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Trends Pharmacol Sci. Author manuscript; available in PMC 2021 July 29.
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Published in final edited form as:

Trends Pharmacol Sci. 2019 November ; 40(11): 833–852. doi:10.1016/j.tips.2019.09.009.
Pharmacogenomic approach to anti-myopia drug development:

pathways lead the way
Tatiana V. Tkatchenko1, Andrei V. Tkatchenko1,2,*
1Department of Ophthalmology, Columbia University, New York, NY, USA
2Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
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Abstract
Myopia is the most common eye disorder in the world, which is caused by a mismatch between
the optical power of the eye and its excessively long axial length. Recent studies revealed that the
regulation of the axial length of the eye occurs via a complex signaling cascade, which originates
in the retina and propagates across all ocular tissues to the sclera. The complexity of this
regulatory cascade has made it particularly difficult to develop effective anti-myopia drugs. The
current pharmacological treatment options for myopia are limited to atropine and 7-
methylxanthine, which have either significant side effects or low efficacy. This review focuses on
the recent advances in genome-wide studies of the signaling pathways underlying myopia
development and discusses the potential of systems genetics and pharmacogenomic approaches for
the development of anti-myopia drugs.
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Keywords
refractive eye development; emmetropization; signaling pathways; pharmacogenomics; drug
discovery; myopia
Role of optical defocus and molecular signaling in etiology of myopia

Myopia (see Glossary) is the most common eye disorder in the world. Its worldwide
prevalence is predicted to increase from the current 23% to 50% by 2050 [1]. Because of its
increasing prevalence, myopia is rapidly becoming one of the leading causes of vision loss
due to serious blinding complications such as retinal tears, retinal detachment, and myopic
macular degeneration [2]. The etiology of myopia and the mechanisms of refractive eye
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development have been the subjects of intense investigation for at least a century (Box 1)
[3]. These studies revealed that refractive eye development is controlled by both
environmental and genetic factors, which shape optical geometry of the eye in a process
called emmetropization [4, 5]. Several environmental factors appear to influence refractive
*
Correspondence: avt2130@cumc.columbia.edu (A.V. Tkatchenko).
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Tkatchenko and Tkatchenko Page 2
eye development and susceptibility to myopia, including intensity of ambient lighting and
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light cycle [4, 6–9]; however, human population studies suggest that the leading
environmental factors causing human myopia are nearwork and urban indoor environments
[5, 10, 11]. Nearwork is believed to be associated with negative optical defocus (Box 2)
produced by lag of accommodation [12–16]. The optical blur produced by the negative
defocus appears to be an important signal that drives excessive eye growth which causes
myopia. The role of optical defocus in emmetropization is supported by animal studies
where it was revealed that postnatal eye growth is regulated by the sign of optical defocus
[17–22]. Negative optical defocus stimulates eye growth and causes myopia, while positive
defocus suppresses it and leads to the development of hyperopia (Box 2, Figure I, lower
panel).
Although the increase in the prevalence of myopia in recent decades is primarily attributed
to rapidly increasing exposure of young children to nearwork [11], the contribution of
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genetic factors to myopia development has been estimated to be between 60% and 80% [5].
Common myopia is a complex genetic disease, which is controlled by hundreds of genes;
similar to height and weight [5, 23]. Genetic mapping studies have identified over 250
chromosomal loci linked to human myopia [5, 23–26]. These loci account for less than 10%
of variance in refractive error in the human population because the majority of genetic
variants causing myopia appear to be either low-frequency or low-effect variants, which are
not readily identified by current genetic mapping methodologies [27]. Gene expression
profiling studies have uncovered that development of myopia is accompanied by large-scale
changes in gene expression in the retina, choroid, and sclera, suggesting that optical defocus
triggers sign-of-defocus-specific signaling which regulates refractive eye development [23,
28–32]. Genetic variations in these signaling pathways appear to modulate the impact of
visual environment on refractive eye development and determine whether a particular
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subject becomes emmetropic, hyperopic, or myopic [5, 23].
Optical correction using single-vision corrective lenses, which is the most widely used
treatment option for myopia, does not stop the progression of myopia and does not prevent
the pathological complications associated with the disease [33]. Several experimental optics-
based and drug-based clinical interventions to slow myopia progression, such as multifocal
lenses imposing positive defocus at the retinal periphery and atropine eye drops, have shown
some promise; however, these treatment options are either associated with significant side
effects or have low efficacy [34]. Recent identification of potential signaling pathways that
control the eye’s response to optical defocus and susceptibility to myopia provide a
framework for the development of new drugs for myopia control. Here we review recent
developments in the genome-wide studies of signaling pathways underlying myopia and
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discuss the potential of emerging pharmacogenomics-based approaches for the development

