REVIEW ARTICLE

Canadian Journal of Ophthalmology Lecture: Translational

research advances in glaucoma neuroprotection
James C. Tsai, MD
ABSTRACT RE
SUME

Given that glaucoma is a disease of the central nervous system, there must be greater emphasis and focus on developing
intraocular pressureindependent therapies. In addition, scientific research investigating the role of sustained drug delivery is critical
for advancing the field. Exciting innovation will require close collaboration and full integration of clinical and basic research efforts.
Thus, translational research advances in neuroprotection may lead to future development of truly revolutionary therapies for
glaucoma (e.g., neuroregeneration).

Comme le glaucome est une maladie du systeme  nerveux central, il faut mettre plus demphase et de concentration sur le
developpement de therapies independantes de la PIO. En outre, la recherche scientifique dinvestigations sur le role
de la livraison
soutenue des medicaments est critique pout faire progresser ce secteur. Les innovations passionnantes demanderont une etroite
 des efforts cliniques et fondamentaux. Ainsi, les progres
collaboration et une integration entiere  de la recherche translationnelle de la
neuro-protection peut mener a un developpement de therapies vraiment revolutionnaires du glaucome (e,g, neuro-regeneration).

According to the World Health Organization, glaucoma
is the second leading cause of global blindness; by 2010,
nearly 80 million persons worldwide will be afflicted with
the disease.1 Because of its often asymptomatic nature and
gradual loss of vision, primary open-angle glaucoma
(POAG) has been described as a thief in the night.2
Treatment does not always slow disease progression in
patients with open-angle glaucoma. In the Early Manifest
Glaucoma Treatment (EMGT) study, 45% of patients
randomized to initial treatment still had progression of
their visual fields at 5 years of follow-up.3
Intraocular pressure (IOP) is currently recognized as
the most significant contributing factor in the initial
development, as well as progression, of open-angle
glaucoma. Glaucoma can be best viewed as an IOP-
associated optic neuropathy, with glaucoma clinical trials
and observational studies strongly supporting the need to
reduce IOP substantially and to maintain these pressures
in patients with advanced disease.4 Because the lateral
geniculate nucleus (LGN) of the midbrain is the major
synaptic target for retinal ganglion cells (RGCs), glau-
coma must be viewed as a central nervous system (CNS)
disease.5
A clinicians decision to prescribe IOP-lowering ther-
apy results often from estimation of IOP risk in the
context of the individual patients existing optic nerve
damage and/or visual field deficits, taking into account
the slowly progressive course of the disease. In addition,
follow-up of patients with glaucoma may be challenging
given the subjective and fluctuating nature of current
visual field testing. Recent advances in vision function
assessment include the multifocal and isolated check
visual evoked potential technologies that may provide
objective visual function parameters and complement
standard automated perimetry.6,7
Currently accepted therapeutic strategies for glaucoma,
whether by medication, laser procedure, or incisional
surgery, aim to lower the IOP below a presumed thresh-
old level.810 Given the nontissue-specific targeted nature
of these therapies (i.e., they only lower the IOP risk
factor), the marked variability in patient outcomes is not
at all surprising (Fig. 1). Furthermore, multiple additional
disease risk factors must be taken into account; these
include history of previous IOP levels (with or without
treatment), central corneal thickness values, patient age
and life expectancy, family history, vascular factors (e.g.,
low perfusion pressure), and other comorbidities (e.g.,
cardiovascular disease).3,811
As a chronic neurodegenerative disease, POAG is
characterized by primary optic nerve head injury and
subsequent loss of RGCs.12 Although initial experimental
primate studies showed a selective loss of magnocellular
RGC bodies and axons, recent contrast sensitivity testing of
patients with glaucoma suggests nonselective impairment
of the low-spatial-frequency components of both magno-
cellular and parvocellular pathways, presumably mediated
by cells with larger receptive fields.13 In addition to RGC
death, there is atrophy and loss of target neurons in the
LGN of the brain. Studies using experimental primate
models of glaucoma have shown reduced dendrite

From the Department of Ophthalmology and Visual Science, Yale
University School of Medicine, New Haven, Conn.
Originally received Oct. 16, 2012. Final revision Feb. 11, 2013.
Accepted Feb. 12, 2013
Can J Ophthalmol 2013;48:141145
0008-4182/13/$-see front matter & 2013 Canadian Ophthalmological
Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcjo.2013.02.003

