
6
The objective of treatment is to arrest progres-
sion and reverse neurotrophic keratitis changes that have
occurred at the time of presentation. Conventional therapy
for stage 1 aims to prevent epithelial breakdown, generally
by administering lubricating agents such as preservative-free
articial tears, autologous serum drops, and discontinuing
toxic topical medications specically unnecessary use of anti-
biotics and anti-inammatory agents. However, they all pro-
vide nonspecic symptomatic relief, which may be temporary.
Stage 2 and 3 therapies aim to facilitate corneal healing and
prevent corneal melting and perforation; these include proce-
dures such as tarsorrhaphy, botulinum-induced ptosis, con-
junctival ap, and amniotic membrane transplantation to
restore ocular surface integrity. However, these procedures
are usually performed late and therefore carry the risk of
corneal scarring and poor vision. Collectively, current medical
and surgical treatments poorly tackle the essential problem of
corneal anesthesia and hence fail to provide a permanent cure.
Substantial evidence supports the use of neurotrophic
factors to fulll the unmet need in the treatment of neuro-
trophic keratitis. Specically, the role of NGF in maintain-
ing corneal homeostasis in vitro, ex vivo, and in animal
models.
17,18
Pilot studies also demonstrated the efcacy
and reproducibility of using murine NGF (mNGF) for the
treatment of corneal neurotrophic ulcers.
1921
However,
the development of mNGF has been mired by its complex
tertiary structure, which complicates the manufacturing of
recombinant human NGF (rhNGF) suitable for clinical
use. Recently, an Escherichia coliderived rhNGF formu-
lation for topical ophthalmic use has been introduced and
demonstrated safety and efcacy in treating moderate-to-
severe neurotrophic keratitis, as will be discussed in detail
below.
22,23
Cenegermin Eye Drops
Cenegermin is an rhNGF produced in Escherichia Coli as a
pro-peptide, with a molecular formula of C
583
H
908
N
166
O
173
S
8
. After topical instillation, cenegermin is cleaved to
mature NGF, which is a small (13kDa) protein composed of
118 amino acids with 3 disulde bonds that forms a cysteine
knot structure. Like the neurotrophin family, NGF binds to
cell receptors TrkA and p75 receptors to regulate growth,
survival, and differentiation of neuronal cells.
24
Figure 2 Corneal nerves distribution: Nerve bers penetrate the corneal periph-
ery at the limbus and approach toward the central cornea at the level of the
anterior stroma while penetrating the Bowmans membrane to create the sub-
basal nerve plexus, at the level of the basal epithelial cells and basement membrane
of the epithelium. Terminal branches from the sub-basal plexus pass anteriorly into
the epithelial cell layers, terminating within or in between epithelial cells.
Figure 3 Stages of neurotrophic keratitis: Impaired cornea sensitivity and lack of
trophic support trigger nonspecic epithelial irregularity and tear lm changes (A, B).
Stage 1- mild (C, D) is characterized by corneal punctate keratopathy due to focal
epithelial damage and loss of tight junctions. It is associated with mild stromal edema
with or without corneal neovascularization. Stage 2 moderate (E, F) is distinguished
by the presence of central persistent epithelial defect, surrounded by edematous,
cloudy, and poorly adherent epithelium. Stage 3- severe (G, H) is characterized by
stromal ulceration and thinning that may progress to melting and perforation (arrows).
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Cenegermin under the tradename (OXERVATE
TM
) was
approved for the treatment of neurotrophic keratitis in the
United States on August 22, 2018, and for the treatment of
moderate to severe neurotrophic keratitis in the European
Union on July 20, 2017. Due to the assumed rarity of this
disease, cenegermin granted orphan drug designation in
the United States and the European Union in 2014 and
2015, respectively. Cenegermin eye drops is a sterile,
preservative-free ophthalmic solution containing 0.002%
(0.02mg/mL) of the active ingredient, cenegermin. It is
packaged in a carton of 7 multi-dose vials (1.0ml) intended
to be used 6 times a day at 2 hr intervals for eight weeks.
Only one vial is used per day before being discarded. The
remaining vials in the carton are refrigerated between 2°C
to 8°C for up to 14 days or until time of use. The other
inactive ingredients in the product include disodium
hydrogen phosphate anhydrous, hydroxypropylmethylcel-
lulose, L-methionine, mannitol, polyethylene glycol 6000,
sodium dihydrogen phosphate dihydrate, trehalose dihy-
drate, water, and hydrochloric acid and/or sodium hydro-
xide to adjust pH to 7.17.3.
Mechanism Of Action Of Cenegermin
Neurologist Dr. Rita Levi-Montalcini of Italy rst discov-
ered NGF in the 1950s, and this work won her the Nobel
prize in 1986. As stated earlier, NGF is known to support
corneal integrity via many mechanisms, although its exact
role in treating neurotrophic keratitis is not entirely clear.
NGF acts directly on corneal epithelial cells to stimulate
their growth and survival, maintains limbal epithelial stem
cell potential, binds receptors on lacrimal glands to pro-
mote tear production and has been experimentally shown
to support corneal re-innervation.
17,2527
These mechan-
isms are essential to overcome the degenerative cycle of
neurotrophic keratitis including impaired corneal innerva-
tion, loss of corneal sensitivity, reduced reex blinking and
tear production, and corneal epithelial breakdown.
28
NGF is typically released in the aqueous humor and
tear lm and binds to NGF receptors expressed on anterior
segments of the eye including iris, ciliary body, lens,
cornea, and conjunctiva,
29,30
by the lacrimal gland,
31,32
and by all the intraocular tissues.