of anti-myopia drugs.
The current state of anti-myopia drug development

While experimental optics-based treatment options for myopia such as orthokeratology
(OrthoK) and multi-focal contact lenses have recently gained much attention; however, the
best estimates suggest that these methods can only slow the progression of myopia, but not
stop it (reviewed in [34]). Therefore, the development of anti-myopia drugs remains a very
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high priority. The current pharmacological options for myopia control, however, are
essentially limited to two drugs, atropine and 7-methylxanthine, which have significant side
effects and/or relatively low efficacy.
Atropine
Atropine, a nonselective muscarinic antagonist, is an alkaloid produced by Atropa
belladonna, which has been traditionally used in ophthalmic practice as a mydriatic and
cycloplegic drug [35]. Atropine has been receiving a lot of attention as a potential anti-
myopia drug in recent years [36, 37]. Although the exact mechanism of the suppressive
effect of atropine on myopia is unknown, Fischer et al. demonstrated that cholinergic
signaling in the retina is not required for the atropine-mediated suppression of myopia [38]
in spite of several earlier reports which suggested that cholinergic amacrines might be
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involved [18, 36, 37, 39]. Carr et al. found that myopia-inhibiting effect of atropine might be
mediated by α2a-adrenergic receptors [40], whereas Barathi et al. suggested that gamma-
aminobutyric-acid-mediated (GABAergic) signaling is involved [41]. Other studies
demonstrated that administration of atropine caused a significant increase in the release of
retinal dopamine [42] and implicated nitric oxide (NO) downstream of dopamine in myopia
signaling [43, 44].
Several clinical trials have evaluated the effects of different concentrations of atropine on
myopia development and its long-term effects on visual function in children. The first trial,
Atropine for the treatment of Myopia 1 (ATOM1), revealed that the 1% atropine eye drops
retard the progression of myopia by approximately 76% over the 2-year treatment period
[45]. However, the follow up study found that the discontinuation of treatment led to a
strong rebound effect resulting in the 300% increase in the myopia progression rate
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compared to placebo during the first 12 months after the cessation of atropine, which
eliminated approximately 60% of the 2-year treatment effect [46]. Moreover, 1% atropine
caused uncomfortable side effects such as photophobia, reduced accommodation
amplitude, and blurred vision. The follow up trial, ATOM2, evaluated the effects of 0.5%,
0.1%, and 0.01% atropine on the progression of myopia in children and found that 0.5%
atropine suppressed the progression of myopia by 75%, while 0.1% and 0.01% atropine
retarded progression by 68% and 59% respectively [47]. The cessation of treatment caused a
218% rebound increase in the progression rate compared to placebo in the group treated
with 0.5% atropine and 170% increase in the group treated with 0.1% atropine during the
first 12 months after stopping the administration of the drug [48]. However, the progression
rate dropped by approximately 30% in the group treated with 0.01% atropine, suggesting
that 0.01% concentration represents a good option for myopia control [48]. These findings
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were reinforced by the recent 5-year follow up study, which revealed that a higher initial
atropine dose predisposed children to greater myopia progression after the cessation of
treatment and suggested that 0.01% atropine provides the best long-term outcome [49].
These findings were refined by a recent trial, Low-Concentration Atropine for Myopia
Control (LAMP) study, which suggested that low-dose atropine has a dose-dependent
suppressive effect on myopia progression [50]. This study found that 0.01% atropine
retarded progression of myopia by 27% over 1-year period, compared to 43% and 67%
achieved with 0.025% and 0.05% atropine respectively. Considering that all these
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concentrations were well tolerated by patients and caused minimal side effects, these results
suggested that low-dose atropine could be used to control myopia progression in children.
However, recent data on the long-term adverse effects of atropine on the development of
ocular components and emmetropization in juvenile marmosets put in doubt the utility of
atropine as anti-myopia drug [51].
7-methylxanthine
7-methylxanthine (7-MX), a nonselective adenosine receptor antagonist, is a natural
metabolite of caffeine and theobromine, two alkaloids produced by several plant species and
major constituents of cacao, coffee, and tea [52]. The first indication that 7-MX might be a
potential medication for myopia control came from an observation that 7-MX causes
thickening of the sclera and an increase in the diameter of the scleral collagen fibrils [53],
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i.e. it causes changes in the sclera opposite to those observed in myopic eyes. A small
follow-up clinical trial analyzed the effect of a daily oral consumption of 400 mg (~15
mg/kg) of 7-MX on the progression of myopia in children and revealed that 7-MX can
potentially suppress myopia by approximately 22% in subjects with slow progressing
myopia, while had no effect on myopia progression in the subjects with high rates of
progression [54]. In guinea pigs, a 300 mg/kg dose of 7-MX was shown to suppress myopia
by 49% [55]. Similarly, a 30 mg/kg dose of 7-MX reduced the extent of induced myopia in
rabbits by ~67% [56]. The latest data from a study in monkeys also suggested that 7-MX can
suppress myopia in primates, but the effect strongly depended on the genetic background of
a specific subject [57]. Thus, preliminary data suggest that 7-MX has therapeutic potential
for myopia control in subjects with slow progressing myopia, but the questions of the
effective dose and efficacy in humans remain to be clarified. It also should be noted that the
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safety profile and long-term effects of daily oral consumption of 7-MX in children is
currently unknown.
Other pharmacological compounds with anti-myopic potential

Several other compounds have been demonstrated to suppress myopia. The muscarinic
receptor antagonists pirenzepine and himbacine were shown to inhibit the development of
experimental myopia in tree shrews, rhesus monkeys, and chickens [18, 58, 59]. While
pirenzepine was found to suppress the progression of myopia in children by ~40%, clinical
trials were eventually discontinued [60–62]. Several GABAB and GABAC receptor
antagonists, such as (1,2,5,6-tetrahydropyridin-4yl) methylphosphinic acid (TPMPA),
CGP46381, and (3-aminocyclopentanyl) butylphosphinic acid (3-ACPBPA) were shown to
suppress myopia development in chickens and guinea pigs [63–66]. Further, α-adrenergic
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agonists, such as clonidine and guanfacine, were shown to inhibit experimentally induced
myopia in chickens [67], while brimonidine suppressed myopia in chickens [67] and guinea
pigs [68]. Moreover, apomorphine, a dopamine receptor agonist, was found to inhibit
myopia development in several animal models, such as chicken, mouse and non-human
primates [69–73], and an intraocular-pressure-lowering drug latanoprost was found to reduce
progression of myopia in guinea pigs [74]. Finally, a recent drug screen in a mouse model of
myopia identified crocetin, a natural carotenoid found in the crocus flowers and Gardenia
jasminoides fruits, as a potential anti-myopia agent [75].
Pharmacogenomics and development of new drugs

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Pharmacogenomic approaches are increasingly being used to identify new pharmacological

compounds and identify existing drugs that can be repurposed for other diseases [76]. One
of the strategies is to use information about disease-causing genes obtained from genome
wide association studies (GWAS) and gene linkage studies to identify molecular targets that
are then pursued for drug development [76, 77]. This approach is based on the observation
that genes, which are associated with disease traits, are more likely to code for druggable
proteins than the rest of the genome [78]. The increasingly used approach is to identify
potential drugs by matching a disease-associated gene expression profile with a transcription
signature of a particular drug [79]. This method seeks to identify drugs, which can reverse a
disease-associated gene expression signature and “normalize” the phenotype [76].
Considering that disease-causing genes are often not amenable as drug targets or cannot be
identified due to small effect or low frequency of disease-causing genetic variants (as is the
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case for myopia), a very promising emerging approach is identification of druggable targets
within genetic networks and signaling pathways underlying a disease, reconstructed using
genome-wide gene expression profiling data. This approach also allows the identification of
drug combinations targeting several disease-associated pathways. Such multidrug therapy
can increase efficacy by targeting multiple pathways at once and reduce side effects because
the effective concentration of each individual drug can be significantly reduced. This
strategy has been successfully used to identify a number of drugs and drug combinations for
the treatment of several disorders such as Charcot-Marie-Tooth disease [80], CMT1A
neuropathy [81, 82], Alzheimer’s disease [83], Parkinson’s disease [84], and many others
[76]. Recent successes in identification of signaling pathways regulating refractive eye
development provide a solid foundation for the application of pharmacogenomic approaches
to the development of anti-myopia drugs.
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Signaling pathways regulating refractive eye development