Correspondence to James C. Tsai, Yale Eye Center, 40 Temple Street,

Suite 1B, New Haven, CT 06510; james.tsai@yale.edu

CAN J OPHTHALMOL VOL. 48, NO. 3, JUNE 2013 141

Neuroprotection in glaucomaTsai

involving in vivo imaging and identification of dying RGCs

with fluorescent biomarkers are facilitating the clinical
evaluation of potential neuroprotection-focused strategies.17

Medication: Surgery:
-adrenergic agonists
Beta-blockers IOP
CAIs (topical & oral)
Prostaglandins Control
Miotic agents
Combination agents
Fig. 1 Current glaucoma treatment. CAI: Carbonic Anhy-
drase Inhibitors (Topical & Oral).
complexity by 47% and 41% in magnocellular layer 1 and
parvocellular layer 6, respectively, in experimental animals
compared with control animals.14 The first clinicopatho-
logic case of human glaucoma also reported neural
degeneration of the CNS involving the intracranial optic
nerve, LGN, and visual cortex.15
NEUROPROTECTION
Although current glaucoma treatment is focused on
lowering IOP, future therapeutic strategies may involve
disease modification/lifestyle intervention and develop-
ment of non-IOPdependent therapies to prevent against
optic nerve head damage, RGC death, or both.4,10,12 The
desired aim would be to intervene at an early stage of the
disease to halt or slow down the neurodegenerative
process. Thus, any treatment that eliminates or attenuates,
or both, Z1 of these disease risk factors, thus delaying or
halting RGC degeneration and reducing the rate of
disease progression, can be legitimately classified as a
neuroprotective therapeutic modality.12 Implicated causes
of RGC death include ischemia, reactive oxygen species,
excitotoxicity, defective axonal transport, trophic factor with-
drawal, and loss of RGC electrical activity (involving specific
molecular pathways).12,16 In addition, technologic advances
Laser trabeculoplasty
Laser iridotomy
Trabeculectomy
Glaucoma implants
Cyclodestruction
Trabecular-based
Schlemms canal prospective clinical trial randomizing initial topical therapy
Suprachoroidal
an experimental glaucoma model in primates,19 a recently
with the human CNTF gene and sequestered within
Investigational agents
Drugs/Biotechnology. It is important to recognize that
lowering IOP itself is neuroprotective. However, the devel-
opment of non-IOPdependent neuroprotective therapies
would be an attractive alternative (Table 1). A recent
with either brimonidine or timolol in patients with normal
tension glaucoma demonstrated a neuroprotection benefit
of brimonidine.18 Although memantine, a low-affinity,
open-channel blocker of the N-methyl-D-aspartatetype
glutamate receptor, was shown to be neuroprotective in
completed Phase III trial showed no beneficial effect in
patients with glaucoma treated with oral memantine as well
as conventional IOP-lowering therapies.20
Neurotrophic factors show promise in retarding pro-
gression of neurodegenerative diseases. Current preclinical
and clinical studies are ongoing involving factors such as
ciliary neurotrophic factor (CNTF), brain-derived neuro-
trophic factor (BDNF), glial-derived neurotropic factor
(GDNF), and pigment epithelium-derived factor (PEDF).21
Moreover, inhibition of the process of reactive gliosis, a
hallmark of many neurodegenerative conditions including
glaucoma, has been shown to prevent apoptotic death of
retinal neurons and to provide substantial neuroprotection
in mice.22 In humans, a Phase I clinical safety trial described
the successful delivery of human CNTF via cells transfected
surgically implanted capsules, thereby suggesting its safety
and possible future applicability in patients with glaucoma.23
In addition to their known ocular hypotensive effects,
inhibitors of both Rho kinase (ROCK) and Rho GTPase
have been shown to enhance ocular blood flow, RGC
survival, and axon regeneration.24 Application of a cell-
permeable Rho antagonist (C3-07) to either neuronal cell
bodies or distal axons promotes axonal growth on myelin-
associated glycoprotein substrates.24
In vivo injection of the C3-07 Rho antagonist also
promoted regeneration of RGC axons in the optic nerve
of rats after microcrush lesion.25 Therefore, these animal