29
NGF binds with two
transmembrane receptors: the low-afnity receptor P75
NTR
and high-afnity tropomyosin receptor kinase A (TrkA).
NGF binding to TrkA leads to intracellular activation of
Ras, Cdc42/Rac/Rho, MAPK, PI3K, and PLC-γ.
33
The
biological activity and potency of cenegermin have been
evaluated in vitro using a TF-1 human bone marrow
erythroblast cell line that expresses the TrkA receptor.
The quantied amount of TF-1 cells proliferation was
similar after exposure to either NGF or cenegermin.
Safety And Efcacy Of Cenegermin
For The Treatment Of
Neurotrophic Keratitis
The safety and efcacy of cenegermin eye drops for the
treatment of neurotrophic keratitis have been evaluated in
several clinical trials (Table 1). First, an open-label uncon-
trolled study as performed in 12 patients (14 eyes) with
severe corneal neurotrophic ulcers that had been present for
45±24 days. After treatment with murine NGF (200 μg/mL)
10 times/day for two days followed by 6 times/day, complete
corneal healing with scarring was achieved between 10 days
to 6 weeks (mean 34 days). During an average follow-up of
6.6 months, scarring disappeared, none of the patients had
systemic or ocular side effects, and corneal integrity, visual
acuity, and sensitivity were maintained without disease
relapse.
19
The same research group subsequently performed a
prospective, noncomparative, interventional case series in
45 eyes of 43 patients with stage 23 neurotrophic keratitis
unresponsive to other treatments within 6 weeks. Patients
received murine NGF (200µg/mL) every 2 hrs for 2 days
followed by six times/day. After 12 days to 6 weeks of
treatment (mean ~1 month), all patients had complete heal-
ing with signicant improvement of corneal sensitivity and
visual acuity. Hyperemia (100% of cases), photophobia
(85%), and ocular and periocular pain (70%) were side
effects reported during the rst 2 to 7 days. During a mean
follow-up of 15.8 months, recurrence of PED has observed
in 3 cases with trigeminal nerve resection, and 28.6% of
cases had supercial or deep new corneal blood vessels.
20
Following these studies conducted with murine NGF,
regulatory studies commenced with rhNGF. To support
regulatory approval, one Phase I study (NGF0112)
22
in
healthy volunteers, and two randomized, controlled, dou-
ble-masked Phase II studies (NGF0212 and NGF0214) in
neurotrophic keratitis patients were conducted.
23,34
Data
from additional studies in other conditions, including mod-
erate to severe dry eye disease
35
were also provided to
support the safety database.
In the two-Phase II studies, the safety and efcacy of
cenegermin eye drops were evaluated in patients with
neurotrophic keratitis for eight weeks. In the rst study,
34
patients were eligible if they had unilateral stage 2 or 3
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Table 1 Summary Of Clinical Studies Evaluating Safety And Efcacy Of Recombinant Human Nerve Growth Factor (rhngf) Eye Drops
Study Design Subjects Study Groups Treatment
Regimen
Outcome
Measures
Results
NGF0112
(Phase 1)
NCT01744704
Ferrari et al 2014
20
RCT, double
masked, dose
ascending in
Switzerland and UK
74 healthy
volunteers
0.55 µg/mL NGF
20 µg/mL NGF
60180 µg/mL
NGF
Vehicle (control)
(1:1:1:1)
One drop
Up to 3 times/
day for 15
days
S (AEs) and
PK
All doses were well
tolerated
Mild discomfort at
highest dose
No signicant systemic
effect
NGF0212
(Phase 1)
NCT01756456
Bonini et al 2018
21
Multicenter, RCT,
double-masked,
vehicle-controlled
in Europe
18 with
unilateral NK
10 µg/mL rhNGF
20 µg/mL rhNGF
Vehicle
(1:1:1)
One drop
6 times/day for
8 weeks; 48 or
56 weeks
follow up
period
S, PK and E Ocular pain (28%)
No signicant systemic
effect
Corneal Healing at week
4 in 25% (control), 42%
(both doses) and at
week 8 in 50% (control),
67% (10 µg) and 85%
(20 µg).
NGF0212
(Phase 2)
NCT01756456
Bonini et al 2018
33
Multicenter, RCT,
double-masked,
vehicle-controlled
in Europe
156 with
unilateral NK
10 µg/mL rhNGF
20 µg/mL rhNGF
Vehicle
(1:1:1)
One drop
6 times/day for
8 weeks; 48 or
56 weeks
follow up
period
S and E Well tolerated, Mild
transient AEs
No signicant systemic
effect
Corneal Healing at
week4in20%
(control), 55% (10 µg)
and 58% (20 µg). At
week8in43%
(control), 75% (10 µg)
and 74% (20 µg). 96%
no recurrence
NGF0214
(Phase 2)
NCT02227147
Multicenter, RCT,
double-masked,
parallel group study
in US
48 with uni- or
bilateral NK
20 µg/mL NGF
(n= 24)
Vehicle (n=24)
(1:1)
One drop 6
times/day for 8
weeks
S and E Corneal healing in 65% of
NGF group and 17% of
control
NGF0213
(Phase 2a)
NCT02101281
Sacchetti et al
2018
20
Single-center,
open-label, two dose
study in Austria
40 with
moderate to
severe dry eye
20µg/mL rhNGF
4µg/mL NGF
One drop
BID for 28
days
S and E Both doses were well
tolerated, safe and
effective in improving
symptoms and signs of
DED.