Evidence suggests that refractive eye development is regulated by optical defocus [4].
Animal studies in which experimental myopia was induced with all the feedback from the
central nervous system (CNS) to the eye interrupted by sectioning the optic nerve, revealed
that refractive eye development is largely controlled locally by the retina [85, 86]. These
findings were further extended by work which found that simultaneous exposure of different
parts of the same retina to the defocus of opposite signs triggers opposite changes in
different parts of the same eye, thus suggesting that refractive eye development is regulated
by the sign of optical defocus [4, 87, 88]. This information about the sign of optical defocus
is processed by the retina and then converted into molecular signals that regulate the
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peripheral retinal growth and connective tissue turnover in the sclera, resulting in either
increased or decreased rate of growth of the posterior segment of the eye [4, 30, 31, 89–93].
The balance between optical power of the eye (combined optical power of the cornea and
crystalline lens) and its axial length determines the refractive state of the eye [94, 95]. The
molecular signals produced by the retina in response to optical defocus have to propagate
across several ocular tissues before they reach neuronal progenitors at the peripheral retina
and scleral fibroblasts. This appears to be achieved via a multilayered signaling cascade
which comprises signaling pathways in the retina, retinal pigment epithelium (RPE),
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choroid, and sclera (Figure 1) [4].
Signaling in the retina

The retina is a multicellular tissue with complex intercellular signaling [96]. The
composition of the retinal neuronal network that processes the response to optical defocus is
unknown. However, electrophysiological studies suggest that the inner retina plays an
important role in refractive eye development [97]. Chicken studies found that wide-spread
chemical ablation of amacrine cells blocked the development of form-deprivation myopia,
suggesting that amacrine cells are necessary for emmetropization and myopia development
[98]. Dopaminergic amacrine cells were among the first to be implicated in myopia
development because retinal concentration of dopamine was found to be reduced in form-
deprivation myopia and administration of dopamine receptor agonists apomorphine and
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quinpirole suppressed the development of myopia in chickens [44, 70–72, 99]. A discovery
that the early growth response 1 (Egr-1) transcription factor exhibits optical defocus-specific
expression in the chicken model of myopia directly implicated glucagonergic amacrine cells
in the development of myopia [100]. Although glucagonergic amacrine cells have not been
found in mammals [101], Egr-1 is also regulated by optical defocus in mammals and is
expressed in a subset of GABAergic amacrines which are positive for vasoactive intestinal
peptide (VIP) [101, 102]. Interestingly, VIPergic amacrines were the first to be directly
implicated in myopia development [103]. The findings that opiate, serotonin, and gamma-
aminobutyric acid (GABA) antagonists suppress the development of experimental myopia in
chicks pointed to a possible involvement of other retinal interneurons in myopia
development [63, 104, 105]. A recent finding that a human myopia gene amyloid beta
precursor like protein 2 (APLP2) most likely exerts its effect on refractive eye development
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by modulating synaptic transmission at the level of glycinergic amacrines also supports the
involvement of retinal interneurons in refractive development [106]. Several studies also
implicated synaptic transmission at the level of bipolar cells and photoreceptors [107,
108]. Optical blur also triggers an increase in retinal neurogenesis at the retinal periphery,
which further complicates the overall understanding of the retinal mechanisms of
emmetropization [30, 93].
It is hypothesized that the visual environment modulates refractive eye development via the
Bidirectional Emmetropization by the Sign of Optical Defocus (BESOD) mechanism,
which propagates via two largely distinct sign-of-defocus-sensitive signaling cascades [31].
In support of this, several recent studies shed light on the retinal signaling pathways involved
in the visual regulation of eye growth (Table 1). A genome-wide gene expression profiling
study in marmosets found that the retinal responses to optical defocus of opposite signs
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propagate via two largely distinct sets of pathways and that the signaling underlying retinal
response to defocus undergoes dynamic changes, which depend on the duration of the retinal
exposure to defocus [31]. This study performed in marmosets exposed to either negative or
positive optical defocus revealed that the early retinal response to negative defocus primarily
involved pathways regulating glycogen degradation, ephrin receptor signaling, and choline
biosynthesis, whereas the sustained response was mediated by several canonical pathways,
including ß-adrenergic signaling, protein kinase A (PKA) signaling, calcium signaling,
neuronal nitric oxide synthase (nNOS) signaling, ras-related nuclear protein (RAN)
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signaling, Hippo signaling, phosphatase and tensin homolog (PTEN) signaling,

phototransduction pathway, synaptic long term potentiation, androgen signaling, Wnt/Ca+
pathway, and dopamine-DARPP32 feedback signaling [31]. In contrast, in the retinae
exposed to positive defocus, there was transition from receptor activator of nuclear factor κB
(RANK) signaling, stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK)
signaling, nerve growth factor (NGF) signaling, and gap junction signaling during the early
response to α-adrenergic signaling, protein ubiquitination pathway, eukaryotic initiation
factor 2 (EIF2) signaling, eukaryotic initiation factor 4 (eIF4) and ribosomal protein S6
kinase beta-1 (p70S6K) signaling, mammalian target of rapamycin (mTOR) signaling,
glutamate receptor signaling, oncostatin M and somatostatin receptor 2 signaling,
glucocorticoid receptor signaling, and cAMP response element-binding protein (CREB)
signaling during the sustained response [31].
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Another recent study, which analyzed retinal genetic networks regulating baseline trajectory
of refractive eye development versus genetic networks regulating susceptibility to myopia
induced by visual form deprivation (usually induced by placing a frosted diffuser in front of
the eye) in the mouse, found that baseline refractive development and susceptibility to
myopia are regulated by overlapping but largely distinct genetic networks [23]. Multiple
pathways were implicated in both baseline refractive development and susceptibility to
myopia, including nuclear factor-erythroid 2-related factor 2 (NRF2) mediated oxidative
stress response, PTEN signaling, opioid signaling pathway, EIF2 signaling, PKA signaling,
regulation of eIF4 and p70S6K signaling, tight junction signaling, estrogen receptor
signaling, GABA receptor signaling, mTOR pathway, HIPPO pathway, axonal guidance
signaling, and peroxisome proliferator-activated receptor alpha/retinoid X receptor alpha
(PPARα/RXRα) activation pathway [23]. Conversely, dopamine-DARPP32 feedback
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signaling, dopamine receptor signaling, α-adrenergic and β-adrenergic signaling, androgen