Table 1Selective list of investigational agents for neuroprotection in glaucoman

Drug/Therapy Mechanism Approval indication Outcome in humans
Brimonidine a2 receptor Approved for IOP Positive Phase IV trial18
Memantine NMDA receptor None Failed Phase III trials20
CNTF Neurotrophic factor None Completed Phase I trial23
ROCK inhibitors Rho kinase antagonism None Ongoing Phase II/III trials
Erythropoietin HIF-mediated None No human trials
TNF-a blockers TNF-a inhibition None No human trials
Cop-1 T-cellbased vaccination None No human trials

IOP, intraocular pressure; NMDA, N-methyl-D-aspartate; CNTF, ciliary neurotrophic factor; ROCK, Rho kinase; HIF, hypoxia-inducible factor; TNF, tumor necrosis factor; Cop-1, copolymer
glatiramer acetate.
n
Currently, none is approved by U.S. Food and Drug Administration for neuroprotection indication.

142 CAN J OPHTHALMOL VOL. 48, NO. 3, JUNE 2013


studies have stimulated interest in the results of upcoming
Phase II/III clinical trials of ROCK inhibitors in humans.
Erythropoietin (EPO), a naturally occurring cytokine
used to treat anemia by inhibiting apoptosis in erythro-
cyte progenitors, has a neuroprotective effect in animal
models of glaucoma.26 The EPO and EPO-R systems are
thought to convey endogenous feedback loop through
activation via hypoxia-inducible factor. Intravitreal injec-
tions of EPO have been shown to rescue RGCs and
prevent caspase-3 activation in axotomized rats, as well as
retard against RGC loss in a rat model of ocular hyper-
tension.27,28 Dose toxicity studies of intravitreal injections
of recombinant EPO in rats were shown to be safe based
on electroretinography and histopathology studies.29
Additional safety studies of intravitreal recombinant
human EPO were conducted in rabbits using electro-
retinography and fluorescein angiography.30
Gene therapy/stem cell therapy. Another approach in the
prevention of RGC loss is gene therapy to reprogram cells to
produce antiapoptotic neurotrophic proteins. As noted ear-
lier, a recent human Phase I safety trial demonstrated the
successful delivery of CNTF by cells transfected with the
human CNTF gene.23 Gene therapy has shown promise in
promoting RGC survival in experimental models of optic
nerve injury using adeno-associated virus (AAV), adenoviral,
and lentiviral methods.31 For example, rat RGCs have been
successfully transfected with the gene for the prosurvival
protein Bcl-XL using both the AAV and HIV-Tatderived
fusion proteins.32 An AAV vector capable of efficient trans-
fection of rat RGCs has been developed to deliver BDNF.32
In this experimental study, animals transfected with the
AAV-BDNF gene were more resistant to RGC death in the
hypertensive model of glaucoma. A recent study reported the
effectiveness of stem cellbased delivery of the BDNF gene
to rat retina using rat bone marrow mesenchymal stem cells;
at 4 weeks after transplantation, BDNF mRNA and protein
expression were shown to be increased.33
Immune system modulation. Involvement of the immune
system in modulating RGC survival may occur via oxida-
tive stressstimulated antigen presentation by both retina
and optic nerve head glial cells.34 Tumor necrosis factor-a
(TNF-a) has been shown to cause a cascade of events that
leads to loss of RGCs. In a laser irradiation-induced murine
model of ocular hypertension, increased levels of TNF-a
led to microglial activation, loss of oligodendrocytes in the
optic nerve, and loss of RGCs.35 This same sequence of
biological events was also observed after injection of TNF-a
in a control group of mice with normal IOP levels.
Conversely, no appreciable loss of RGCs was observed
(above baseline control levels) when animals with elevated
IOP were treated with TNF-a inhibitors.35 Similar preser-
vation of RGCs was observed in knockout mice with
elevated IOP that were unable to produce TNF-a.35
Based on the earlier noted TNF-a research, future
treatments for glaucoma may involve modulation of this
pathway including direct blockage of TNF-a function
Neuroprotection in glaucomaTsai
and inhibition of downstream microglial activation.35
Possibilities include blocking antibodies that interfere
with TNF-a, soluble receptor(s), and a TNF-aconvert-
ing enzyme inhibitor(s). Infliximab, a TNF-a receptor
blocker, has been used to successfully control ocular
inflammatory disease refractory to traditional immuno-
modulatory therapy with a low rate of adverse effects.36
In the near future, T-cellbased vaccination for mor-
phologic and functional neuroprotection will likely become
a reality.37 This therapeutic option has been shown to be
effective in retarding RGC cell loss in a rat model of