NGF0116
(Phase 2)
NCT03035864
Single center RCT,
double-masked,
Parallel group study
in Italy
120 with post
cataract and
refractive
surgery
20µg/mL NGF
Vehicle
(2:1)
One drop
6 times/day for
8 weeks
S and E Not available
NGF0216
(Phase 2)
NCT03019627
Single center RCT,
double-masked,
Parallel group study
in the US
150 with dry
eye disease
20µg/mL NGF
Vehicle
(2:1)
One drop
6 times/day for
8 weeks
S and E Not available
Abbreviations: RCT, Randomized clinical trial; S, Safety; E, Efcacy; AEs, Adverse Events; PK, Pharmacokinetics.
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neurotrophic keratitis refractory to conventional non-sur-
gical treatments for at least 2 weeks and had decreased
corneal sensitivity (<40 mm by Cochet-Bonnet aesthesi-
ometer). The study subjects (n=156) had a mean age of 61
years, with majority female (61%) and white (91%).
Patients were randomized to receive 20µg/mL rhNGF,
10µg/mL rhNGF, or placebo 6 times daily for 8 weeks.
After the treatment period, patients entered a 48-week
follow-up period. The primary endpoint was the percen-
tage of eyes achieving corneal healing (dened as com-
pletely staining free cornea with no residual uorescein
staining in the area of the corneal lesion). Results showed
cenegermin group had a signicantly higher proportion of
patients with complete healing compared to placebo. At 4
weeks, complete healing was observed in 55% of patients
in 10µg/mL rhNGF, 58% in 20µg/mL rhNGF, and 20% in
the vehicle group. At 8 weeks, complete healing increased
to 75% of patients in 10µg/mL NGF, 74% in 20µg/mL
NGF, and 43% in the vehicle group. Interestingly, there
were no statistically signicant differences in improve-
ment in corneal sensitivity in patients of the treatment
groups, who achieved complete corneal clearing at week
4, 6, or 8. Additionally, the recurrence of PED or corneal
ulcer during follow-up was more frequent in the ceneger-
min groups. Of the completely healed patients at 8 weeks,
17% of 10µg/mL NGF, 20% of 20µg/mL NGF, and 10%
of vehicle patients had recurrences.
In the second study (clinical trial #NCT02227147), the
eligibility criteria were similar to the rst study, aside from
both unilateral and bilateral patients were eligible. Patients
(n=48) were randomized to receive 20µg/mL Oxervate or
placebo 6 times daily for 8 weeks. The mean patient age
was approximately 65, and the majority of patients were
female. The primary endpoint was the percentage of
patients achieving complete resolution of corneal uores-
cein staining (0 mm lesion size and no residual staining) at
week 8. Results showed that 65.2% of NGF patients
achieved closure at week 8, compared to 16.7% in the
placebo (p<0.001).
Overall, complete corneal healing was shown in 70% of
patients treated with cenegermin compared to 28% of
patients treated with placebo. Cenegermin eye drops
worked similarly in men and women, and in patients
above and below age 65 years. No differences in response
among races could be determined as the majority of patients
(90%) were White.
Regarding adverse events, 64% of NGF patients
experienced an adverse event compared to 50% in the
placebo group. In patients that received NGF, the most
common adverse event was eye pain reported in 16% of
patients (compared to 7.9% reported in the placebo group).
Other adverse reactions occurring more frequently than in
the placebo group included visual acuity reduction
(10.7%), corneal deposits (4%), cataract (4%), foreign
body sensation (2.7%), ocular hyperemia (6.7%), inam-
mation (5.3%) and tearing (5.3%). Based on the conducted
studies, ocular NGF at treatment doses had no immuno-
genic systemic potential. The ocular metabolizing
enzymes do not metabolize NGF except for tissue pro-
teases that could degrade it to the corresponding amino
acids. After ocular administration, the majority passes
through the nasolacrimal duct reaching the nasal and
then the oropharyngeal cavity and is then degraded by
proteases. However, long-term safety has not been estab-
lished. Further studies should also be performed to evalu-
ate changes in corneal nerves in terms of morphology and
function.
When To Use Cenegermin For
Neurotrophic Keratitis
As stated earlier, until now, treatment options for neuro-
trophic keratitis have been limited to palliative treatments
aimed at reducing symptoms and not directly targeting the
underlying pathology. Cenegermin eye drops (Oxervate
Dompé US Inc., Boston, MA) represents the rst-ever
topical biologic medication approved in ophthalmology
and is the rst-ever application of a human NGF as drug
or treatment. It may be used as a rst-line treatment for
patients with Stage 2 or 3 neurotrophic keratitis that have
not responded to other conventional non-surgical treat-
ments for ~2 weeks. The recommended dose is one drop
in the affected eye(s), 6 times per day at 2 hr intervals, for
eight weeks. If a dose is missed, treatment should be
continued as normal, at the next scheduled administration.
If more than one topical ophthalmic product is being used,
administer the eye drops at least 15 mins apart to avoid
diluting the drug.
Side Effects And Limitations
As reported in the preliminary clinical trials, the most
common adverse reaction is eye pain following instilla-
tion, which was reported in approximately 16% of
patients. Other adverse reactions occurring in 1-10% of
patients included corneal deposits, foreign body sensation,
ocular hyperemia. Because clinical studies are conducted
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under widely varying conditions, adverse reaction rates
observed in the clinical studies may not reect the rates
observed in practice.