signaling, glucocorticoid receptor signaling, aldosterone signaling, glutamate receptor
signaling, protein ubiquitination pathway, ephrin receptor signaling, synaptic long-term
potentiation, somatostatin receptor 2 signaling, and nNOS signaling were chiefly associated
with baseline refractive development. The amyloid processing, retinoic acid receptor (RAR)
activation, insulin-like growth factor 1 (IGF-1) signaling, RAN signaling, oncostatin M
signaling, choline biosynthesis, epithelial-mesenchymal transition pathway, transforming
growth factor beta (TGF-β) signaling, DNA methylation and transcriptional repression
signaling were found to be involved in regulation of susceptibility to myopia [23].
Interestingly, many of the same pathways were implicated in refractive eye development by
large-scale gene expression and proteomics studies in chickens too (Table 1) [109–113],
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highlighting the fact that retinal signaling pathways regulating refractive eye development
are highly conserved across different vertebrate species. Taken together, these data suggest
that the trajectory of refractive eye development and the sensitivity of the eye to visual input
are regulated by the overlapping but largely unique signaling cascades.
Signaling in the RPE and choroid

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The RPE and choroid were long implicated in refractive eye development by virtue of their
location between the retina, which processes information about optical defocus, and the
sclera, which undergoes restructuring in myopic eyes (Figure 1). The direct experimental
evidence regarding the involvement of the RPE came from the RPE-sclera co-culture
experiments, which demonstrated that the presence of the RPE significantly influenced
scleral fibroblast proliferation believed to be underlying eye growth in myopia [114, 115].
The important role of the RPE in refractive development was also highlighted by the
findings that mutations in the low density lipoprotein receptor-related protein 2 (LRP2)
gene, encoding LRP2 protein expressed in the RPE, cause high myopia [116]. Studies in
animal models also discovered that the choroid reacts to optical defocus with the sign-of-
defocus-specific changes in thickness, thus, implicating the choroid in refractive eye
development [117].
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Although molecular signaling in the RPE and choroid during refractive eye development has
not been investigated on a genome-wide scale, one gene expression profiling study
performed in marmosets found that toll-like receptor (TLR) signaling, xenobiotic
metabolism signaling, p38 mitogen-activated protein kinase (MAPK) signaling, SAPK/JNK
signaling, GABA receptor signaling, epidermal growth factor (EGF) signaling, interleukin-2
(IL-2) signaling, hypoxia signaling, Huntington’s disease signaling, G2/M DNA damage
checkpoint regulation, and pentose phosphate pathways were involved [28]. Other studies
implicated a number of specific genes; however, no information about pathways could be
ascertained due to small scale of the studies [118–120]. Several of these genes, such as
BMP2, BMP4, BMP7, and TGF-β2, exhibited defocus-sensitive regulation in the RPE,
suggesting that they might be involved in the processing of the defocus signal [121–123].
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Signaling in the sclera

The sclera plays a key role in refractive eye development and development of myopia [89].
The sclera forms a tunic for the eye and ultimately determines its shape and size in all
species [89–91]. The main components of the mammalian sclera are an extracellular matrix
(ECM) composed of collagen fibrils embedded in a matrix of proteoglycans and
glycoproteins and fibroblasts [89]. The sclera undergoes substantial restructuring during
emmetropization which affects its elasticity [89–92, 124]. In mammals, negative defocus
leads to an increase in elasticity and a thinning of the sclera, whereas positive defocus causes
a decrease in elasticity and a thickening of the sclera [90–92]. Molecular studies revealed
that restructuring of the sclera during refractive eye development is primarily accomplished
through changes in the production of type I collagen and several other extracellular matrix
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proteins [89, 125, 126]. Proteomics studies revealed that the most prominent changes
occurred in expression of type I collagen, calcium-dependent activator protein for secretion
2 (CAPS2), crystallins, and several other proteins associated with cell adhesion,
cytoskeleton and transcriptional regulation, as well as the restructuring of extracellular
matrix [127, 128]. A genome-wide gene expression profiling study in a guinea pig model
suggested that the signaling pathways regulating L-dopachrome, catecholamine, and
eumelanin biosynthesis, as well as Gαi signaling were involved in the scleral restructuring
during myopia development [32]. However, the biggest breakthrough in our understanding
of the molecular signaling underlying the restructuring of the sclera in myopia came from a
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recent study, which analyzed genome-wide gene expression in the myopic sclera at the
single cell level [129]. This study revealed that the changes in elastic properties of the sclera
underlying myopia development result from a large-scale transdifferentiation of fibroblasts
into myofibroblasts and subsequent activation or suppression of several signaling pathways,
including EIF2 signaling, mTOR signaling, regulation of eIF4 and p70S6K signaling,
protein ubiquitination pathway, Huntington’s disease signaling, PKA signaling, androgen
and glucocorticoid receptor signaling, epithelial adherens junction signaling, and circadian
rhythm signaling, among other pathways (Table 1). Importantly, it was found that hypoxia
signaling plays a prominent role in the scleral restructuring underlying myopia [129]. In the
work, the authors speculated that the hypoxia caused by the thinning of the choroid and
reduced choroidal blood flow in myopia triggers activation of the hypoxia-inducible factor 1
alpha (HIF-1α) signaling pathway, which leads to the transdifferentiation of fibroblasts into
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myofibroblasts expressing low levels of type I collagen. This leads to an increased elasticity
of the mammalian sclera and excessive growth of the posterior segment of the eye.
Common pathways underlie myopia signaling across different ocular tissues

Many of the studies reviewed above reveal a very intriguing aspect of the molecular
signaling underlying myopia development [23, 31, 129]. It turns out that several of the same
canonical pathways are involved in the signaling regulating refractive development in the
retina, RPE/choroid, and sclera (Table 1). For example, xenobiotic metabolism signaling,
p38 MAPK signaling, SAPK/JNK signaling, GABA receptor signaling, and EGF signaling
are involved in myopia signaling in both the retina and the RPE/choroid. The hypoxia and
Huntington’s disease signaling pathways are implicated in the signaling underlying
refractive eye development in both RPE/choroid and sclera, while the Huntington’s disease
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signaling pathway is involved in the signaling in all three tissues.
Ultimately, taken together, these data suggest that refractive eye development is regulated by
a multilayered and continuous signaling cascade which originates in the retina in response to
optical defocus and propagates across the RPE and choroid to the sclera (Figure 1 and Table
1) where the RPE and choroid appear to serve as a signaling relay between the retina and
sclera.
Concluding remarks and future directions