glaucoma. In experimental animals with chronically ele-
vated IOP, vaccination with the synthetic copolymer
glatiramer acetate (Cop-1) was shown to be protective
against IOP-induced loss of RGCs by eliciting a systemic
T-cellmediated response capable of cross-reacting with
self-antigens in the eye.38 The antigen-specific autoimmune
T cells and/or their cytokines may tailor the microglial
phenotype to facilitate glutamate clearance.39 However, it
is important to note that any benefits of the T-cell
mediated immune response should be balanced against
the real risks of inducing autoimmune disease.
NEUROREGENERATION
Growth of injured axons in the adult mammalian CNS
is quite limited after injury. Thus, one of the ultimate
goals for glaucoma therapy would likely be neuroregen-
eration, the process of restoring damaged axons and/or
reversing RGC death in hopes of functional recovery of
lost vision. Methods are currently being developed to
deliver stem cells to replace RGCs and their axons,
thereby reestablishing functional vision.40 In addition,
novel approaches for neuroenhancement of surviving
RGCs (e.g., electrical stimulation) have been studied.12
Advances in intravitreal drug delivery of neuroprotective
agents (e.g., embedded poly(lactic-co-glycolic acid) nano-
spheres) in a rat optic nerve crush model may also yield
novel treatment strategies.41
One therapeutic strategy for neuroregeneration may
involve modulation of the Nogo-66 receptor (NgR)
pathway. Three myelin proteins, Nogo, myelin-
associated glycoprotein (MAG), and oligodendrocyte
myelin glycoprotein (OMgp), bind to NgR and inhibit
CNS axonal growth.42 Administration of the soluble
function-blocking NgR ectodomain has been shown to
cause axonal sprouting in spinal-injured rats with corre-
lation to improved spinal cord electrical conduction and
improved locomotion.42 In addition, soluble LINGO-1
(LINGO-1-Fc), which acts as an antagonist of these
axonal outgrowth inhibition pathways by blocking
LINGO-1 binding to NgR1, significantly improves func-
tional recovery and promotes axonal sprouting after spinal
cord injury in rats.43 Preliminary research in our labo-
ratory suggests that intravitreal injections of an anti-Nogo
CAN J OPHTHALMOL VOL. 48, NO. 3, JUNE 2013 143
Neuroprotection in glaucomaTsai
receptor blocking protein in rats with episcleral venous
cautery-induced ocular hypertension may confer neuro-
protective and neuroregenerative effects (Association for
Research in Vision and Ophthalmology (ARVO) 2010
Annual Meeting, Ft. Lauderdale, FL).
CONCLUSION
Recent discoveries of the molecular mechanisms under-
lying POAG have provided novel insights into its com-
plex pathogenesis. This enhanced understanding offers
tremendous opportunities for the development of inno-
vative therapeutic strategies. Future approaches including
anti-Nogo receptor agents, small interfering RNA-based
caspase inhibitors, and neurotrophic factor replacement
therapy should be explored.12
The challenges of translating advances from the basic
science laboratory into real and proven benefits in the
clinical care of patients with glaucoma cannot be under-
stated. These challenges include the lengthy and slow
course of the disease with its variable rate of progression;
the substantial variability and reliability of its main
outcome measure, the visual field test; and the need for
minimal treatment side-effects/complications given the
diseases often asymptomatic nature. Furthermore, inher-
ent challenges in formulating suitable pharmacologic/
biotherapeutic dosages and delivery regimens in humans
include the following: differences in anatomy and phys-
iology between animals and humans, marked differences
in duration between animal studies and human glaucoma
(e.g., weeks vs years), and inadequate in vivo laboratory
models of glaucoma (i.e., majority of models use elevated
IOP in normal, young animals). Although there are
substantive barriers, clinical trials for glaucoma neuro-
protection are not impossible44; I also believe that some
will prove successful in the near future.
Disclosure: The author has no proprietary or commercial interest
in any materials discussed in this article. Over the past 2 years,
J.C.T. has received research funding, travel funds, and lecture and
consulting honoraria from the National Eye Institute, Research to
Prevent Blindness, Alcon, Allergan, Bausch and Lomb, Inspire,
Merck, Pfizer, QLT, Quark, Rhodes, and Sucampo.
Support: Supported in part by endowment funds from the Robert
R. Young Professorship at Yale University School of Medicine.
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