Like other temperature-sensitive medications, the sto-
rage and handling of cenegermin remain a signicant
concern. Cenegermin is stored in a freezer, and it usually
takes about 30 mins to be thawed at room temperature
before use. The multiple steps used to withdraw the eye
drops and the multi-dose vial carry the risk of contamina-
tion. Also, the treatment cost may be prohibitive to some
patients. In Europe, eight-week course of cenegermin
treatment typically costs £14,500.
Conclusion
Neurotrophic keratitis is an underdiagnosed degenerative
condition induced by impairment of corneal nerves and
may lead to corneal blindness. Cenegermin has been
demonstrated to be safe and effective in the treatment of
neurotrophic keratitis based on conducted regulatory trials.
However, the clinical experience with this drug is still
limited. Further studies are needed to evaluate corneal
nerve morphology and function. A single-dose generic
medication with a controlled delivery and an affordable
cost is necessary.
Disclosure
The authors report no conicts of interest in this work.
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human nerve growth factor eye drops in patients with dry eye: a
phase IIa, open label, multiple-dose study. Br J Ophthalmol.2019.
doi:10.1136/bjophthalmol-2018-312470
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... NGF plays a vital role in the growth, differentiation, and regeneration of nerve cells. It is not only effective for the treatment of various neuronal ailments such as glaucoma and Alzheimer's disease but also has promising therapeutic potential for some non-neuronal disorders such as vascular and immune diseases [17][18][19][20][21]. Human NGF (hNGF) synthesized by E. coli recently has been approved in the USA and Europe for clinical treatment of a corneal nerve impairment disease called neurotrophic keratitis in humans [22]. However, bacteria-expressed hNGF may exhibit a lower activity than mammalian cell-produced hNGF because bacteria usually are unable to provide proper post-translational modifications for human proteins [3,23,24]. ...
... At present, the cost of the approved bacteria-produced hNGF protein for treating neurotrophic keratitis is high. It is about 12.9 GBP/µg, since a typical eight-week treatment of neurotrophic keratitis with the Cenegermin (OXERVATE ® ) drug containing 1.12 mg of bacteria-synthesized hNGF costs GBP 14,500 [22]. Considering that the prevalence of neurotrophic keratitis was estimated as 1.6 per 10,000 people [37], the total number of neurotrophic keratitis patients in the country with the largest population, China, is predicted to be about 220,000, which requires approximately a total of 250 g of hNGF protein for treatment. ...
Article
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Farm animal salivary glands hold great potential as efficient bioreactors for production of human therapeutic proteins. Nerve growth factor (NGF) is naturally expressed in animal salivary glands and has been approved for human clinical treatment. This study aims to employ transgenic (TG) pig salivary gland as bioreactors for efficient synthesis of human NGF (hNGF). hNGF-TG pigs were generated by cloning in combination with piggyBac transposon-mediated gene transfer. These hNGF-TG pigs specifically expressed hNGF protein in their salivary glands and secreted it at high levels into saliva. Surgical and nonsurgical approaches were developed to efficiently collect saliva from hNGF-TG pigs. hNGF protein was successfully purified from collected saliva and was verified to be biologically active. In an additional step, the double-transgenic pigs, where the endogenous porcine NGF (pNGF) gene was replaced by another copy of hNGF transgene, were created by cloning combined with CRISPR/Cas9-mediated homologous recombination. These double-transgenic pigs expressed hNGF but not pNGF, thus avoiding possible “contamination” of hNGF with pNGF protein during purification. In conclusion, TG pig salivary glands can be used as robust bioreactors for a large-scale synthesis of functional hNGF or other valuable proteins. This new animal pharming method will benefit both human health and biomedicine.
... 6 There is substantial evidence to support the use of neurotrophic growth factors to treat NK to re-establish corneal homeostasis, corneal integrity, and re-innervation of the corneal nerves. 5,15,16 Cenegermin (OXERVATE™) is a topical recombinant Human Nerve Growth Factor (rhNGF) that was approved for the treatment of NK in the US in August 20,18. 13,14,18 In the REPARO 13 and US pivotal trials, 14 10.9% and 12.5% respectively had DED listed as the underlying cause of stage 2 and 3 NK in the clinical trial participants. ...
... Therefore, the clinical data that the FDA used to evaluate for the approval of cenegermin was based on patients with Stage 2 and 3 NK. 13,14 However, cenegermin is approved for all stages of NK. 16,17 There have been several reports that have confirmed good outcomes for the clinical application of cenegermin in Stage 2 and 3 NK. [18][19][20][21] Published literature on the use of cenegermin in adult patients with Stage 1 NK is limited. ...
Article
Full-text available
Purpose To report on the management and effectiveness of treating patients with stage I Neurotrophic Keratitis using an 8-week course of topical recombinant human nerve growth factor (rhNGF, cenegermin). Observations In this retrospective case series, punctate epithelial erosions (PEE), best corrected visual acuity (BCVA) and corneal sensation were followed and documented from 2 to 12 months in patients treated as per the standard of care. Clinical outcomes including changes in PEEs, corneal sensation and BCVA are reported. Most patients also had preexisting thyroid disease. Conclusions All patients had clinically significant improvements in PEE, corneal sensation. Three of the four patients had a significant improvement in BCVA, one patient had no change in their pre-treatment visual acuity (BCVA 20/20) The four patients studied also reported decreased photophobia and improvements in their quality of life. This case series provides real-world evidence of the safety and efficacy of cenegermin treatment of stage I NK for all four patients.