Myopia and refractive eye development have been a subject of intense investigation for the
last four decades. These studies led to important insights into the mechanisms underlying
visually guided eye growth and the key role of genetic factors and environment in this
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process. These in turn led to the development of several optics-based methods (such as
OrthoK and multifocal lenses) for myopia control. Although the optics-based approaches
provide a much needed hope to the myopic population at a time of rapidly increasing
prevalence of the disease, the efficacy of these methods is low [34]. The development of
drugs for myopia control has been based on sporadic, accidental findings and has been
lacking a systematic approach; hence, identified drugs have low efficacy and/or significant
side effects. However, recent developments in the field promise to change that trend. It is
now becoming increasingly clear that refractive eye development is regulated by signaling
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pathways, which control refractive eye development by inhibiting eye growth in response to
positive optical defocus and by stimulating eye growth in response to negative optical
defocus. The discovery that the signals generated by the optical defocus of opposite signs
propagate along different signaling cascades in the retina, as well as recent identification of
signaling pathways underlying refractive error development in the RPE/choroid and sclera,
open up a new and exciting venue for anti-myopia drug development. The
pharmacogenomic approach (Figure 2), which combines whole-genome gene expression
profiling, genetic mapping, reconstruction of signaling pathways using cutting edge
bioinformatics, and identification of new drug targets and drug candidates using causal
network analysis, has already produced very promising results. Well-established and
recently developed animal models of myopia have allowed the application of genome-wide
gene expression profiling methods such as RNA-seq and cutting-edge bioinformatics to
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reconstruct the signaling pathways involved in refractive eye development, while genetic
mapping in the human and mouse populations have provided information about the impact
of genetic variation on the signaling underlying refractive error development. The
combination of gene expression profiling and genetic mapping has provided a systems
genetics platform for the dissection of signaling pathways involved in refractive eye
development (Figure 2). Once the signaling cascades are established, this information is
processed using causal network analysis and other computational approaches, which allows
identification of potential drug targets and drug candidates. Potential drug targets are passed
through a medicinal chemistry pipeline, which allows for the identification of the existing
pharmacological compounds and the development of novel drugs with anti-myopic activity
(Figure 2). Both drug candidates predicted by the causal network analysis and those
generated by the medicinal chemistry pipeline can be screened using a mouse model of
myopia, which provides a convenient platform for preclinical drug testing.
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Several of the identified pathways were previously implicated in mediating the effect of drug
compounds with anti-myopic activity. For example, dopamine, NO, α-adrenergic, and
GABA receptor signaling were suggested to underlie the anti-myopic effect of atropine [40–
44]. The efficacy of α-adrenergic and GABA receptor agonists in experimental myopia
models also point to the involvement of α-adrenergic and GABA receptor signaling
implicated by the systems genetics studies [63–68]. The suppressive effect of a dopamine
receptor agonist apomorphine on myopia development in several animal models also in line
with the findings that dopamine receptor signaling is involved in refractive eye development
[69–73]. The pharmacogenomic approach combined with single-cell gene expression
profiling in the sclera of mice with induced myopia led to the identification of the
antihypoxic drugs salidroside and formononetin, as well as the eIF2α phosphorylation
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inhibitor GSK2606414, as potential anti-myopia drugs [129]. Preliminary work from our lab
also show strong suppression of myopia in a mouse model by several drug compounds
identified by the pharmacogenomic approach. These data point to the feasibility of the
approach and a strong potential for anti-myopia drug development.
The future of myopia research and the prospects for the development of more effective anti-
myopia drugs look bright. However, recent advances in the field also uncovered important
challenges (see Outstanding Questions). The identified chromosomal loci linked to myopia
explain less than 10% of phenotypic variance in refractive error in humans, leaving a large
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proportion of myopia heritability unexplained. The signaling cascades that control refractive
eye development are complex and comprise hundreds, if not thousands, of genes/proteins.
This diverse signaling network is compartmentalized within many different cell populations
in the retina, RPE, choroid, and sclera. The identification of new drug targets and drug
candidates for myopia control will depend to a large extent on our ability to identify and
characterize the cell-specific signaling pathways underlying refractive eye development.
Although recent advances in whole-genome approaches allow the dissection of the most
complex signaling networks at the single-cell level, the identification of the key pathways
underlying emmetropization and druggable targets within those pathways may not be a
straightforward process. Nevertheless, these approaches have been increasingly used to
dissect signaling cascades underlying various developmental and disease processes. In
combination with the emerging pharmacogenomic approaches, these new technologies may
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provide a powerful platform for the development of new anti-myopia drugs in the near
future.
Acknowledgments
This work was supported by the National Institutes of Health grant R01EY023839 to A.V.T., National Institutes of
Health grant P30EY019007 (Core Support for Vision Research) to the Department of Ophthalmology, Columbia
University, and unrestricted funds from Research to Prevent Blindness to the Department of Ophthalmology,
Columbia University. Illustrations in this review were prepared using BioRender (https://biorender.com/).
Glossary
Amacrine cells
a diverse group of interneurons localized in the inner nuclear layer of the retina. Amacrine
cells lack typical axons and connect to the bipolar cells, ganglion cells and other amacrines
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through dendritic synapsis. The function of the amacrine cells is to integrate and modulate
the output presented to the ganglion cells. More than 30 morphological subtypes of
amacrines are distinguished in the retina. Amacrine cells can be classified by the
neurotransmitters they release, such as the GABAergic, glycinergic, dopaminergic,
cholinergic, VIPergic, or glucagonergic amacrines discussed in this review.
Accommodation amplitude
the maximum increase in optical power that the eye can achieve during accommodation.
Bidirectional Emmetropization by the Sign of Optical Defocus (BESOD)

a molecular mechanism underlying emmetropization, which utilizes sign of optical defocus
to guide postnatal eye growth. BESOD converts information about positive and negative
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defocus into molecular signals, which propagate in the retina via two distinct signaling
cascades.
Bipolar cells
a group of secondary retinal neurons connecting the outer and inner retina. The function of
the bipolar neurons is a transmission of electrical signals from the photoreceptors to the
amacrine and ganglion cells.
Cornea
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an optically transparent, dome-shaped structure forming the front of the eye. It has a high
refractive power. The main functions of the cornea are to refract the light and protect the
inner structures of the eye.
Crystalline lens
a transparent biconvex lens located between the anterior and posterior chambers of the eye.
The main function of the crystalline lens is to refract light and focus images onto the retina.
In the majority of mammals, the crystalline lens can change its shape in a process called
accommodation; this allows the eye to focus the images of objects located at various
distances on the retina.
Cycloplegia
a paralysis of the ciliary muscle of the eye. The ciliary muscle regulates the thickness and
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the curvature of the crystalline lens underlying accommodation. Cycloplegia leads to loss of
accommodation and is caused by so-called cycloplegic drugs.
Emmetropization
a developmental process guided by the visual input, which coordinates the axial growth of
the eye and ensures that the eye’s optical power matches its axial length.
Form-deprivation myopia
myopia, which develops in response to elimination of high spatial frequency vision usually
achieved by placing a frosted diffuser in front of the eye.
Inner retina
the part of the retina which combines the inner nuclear layer, inner plexiform layer, and
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ganglion cell layer.
Lag of accommodation
insufficiently strong accommodative response when a subject is engaged in nearwork, which
places focal point slightly behind the retina, producing negative optical defocus.
Mydriasis
a dilation of the pupil of the eye in response to reduced light intensity, certain diseases, or
so-called mydriatic drugs.
Myopia
also known as nearsightedness is a refractive disorder of the eye characterized by the
difficulty seeing distant objects clearly. Myopia develops when the eyeball grows too long
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for the optical power of the eye, which leads to the images of distant objects focusing in
front of the retina. Myopia can be subdivided into two large classes, i.e., syndromic myopia
and common myopia. Syndromic forms of myopia are usually caused by mutations in a
single gene and are transmitted in families as classical Mendelian diseases. Common myopia
(discussed in this review) represents a complex genetic trait controlled by hundreds of genes
with a large contribution of environmental factors.
Optical defocus
blurring of the image projected onto the retina caused by refractive errors. Optical defocus is
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subdivided into hyperopic (negative) and myopic (positive) optical defocus. Hyperopic
defocus occurs when the image is focused behind the retina; myopic defocus occurs when
the image is focused in front of the retina.
Photophobia
light sensitivity that leads to an intolerance of bright light. Photophobia can be caused
mydriatic drugs, which dilate the pupil and prevent the eye from being able to regulate the
amount light entering the eye.
Photoreceptors
a group of primary retinal neurons comprising the outer nuclear layer of the retina. The
function of the photoreceptor cells is to convert light into electrical signals, which are then
processed by the secondary retinal neurons and transmitted to the visual cortex.
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Box 1.
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Major milestones in the history of myopia research
350 BC Aristotle Introduction of the term myopia [3]

1280– Bacon, R. Introduction of concave beryl lenses for optical correction of
1311 myopia [3]
1855 Von Graefe, F.W. Proposed that myopia is caused by excessive axial elongation of
the eyeball [3]
1965 Young, F.A. Experimental confirmation that atropine can suppress myopia in
animal models [36]
1977 Wiesel, T.N. and Discovery that visual form deprivation causes myopia;
Raviola, E. development of the monkey model of myopia [22]
1987 Troilo, D. et al. Discovery that refractive eye development is controlled locally
by the retina [85]
1988 Schaeffel, F. et al. Discovery that negative optical defocus stimulates eye growth
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and positive optical defocus inhibits it [21]

1990 Schwartz, M. et al. Mapping of the first genetic locus linked to myopia [24]
1995 Norton, T.T. and Discovery that development of myopia is accompanied by
Rada, J.A. restructuring of the sclera [124]
2000 Fischer, A.J. and Reh, Discovery that development of myopia is accompanied by
T.A. increased neurogenesis at the retinal periphery [93]
2006 Tkatchenko, A.V. et Discovery that development of myopia is accompanied by large-
al. scale changes in gene expression in the eye [30]
2013 Smith et al. Discovery that peripheral optical defocus plays an important role
in refractive eye development [88]
2013 CREAM and Discovery that refractive error development is controlled by
23andMe multiple chromosomal loci [25, 26]
2015 Tkatchenko, A.V. et Experimental confirmation of gene-environment interaction in
al. myopia; identification of APLP2 as one of the genes responsible
for gene-environment interaction [106]
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2018 Tkatchenko, T.V. et al. Experimental confirmation that the retina can recognize the sign
of optical defocus and discovery that information about the sign
of optical defocus is processed by the retina via BESOD
mechanism; identification of putative signaling pathways
underlying retinal response to optical defocus [31]
2018 Wu, H. et al. Discovery that restructuring of the sclera in myopia is caused by
the transdifferentiation of fibroblasts into myofibroblasts;
identification of putative signaling pathways underlying scleral
restructuring in myopia [129]
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Box 2.
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Refractive eye development

Depending on the relationship between the optical power of the eye and its axial length,
the eye can acquire three refractive states (Figure I, upper panel), i.e., emmetropia,
hyperopia, and myopia [4, 95]. In emmetropic eyes, the image focuses on the
photoreceptors of the retina which ensures sharp vision (Box 2, Figure I, upper left
panel). Hyperopic eyes are too short for the optical power of the eye. In hyperopic eyes,
the image focuses behind the retina which results in a hyperopic (negative) optical
defocus (Box 2, Figure I, upper middle panel). Myopic eyes are too long for the optical
power of the eye. In myopic eyes, the image focuses in front of the retina which leads to a
myopic (positive) defocus (Box 2, Figure I, upper right panel). Positive optical defocus,
which can be imposed by placing a positive lens in front of the eye (Box 2, Figure I,
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lower left panel), inhibits growth of the eye and leads to the development of hyperopia [4,
17, 19–21]. Negative optical defocus, which can be imposed by placing a negative lens in
front of the eye (Box 2, Figure I, lower right panel), stimulates eye growth and leads to
the development of myopia [4, 17, 18, 20, 21]. Increasing evidence suggests that the
information about optical defocus is integrated across the entire surface of the retina and
the balance between positive and negative defocus ultimately determines the growth rate
of the eye [4, 87, 88].
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Box 2, Figure I. Refractive states of the eye and effect of optical defocus on eye growth.
Upper panel shows the three refractive states of the eye that include emmetropia (left,
focal point located at the level of the retina), hyperopia (middle, focal point located
behind the retina), and myopia (right, focal point located in front of the retina). Lower
panels show the effects of positive (left) and negative (right) optical defocus. While
positive optical defocus imposed by a positive lens inhibits eye growth, negative optical
defocus imposed by a negative lens accelerates eye growth.
Highlights
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• Current pharmacological options for myopia control are limited and can only
slow the progression of myopia, but not stop it.
• Eye growth is regulated by the Bidirectional Emmetropization by the Sign of