... It is also crucial in corneal lamellar surgery and in the study of ectatic pathologies, and a proven utility in the evaluation of pterygium, pinguecula, and scleromalacia [2,[4][5][6][7][8]. Different studies have highlighted the role of AS-OCT in the management of corneal infections such as keratitis and peripheral ulcers [9][10][11][12]. ...
... Several studies demonstrated the usefulness of the AS-OCT in the clinical evaluation of a large number of corneal pathologies and in assessing the differences between normal and abnormal epithelium in the ocular surface neoplasia [29][30][31]. The undisputed role of AS-OCT in corneal assessment was reported in cases of edema, corneal infiltrates in microbial keratitis, and in peripheral ulcers [9][10][11][12]22]. AS-OCT also became a fundamental tool in the study of stromal deposits and structural changes in corneal dystrophies and degenerations and in the evaluation of the progression of keratoconus [32][33][34][35][36][37][38][39]. ...
Article
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To prove the role of high-tech investigation in monitoring corneal morphological changes in patients with neurotrophic keratopathy (NK) using Keratograph 5M (K5M) and anterior segment OCT (AS-OCT), corneal healing was monitored with Keratograph 5M (Oculus, Wetzlar, Germany) and AS-OCT (DRI, Triton, Topcon, Tokyo, Japan) in 13 patients (8F and 5M), aged from 24 to 93 years (67.8 ± 19) with severe NK, who were treated with Cenegermin 0.002% (20 μg/mL) (Oxervate®, Dompè, Farmaceutici Spa, Milan, Italy). The surface defects were evaluated on Keratograph 5M with ImageJ software and the corneal thickness variations were measured using DRI-Triton OCT software. Instrumental procedures were performed at baseline, and after 4 and 8 weeks of the treatment, respectively. The main outcome measures were reduction of the ulcers’ area and corneal thickness recovery. The mean area of the corneal ulcers was reduced between baseline and 4 weeks examination in all patients, and at 8 weeks all ulcers were completely healed. An increase of the corneal thickness was evidenced between the baseline visit and after the 4- and 8-week follow-up, respectively. Additionally, only in collaborating subjects the In Vivo Confocal Microscopy (IVCM) was performed with HRT Rostock Cornea Module (Heidelberg Eng GmbH) to study the corneal nerves fibres. High-tech diagnostics with K5M, AS-OCT and IVCM proved useful in the assessment of corneal morphology and the healing process in patients with NK and could be extended to assess other corneal pathologies.
... [52] Topical insulin has also proven to be effective and safe in treating refractory NK. [53] The drops are used at a concentration of 1 unit/mL and are prepared by injecting regular insulin into artificial tears with a polyethylene glycol and propylene glycol base. [53] Nerve growth factor (NGF)-containing eye drops are efficacious in moderate to severe NK. [2,5,7,8,47,[54][55][56] Cenegermin is a recombinant form of human NGF and is approved for use as an ophthalmic solution 0.002% by the United States Food and drug administration (US-FDA) for managing NK. Newer medical therapy for NK has been summarized in Table 2. ...
Article
We present a comprehensive review of existing literature on surgical corneal neurotization (SCN) as a treatment modality for neurotrophic keratopathy (NK) with an interim report of seven cases where SCN was performed using the indirect approach and followed up till 18 months postoperatively to look for improvement in ocular surface, corneal sensations, and nerve regeneration by using in vivo confocal microscopy (IVCM). A literature search was performed for publications with keywords "corneal nerves," "neurotization," "esthesiometry," "corneal anesthesia," and "neurotrophic keratopathy." All literature available till December 31, 2020 was reviewed and included to describe NK and its management options, particularly SCN. NK is associated with absent or reduced corneal sensations and is managed using a step-ladder algorithm ranging from medical management for symptomatic relief to surgical corneal neurotization. Both direct and indirect approaches of SCN have a favorable outcome with reduced surgical morbidity in the indirect approach using sural nerve graft. Post neurotization, corneal sensation recovery may take up to 3-6 months, while nerve regeneration on confocal microscopy can take as long as 6 months-1 year.
... In addition, the combination of neurotrophins with p75NTR can also cause pain [ 52 ]. Therefore, the most common adverse event was eye pain reported in 16% of patients when using recombinant human NGF as eye drops to treat corneal nerve injury [ 53 ]. LM22B-10 cannot bind to p75NTR, so it has unique advantages in treating corneal nerve wounds as eye drops. ...
Article
Corneal nerve wounding often causes abnormalities in the cornea and even blindness in severe cases. In this study, we construct a dorsal root ganglion-corneal stromal cell (DRG-CSC, DS) co-culture 3D model to explore the mechanism of corneal nerve regeneration. Firstly, this model consists of DRG collagen grafts sandwiched by orthogonally stacked and orderly arranged CSC-laden plastic compressed collagen. Nerve bundles extend into the entire corneal stroma within 14 days, and they also have orthogonal patterns. This nerve prevents CSCs from apoptosis in the serum withdrawal medium. The conditioned medium (CM) for CSCs in collagen scaffolds contains NT-3, IL-6, and other factors. Among them, NT-3 notably promotes the activation of ERK-CREB in the DRG, leading to the growth of nerve bundles, and IL-6 induces the upregulation of anti-apoptotic genes. Then, LM22B-10, an activator of the NT-3 receptor TrkB/TrkC, can also activate ERK-CREB to enhance nerve growth. After administering LM22B-10 eye drops to regular and diabetic mice with corneal wounding, LM22B-10 significantly improves the healing speed of the corneal epithelium, corneal sensitivity, and corneal nerve density. Overall, the DS co-culture model provides a promising platform and tools for the exploration of corneal physiological and pathological mechanisms, as well as the verification of drug effects in vitro. Meanwhile, we confirm that LM22B-10, as a non-peptide small molecule, has future potential in nerve wound repair. Statement of Significance The cornea accounts for most of the refractive power of the eye. Corneal nerves play an important role in maintaining corneal homeostasis. Once the corneal nerves are damaged, the corneal epithelium and stroma develop lesions. However, the mechanism of the interaction between corneal nerves and corneal cells is still not fully understood. Here, we construct a corneal stroma-nerve co-culture in vitro model and reveal that NT-3 expressed by stromal cells promotes nerve growth by activating the ERK-CREB pathway in nerves. LM22B-10, an activator of NT-3 receptors, can also induce nerve growth in vitro. Moreover, it is used as eye drops to enhance corneal epithelial wound healing, corneal nerve sensitivity and density of nerve plexus in corneal nerve wounding model in vivo.