Optical Defocus (BESOD) mechanism sensitive to the sign of optical defocus,
where the information about positive and negative optical defocus is
converted by the retina into molecular signals, which propagate via two
different signaling cascades.
• The signaling cascade underlying refractive eye development appears to be

highly integrated and continuous.
• Genetic background appears to modulate the impact of visual environment on

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refractive eye development and contribute to the final determination of the

refractive state of the eye.
• Emerging pharmacogenomic approaches based on whole-genome analyses of

genetic networks provide a powerful platform for accelerated discovery and
preclinical testing of new anti-myopia drugs.
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Outstanding Questions Box

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• What neurons are involved in the detection and processing of optical defocus
in the retina?
• How do retinal neuronal networks process information about optical defocus?
• What cells are involved in the processing of the information about optical
defocus in the choroid?
• What is the composition of the cell-specific signaling cascades underlying

processing of optical defocus in different neuronal subpopulations of the
retina?
• Does sustained exposure to optical defocus cause stable or transient changes

in the retinal signaling?
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• What are the key regulator proteins within each of the signaling pathways
involved in refractive eye development and which proteins within these
pathways can be targeted pharmacologically?
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Figure 1. Gene-environment interaction in refractive eye development.

The refractive state of the eye is determined by a combination of environmental and genetic
factors. Optical defocus is the chief environmental factor that drives refractive eye
development. Genetic background modulates the impact of optical defocus on refractive eye
development via a multilayered signaling cascade and determines whether an individual
becomes emmetropic, hyperopic, or myopic (upper panel). The retina processes information
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about optical defocus and converts this information into molecular signals, which propagate
across the retina, RPE, and choroid to the sclera, which undergoes structural changes
depending on the sign of optical defocus (lower panel).
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Figure 2. Pharmacogenomic pipeline for anti-myopia drug development.

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The pharmacogenomic approach is emerging as a promising avenue for the development of

anti-myopia drugs. This approach takes advantage of the latest developments in systems
genetics and pharmacogenomics. Several animal models of myopia allow the application of
next-generation approaches to reconstruct the signaling pathways involved in refractive eye
development, while genetic mapping in the human and mouse populations provide
information about the impact of genetic variation on the signaling underlying refractive error
development. Once the signaling cascades are established, this information is processed
using cutting-edge bioinformatics to identify potential drug targets and drug candidates.
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Potential drug targets are further explored using a medicinal chemistry pipeline, which
allows for the identification of the existing pharmacological compounds and the
development of new drugs with anti-myopic activity. Both drug candidates predicted by the
computational approaches and those generated by the medicinal chemistry pipeline can be
screened using a mouse model of myopia, which provides a convenient platform for
preclinical drug testing.
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Table 1.
Signaling pathways involved in refractive eye development.
Chicken Mouse Marmoset Human Canonical signaling pathways Retina RPE/choroid Sclera Baseline RD Susceptibility (+) Early (+) Sustained (−) Early (−) Sustained Reference
• • 4-hydroxyproline degradation I • • [23]
• • • Actin cytoskeleton signaling • • • [23, 109, 129]
• • • Aldosterone signaling in epithelial cells • • • [23, 31, 109]
• • • Amyloid processing • • • • [23, 106, 110]

Tkatchenko and Tkatchenko
• • • Amyotrophic lateral sclerosis signaling • • • [23, 31, 109]
• • • Androgen receptor signaling • • • • • [23, 31, 109, 129]
• • Antiproliferative role of somatostatin receptor 2 signaling • • • [23, 31]
• • Antiproliferative role of TOB in cell signaling • • • • [23, 31, 129]
• • • • Calcium signaling • • • [23, 31, 109]
• • Choline biosynthesis III • • • [23, 31]
• • Chondroitin sulfate biosynthesis • • [23]
• • • • Circadian rhythm signaling • • • • [23, 31, 109, 113, 129]
• • • Clathrin-mediated endocytosis signaling • • • • • [23, 31]
• • • CREB signaling in neurons • • • [23, 31, 109]
• • • • CXCR4 signaling • • • • [23, 31, 109]
• • Diphthamide biosynthesis • • • [23]
• • • Dopamine receptor signaling • • • [23, 31, 109]
• • • • Dopamine-DARPP32 feedback signaling • • • [23, 31, 109]
• • EGF signaling • • • • [23, 28, 31]
• • • EIF2 signaling • • • • • [23, 31, 129]
• • eNOS signaling • • [23]
• • • Ephrin B signaling • • • [23, 31, 109]
• • • • Ephrin receptor signaling • • • [23, 31, 109]
• • • • Epithelial adherens junction signaling • • • • • [23, 31, 109, 113, 129]
• • ERK/MAPK signaling • • • • [23, 31]
• • • • Estrogen receptor signaling • • • • • • • [23, 31, 109]
• • • G2/M DNA damage checkpoint regulation • • • • • [23, 28, 31]

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• • • • GABA receptor signaling • • • • • [23, 28, 31, 109]
• • • Gap junction signaling • • • [23, 31, 109]
• • • • Glucocorticoid receptor signaling • • • • • [23, 31, 109, 129]
• • • • Glutamate receptor signaling • • • • [23, 31, 109]
• • • Glutathione biosynthesis • • [23, 109]
• • • Glutathione redox reactions I • • [23, 109]
• • • Glutathione-mediated detoxification • • [23, 109]

• • Glycoaminoglycan-protein linkage region biosynthesis • • • [23]
• • • Gαq signaling • • • • • • [23, 31]
• • Hypoxia signaling • • [28, 129]
• • HIPPO signaling • • • • [23, 31]
• • • HMGB1 signaling • • • [23, 31]
• • • • Huntington’s disease signaling • • • • • • [23, 28, 31, 109, 129]
• • • IGF-1 signaling • • • • [23, 31]
• • • IL-2 signaling • • • • [23, 28, 31]
• • • ILK signaling • • • [23, 109, 129]
• • • Insulin receptor signaling • • • • [23, 31]
• • • Integrin signaling • • • [23, 31]
• • L-cysteine degradation I • • • [23]
• • L-cysteine degradation III • • [23, 31]
• • Lysine degradation • • • • • [23, 28, 31]
• • Mismatch repair in eukaryotes • • • • [23, 31]
• • • mTOR signaling • • • • • [23, 31, 129]
• • • Mitochondrial dysfunction • • • • [23, 31, 109, 129]
• • NF-κB signaling • • • [23]
• • • • nNOS signaling • • • • [23, 31, 109]
• • • NRF2-mediated oxidative stress response • • • • • • [23, 31, 129]
• • Oncostatin M signaling • • • [23, 31]
• • p38 MAPK signaling • • • • [23, 28]
• • Pentose phosphate pathway • • • [23, 28]

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• • • • Phenylalanine metabolism pathway • • • • • [23, 28, 31, 109]
• • • • Phospholipase C signaling • • • • [23, 31, 109]
• • • Phototransduction pathway • • • • [23, 31, 108, 113]
• • • • PI3K/AKT signaling • • • • [23, 31, 109]
• • • PPAR signaling • • [23, 109]
• • • • PPARα/RXRα activation • • • • • • [23, 31, 109, 129]
• • • Production of nitric oxide (NO) and reactive oxygen species • • • • [23, 31]
• • • • Protein kinase A signaling • • • • • [23, 31, 109, 129]
• • • • Protein ubiquitination pathway • • • • [23, 31, 109, 129]
• • • PTEN signaling • • • • [23, 31]
• • Purine nucleotides de novo biosynthesis II • • [23, 109]
• • • Purine nucleotides degradation II (aerobic) • • [23, 109]
• • RAN signaling • • • [23, 31]
• • • RAR activation • • • • [23, 31]
• • • Regulation of eIF4 and p70S6K signaling • • • • • [23, 31, 129]
• • • • Regulation of the epithelial-mesenchymal transition pathway • • • • [23, 31, 109, 111]
• • • Relaxin signaling • • • • [23, 31, 109]
• • • RhoGDI signaling • • • • [23, 109, 129]
• • • SAPK/JNK signaling • • • • [23, 28, 31, 109]
• • Semaphorin signaling in neurons • • [23]
• • • • Signaling by Rho family GTPases • • • • • • [23, 31, 109]
• • • Sumoylation pathway • • • [23, 109, 110]
• • Synaptic long-term depression • • [23, 109]
• • • • Synaptic long-term potentiation • • • [23, 31, 109]
• • • TGF-β signaling • • [23, 109]
• • Tight junction signaling • • • [23, 109, 113]
• Toll-like receptor signaling • [28]
• • • tRNA splicing • • • [23, 31, 109]
• • • Wnt/Ca+ pathway • • • [23, 31]
• • • Xenobiotic metabolism signaling • • • • [23, 28, 31]

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[23, 31, 109]
[23, 31, 109]

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Pharmacogenomic approach to anti-myopia drug development:

Role of optical defocus and molecular signaling in etiology of myopia

subject becomes emmetropic, hyperopic, or myopic [5, 23].

discuss the potential of emerging pharmacogenomics-based approaches for the development

The current state of anti-myopia drug development

Other pharmacological compounds with anti-myopic potential

Pharmacogenomics and development of new drugs

Pharmacogenomic approaches are increasingly being used to identify new pharmacological

Signaling pathways regulating refractive eye development

choroid, and sclera (Figure 1) [4].

Signaling in the retina

signaling, Hippo signaling, phosphatase and tensin homolog (PTEN) signaling,

signaling, dopamine receptor signaling, α-adrenergic and β-adrenergic signaling, androgen

Signaling in the RPE and choroid

Signaling in the sclera

Common pathways underlie myopia signaling across different ocular tissues

signaling pathway is involved in the signaling in all three tissues.

Concluding remarks and future directions

Bidirectional Emmetropization by the Sign of Optical Defocus (BESOD)

ganglion cell layer.

84–91. [PubMed: 15629825]

Res 81 (5), 616–25. [PubMed: 15949800]

Major milestones in the history of myopia research

350 BC Aristotle Introduction of the term myopia [3]

and positive optical defocus inhibits it [21]

Refractive eye development

• Eye growth is regulated by the Bidirectional Emmetropization by the Sign of

• The signaling cascade underlying refractive eye development appears to be

• Genetic background appears to modulate the impact of visual environment on

refractive eye development and contribute to the final determination of the

• Emerging pharmacogenomic approaches based on whole-genome analyses of

Outstanding Questions Box

• How do retinal neuronal networks process information about optical defocus?

• What is the composition of the cell-specific signaling cascades underlying

• Does sustained exposure to optical defocus cause stable or transient changes

Figure 1. Gene-environment interaction in refractive eye development.

Figure 2. Pharmacogenomic pipeline for anti-myopia drug development.

The pharmacogenomic approach is emerging as a promising avenue for the development of

Signaling pathways involved in refractive eye development.

• • 4-hydroxyproline degradation I • • [23]

• • • Actin cytoskeleton signaling • • • [23, 109, 129]

• • • Aldosterone signaling in epithelial cells • • • [23, 31, 109]

• • • Amyloid processing • • • • [23, 106, 110]

• • • Amyotrophic lateral sclerosis signaling • • • [23, 31, 109]

• • • Androgen receptor signaling • • • • • [23, 31, 109, 129]

• • Antiproliferative role of somatostatin receptor 2 signaling • • • [23, 31]

• • Antiproliferative role of TOB in cell signaling • • • • [23, 31, 129]

• • • • Calcium signaling • • • [23, 31, 109]

• • Choline biosynthesis III • • • [23, 31]

• • Chondroitin sulfate biosynthesis • • [23]

• • • • Circadian rhythm signaling • • • • [23, 31, 109, 113, 129]

• • • Clathrin-mediated endocytosis signaling • • • • • [23, 31]

• • • CREB signaling in neurons • • • [23, 31, 109]

• • • • CXCR4 signaling • • • • [23, 31, 109]

• • Diphthamide biosynthesis • • • [23]

• • • Dopamine receptor signaling • • • [23, 31, 109]