... Human nerve growth factor directly promotes tear production, corneal re-innervation, limbal epithelial stem cell potential, and the growth and survival of corneal epithelial cells. 91 Cenergemin (OXERVATE, Dompé farmaceutici S.p.A, L'Aquila, Italy) is a topical recombinant human nerve growth factor used to treat neurotrophic keratopathy ( Table 5). The most common side effects associated with it are eye pain, ocular hyperemia, eye inflammation, and increased lacrimation. ...
Article
Biological drugs, termed biologics, are medications that contain or are derived from a living organism (human, animal, or microorganism). With new biological agents being approved by the Food and Drug Administration (FDA) every year, clinicians need to know potential ocular adverse effects that are associated with these drugs. This review provides an overview of ocular adverse effects of biological medications used to treat both ophthalmic and non-ophthalmic diseases. We searched PubMed for relevant case reports, case series, reviews, and clinical trials reporting ocular adverse effects caused by biologics. This review was conducted in June 2021 and investigated the drugs listed in the most updated (April 2021) FDA Purple Book Database of Licensed Biological Products. This review focuses on monoclonal antibodies, interleukins, and receptor fusion proteins. We explore ocular side effects of 33 biological drugs, stating whether they are frequent, common, or rare.
Article
Endogenously produced peptide growth factors such as keratinocyte growth factor-2 (KGF-2) and nerve growth factor (NGF) play a key role in the natural corneal wound healing process. However, this self-healing ability of the corneal tissue is often impaired in cases of severe corneal damage, as in corneal alkali injuries. In the present study, we investigated the clinical and histopathological effects of topical recombinant human keratinocyte growth factor-2 and nerve growth factor treatments in a rabbit model of corneal alkali burn. After induction of an alkali burn, 24 rabbits were divided equally into three groups: control group, KGF-2 group, and NGF group. Clinical parameters including epithelial healing, opacification, neovascularization and central corneal thickness were evaluated on the first (D1), seventh (D7) and fourteenth (D14) days after injury. Corneal histology was performed using hematoxylin/eosin (H&E) and Masson's Trichrome stains. Immunohistochemical staining for matrix metalloproteinase-2 (MMP-2), MMP-9 and transforming growth factor-β (TGF-β) was performed. On D14, the percentage of epithelial defect and opacity were significantly less in the KGF-2 and NGF groups compared to the control group (p < 0.05). There was no significant difference between the groups in central corneal thickness. In the evaluation of neovascularization on D14, the NGF group was significantly less vascularized than the control group (p = 0.011). Histological examination showed a significant increase in stromal edema and inflammation in the control group compared to both treatment groups (p < 0.05). There was also a significant difference between the NGF and control groups in histological evaluation of epithelial repair and vascularization (p < 0.05). When immunoreactivity of MMP-2, MMP-9 and TGF-β was examined, there was a significant increase in the control group compared to the NGF group (p < 0.05). Taken together, both NGF and KGF-2 treatments were effective for early re-epithelialization and decrease in inflammation, opacity and neovascularization after corneal alkali burn. The inhibitory effect of NGF treatment on chemical-induced neovascularization was found to be superior to KGF-2 treatment.
Article
Neurotrophic keratopathy (NK) is a degenerative corneal disease with a loss of corneal sensitivity and impairment of corneal healing. Low dose insulin eyedrops have been shown to be a simple and effective treatment for refractory NK when the response to the usual treatment is incomplete. At present, there are no commercially available forms, and there is no data regarding the stability of these products as prepared by compounding pharmacies. In this work, we studied the physicochemical and microbiological stability of an insulin ophthalmic formulation obtained by mixing insulin lispro in artificial tears with a polyethylene and propylene glycol base. The stability of this 1 IU/mL insulin ophthalmic formulation was analysed for 12 months in low-density polyethylene (LDPE) multidose eye droppers at 4 °C. The studied parameters of physicochemical stability were: visual inspection, turbidity, UV spectral absorption, osmolality and pH. In addition, insulin and m-cresol concentrations and quantification of impurities (insulin covalent aggregates and insulin fragments) were studied thanks to the development of a new Size Exclusion Chromatographic method. For unopened eye droppers, all tested physicochemical parameters remained stable for 12 months at 4 °C, and excellent microbiological stability was obtained. In conditions of simulated use, these parameters also remained stable for one month at 4 °C, and no impact of potential temperature rises on the insulin and m-cresol concentrations in the insulin eyedropper was observed.
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Dry eye syndrome (DES) is multifactorial and likely to be a cause of concern more so than ever given the rapid pace of modernization, which is directly associated with many of the extrinsic causative factors. Additionally, recent studies have also postulated novel etiologies that may provide the basis for alternative treatment methods clinically. Such insights are especially important given that current approaches to tackle DES remains suboptimal. This review will primarily cover a comprehensive list of causes that lead to DES, summarize all the upcoming and ongoing clinical trials that focuses on treating this disease as well as discuss future potential treatments that can improve inclusivity.
Article
Purpose: To evaluate the efficacy and safety of cenegermin 0.002% ophthalmic drops in the management of pediatric neurotrophic keratopathy (NK). Methods: Retrospective chart review of children under the age of 18 years diagnosed with NK at Boston Children's Hospital/Massachusetts Eye and Ear Infirmary and treated with topical cenegermin 0.002% ophthalmic solution between June 2018 and June 2021 was performed. Data collection included etiology of NK, age at time of initiation of topical cenegermin, laterality, ethnicity, gender, history of previous ocular therapy, pre- and post-therapy best corrected visual acuity, pre- and post-therapy cornea examination, any adverse events from topical cenegermin, associated ocular conditions, and history of ocular surgeries. Results: The current study includes four eyes of four pediatric patients with a mean age of 4.5 ± 2.0 years at the time of initiation of topical cenegermin therapy. The mean time from NK diagnosis until start of topical cenegermin drops was 5.2 ± 4.3 months and mean follow-up time was 15 ± 9.6 months. In all four patients, marked improvement in epitheliopathy was demonstrated after completion of therapy. Best corrected visual acuity was measurable in 3 eyes of 3 patients, and it improved from a mean of 0.07 ± 0.01 to a mean of 0.29 ± 0.26 (P = 0.3). No adverse events related to cenegermin therapy were noted. Conclusion: Topical cenegermin was effective in improving corneal healing for pediatric NK.
Article
Full-text available
Background Dry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED. Methods Forty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days ( NCT02101281 ). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test. Results Of 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1. Conclusions The data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED. Trial registration number NCT02101281 .
Article
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Piera Versura, Giuseppe Giannaccare, Marco Pellegrini, Stefano Sebastiani, Emilio C Campos Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Alma Mater Studiorum University of Bologna, Sant’Orsola-Malpighi Teaching Hospital, Bologna, Italy Abstract: Neurotrophic keratitis (NK) is a degenerative corneal disease caused by damage of trigeminal corneal innervation, which leads to spontaneous epithelial breakdown and corneal ulceration. The impairment of corneal sensory innervation causes the reduction of both protective reflexes and trophic neuromodulators that are essential for the vitality, metabolism, and wound healing of ocular surface tissues. A wide range of ocular and systemic conditions, including herpetic keratitis, ocular chemical burns, corneal surgery, diabetes, multiple sclerosis, and neurosurgical procedures, can cause NK by damaging trigeminal innervation. Diagnosis of NK requires careful investigation of any ocular and systemic condition associated with the disease, complete ocular surface examination, and quantitative measurement of corneal sensitivity. The clinical stages of NK range from corneal epithelial alterations (stage 1) to persistent epithelial defect (stage 2) and ulcer (stage 3), which may progress to corneal perforation. Management of NK is based on clinical severity, and the aim of the therapy is to halt the progression of corneal damage and promote epithelial healing. Although several medical and surgical treatments have been proposed, no therapies are currently available to restore corneal sensitivity, and thus, NK remains difficult and challenging to treat. The purpose of this review is to summarize available evidence on the pathogenesis, diagnosis, and treatment of NK. Novel medical and surgical therapies including the topical administration of nerve growth factor and corneal neurotization are also described. Keywords: neurotrophic keratitis, neurotrophic corneal ulcer, corneal nerves
Article
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Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase 2 multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase 2 study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main outcome measures: Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval [CI], 15.88-54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96-57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25-51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60-51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK.
Article
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Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK.
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Purpose: To determine if corneal subbasal nerve plexus (SBP) parameters derived from wide-area depth-corrected mosaic images are associated with type 2 diabetes. Methods: One hundred sixty-three mosaics were produced from eyes of 82 subjects by laser-scanning in vivo confocal microscopy (IVCM). Subjects were of the same age, without (43 subjects) or with type 2 diabetes (39 subjects). Mosaic corneal nerve fiber length density (mCNFL) and apical whorl corneal nerve fiber length density (wCNFL) were quantified and related to the presence and duration of diabetes (short duration < 10 years and long duration ≥ 10 years). Results: In mosaics with a mean size of 6 mm2 in subjects aged 69.1 ± 1.2 years, mCNFL in type 2 diabetes was reduced relative to nondiabetic subjects (13.1 ± 4.2 vs. 15.0 ± 3.2 mm/mm2, P = 0.018). Also reduced relative to nondiabetic subjects was mCNFL in both short-duration (14.0 ± 4.0 mm/mm2, 3.2 ± 3.9 years since diagnosis) and long-duration diabetes (12.7 ± 4.2 mm/mm2, 15.4 ± 4.2 years since diagnosis; ANOVA P = 0.023). Lower mCNFL was associated with presence of diabetes (P = 0.032) and increased hemoglobin A1c (HbA1c) levels (P = 0.047). By contrast, wCNFL was unaffected by diabetes or HbA1c (P > 0.05). Global SBP patterns revealed marked degeneration of secondary nerve fiber branches outside the whorl region in long-duration diabetes. Conclusions: Wide-area mosaic images provide reference values for mCNFL and wCNFL and reveal a progressive degeneration of the SBP with increasing duration of type 2 diabetes.
Article
Purpose: To measure the thickness and length of corneal nerves and the peri-papillary retinal nerve fiber layer (RNFL) thickness in patients recently diagnosed with diabetes mellitus (DM). Methods: Twenty-two eyes of 22 patients recently diagnosed with type 2 DM and 22 eyes of 22 healthy individuals were consecutively enrolled. Central corneal sensitivity was measured using a Cochet-Bonnet esthesiometer, and corneal nerve length (CNL) and thickness (CNT) were evaluated through in vivo confocal microscopy. The confocal images were examined using software that could semi-automatically trace the corneal nerve pathway. Spectral domain optical coherence tomography (SD-OCT) was performed to quantify the overall and sectorial RNFL thickness. Results: Mean DM duration was 3.5 ± 1.7 months, whereas the mean glycemia and HbA1c levels were 180.5 ± 73.13 mg/dl and 8.6 ± 1.7 % (65.2 ± 19.7 mmol/mol), respectively. Corneal sensation threshold was significantly lower in the DM group compared to control group (p=0.003). CNL and CNT were reduced in the DM group (p=0.043 and p=0.004, respectively). Significant correlations were found between CNT and HbA1c levels (p=0.04; r=-0.47), and between CNT and the corneal sensation threshold (p=0.04; r=0.69). RNFL thickness was significantly reduced in the temporal quadrants, but no correlation was found with CNT and CNL changes (p>0.05). Conclusions: CNL and CNT changes are evident even in the early stages of DM, and RNFL reduction was recorded in the temporal quadrants. These findings indicate that, in the eye with diabetes, neuropathy may represent an early marker of the disease.
Article
Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK.
Article
The trigeminal nerve provides corneal sensitivity and trophic supply to corneal tissues. The impairment of corneal innervation leads to development of neurotrophic keratitis (NK). NK is a rare, degenerative corneal disease characterized by corneal hypo/anesthesia and development of nonhealing corneal epithelial defects and ulcers. NK is a challenging condition with high medical need due to the lack of approved treatments that can restore corneal integrity. Current treatment of NK aims at stimulating corneal healing and preventing disease progression. Cenegermin is a recombinant human nerve growth factor that was safe and well tolerated in preclinical and clinical studies. Cenegermin eye drops were safe and effective in restoring corneal integrity in two phase II clinical trials in patients with NK. The European Commission granted a full marketing authorization to cenegermin eye drops for the treatment of moderate to severe NK in July 2017.
Article
Purpose: To evaluate the long-term alterations in corneal nerves in patients with herpes simplex virus (HSV) keratitis using in vivo confocal microscopy (IVCM). Design: Prospective longitudinal, cross sectional. Methods: This study included 16 patients with history of HSV keratitis and 15 age-matched normal controls. Slit-scanning IVCM was performed in all subjects at baseline and then after a mean follow-up of 37.3 ± 1.7 months in the patient group. Corneal subbasal nerve density and corneal sensation were compared between groups at baseline and follow up. Results: At baseline, the mean subbasal nerve density was significantly lower in both affected eyes (1.4 ± 0.6 mm/mm2) and contralateral unaffected eyes (6.4 ± 0.7 mm/mm2) compared with the controls (14.1 ± 1.6 mm/mm2; all P < .001). At the end of follow-up, the mean nerve density in affected eyes increased to 2.8 ± 0.7 mm/mm2 (P = .006), with no significant change in contralateral unaffected eyes (6.5 ± 1.0 mm/mm2, P = .72). However, both eyes had lower nerve density than controls (all P < .001). Corneal sensation was significantly lower in affected eyes (2.6 ± 0.6 cm) than in the control group (6.0 ± 0.0, P < .001) and showed no significant change at the end of follow-up (2.5 ± 0.6 cm, P = .80). Corneal sensation in contralateral unaffected eyes was not different in comparison with controls at both baseline and follow up (all p > .05). Conclusions: Our results demonstrate that although corneal nerve regeneration occurs in patients with HSV keratitis, this change is not clinically significant and does not results in changes of corneal sensation. Therefore, these patients need to be followed closely for complications of neurotrophic keratopathy and might benefit from neuro-regenerative therapies.
Article
Aims To demonstrate and characterise distinct subepithelial compact nerve endings (CNE) at the human corneoscleral limbus. Methods Ten fresh human donor corneoscleral discs (mean age, 67 years) and 26 organ-cultured corneoscleral rims (mean age, 59 years) were studied. All samples were subjected to enzyme histochemical staining related to endogenous acetylcholinesterase present in nerve tissue and H&E staining. Whole-mount en face imaging with NanoZoomer digital pathology microscope and serial cross-section imaging with light microscope were undertaken. Results Nerves entering the corneoscleral limbus and peripheral cornea terminate under the epithelium as enlarged multiloculated and multinucleated ovoid structures within a 2 mm zone. They are closely associated with the rete pegs of the limbal palisades and the limbal epithelial crypts, often located within characteristic stromal invaginations of these structures. Their numbers ranged from 70 to 300 per corneoscleral rim. The size ranged from 20 to 100 µm. They had one or more nerve connections and were interconnected to other similar endings and to the limbal nerve plexus. Conclusion Human corneoscleral limbus demonstrates a population of nerve terminals resembling CNE with distinct morphological features. They are closely associated with the limbal stem cell niches, suggesting a potential contribution to the niche environment.