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The mechanisms underlying myopia pathogenesis are not well understood. Using publicly-available human and animal datasets, we expound on the roles of known, implicated proteins, and new myopia-related signaling pathways were hypothesized. Proteins identified from human serum or ocular fluids, and from ocular tissues in myopic animal models, were uploaded and analyzed with the QIAGEN Ingenuity Pathway Analysis (IPA) software (March 2023). With each IPA database update, more potentially-relevant proteins and signaling pathways previously unavailable during data acquisition are added, allowing extraction of novel conclusions from existing data. Canonical pathway analysis was used to analyze these data and calculate an IPA activation z-score-which indicates not only whether an association is significant, but also whether the pathway is likely activated or inhibited. Cellular immune response and cytokine signaling were frequently found to be affected in both human and animal myopia studies. Analysis of two publicly-available proteomic datasets highlighted a potential role of the innate immune system and inflammation in myopia development, detailing specific signaling pathways involved such as Granzyme A (GzmA) and S100 family signaling in the retina, and activation of myofibroblast trans-differentiation in the sclera. This perspective in myopia research may facilitate development of more effective and targeted therapeutic agents., (© 2024. The Author(s).)

In myopic eyes, pathological remodelling of collagen in the posterior sclera has mostly been observed ex vivo. Here we report the development of triple-input polarization-sensitive optical coherence tomography (OCT) for measuring posterior scleral birefringence. In guinea pigs and humans, the technique offers superior imaging sensitivities and accuracies than dual-input polarization-sensitive OCT. In 8-week-long studies with young guinea pigs, scleral birefringence was positively correlated with spherical equivalent refractive errors and predicted the onset of myopia. In a cross-sectional study involving adult individuals, scleral birefringence was associated with myopia status and negatively correlated with refractive errors. Triple-input polarization-sensitive OCT may help establish posterior scleral birefringence as a non-invasive biomarker for assessing the progression of myopia., (© 2023. The Author(s).)

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for the design of precise and effective therapeutics. A strong understanding of altered biochemical pathways and underlying pathogenesis leading to myopia may facilitate early diagnosis and treatment of myopia, ultimately leading to the development of more effective preventive and therapeutic measures. In this review, we summarize current data about the genomics and transcriptomics of myopia in human and animal models. We also discuss the potential applicability of these findings to precision medicine for myopia treatment., Competing Interests: The authors declare no conflict of interest.

The aim of this study was to investigate the effect of latanoprost, an ocular hypotensive agent and prostaglandin analog, on choroidal thickness and structure in young adult guinea pigs. Young (three-month-old) guinea pigs (n = 10) underwent daily monocular treatment with topical 0.005% latanoprost for 2 weeks, followed by a washout period of 2 weeks. Tonometry (iCare) and retinoscopy were undertaken to monitor intraocular pressure (IOP) and refractive error (recorded as spherical equivalent refractive error; SER), respectively. Axial length (AL) and choroidal thickness (ChT) were measured using high frequency A-scan ultrasonography, with additional ChT data, as well as choroidal vessel (ChV) areas obtained from posterior segment imaging using Spectral Domain-Optical Coherence Tomography (SD-OCT). Image J was used to analyze SD-OCT images. As expected, latanoprost significantly reduced IOP in treated eyes. Mean interocular IOP difference (±SE) changed from -0.40 ± 0.31 mmHg at baseline to -2.23 ± 0.43 mmHg after 2 weeks of treatment (p = 0.05). However, SER and AL were unaffected; interocular difference changed from 0.41 ± 0.58 to 0.38 ± 0.43 D and from -0.002 ± 0.02 mm to -0.007 ± 0.01 mm (p > 0.05), respectively. Latanoprost had minimal effect on ChT. Interocular ChT differences were 0.01 ± 0.06 μm at baseline and 0.04 ± 0.06 μm after 2 weeks of treatment (SD-OCT; p > 0.05). However, treated eyes had significant increased ChV areas; interocular differences changed from -0.76 ± 69.2 to 100.78 ± 66.9 μm 2 after treatment (p = 0.04). While this study was limited to otherwise untreated young adult guinea pigs, the possibility that choroidal vessel enlargement contributes to the previously reported inhibitory effect of topical latanoprost on myopia progression in young guinea pigs warrants investigation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To identify choroidal characteristics associated with susceptibility to development of naturally occurring and experimentally induced myopia., Methods: We compared choroidal properties between pigmented and albino guinea pig (GP) strains. Biometry, cycloplegic refractive error (RE), and eye wall sublayer thickness were measured from 171 GPs at postnatal day (P)6, 14, and 28. Forty-three P14 GPs underwent two-week monocular form-deprivation myopia (FDM). En face images of choroidal vasculature were obtained with a customized swept-source optical coherence tomography. Multivariate regression analyses were performed, with P28 RE as the outcome and P14 choroidal thickness (ChT) as the main predictor variable. Proteomic analysis was performed on choroidal tissue from P14 albino and pigmented GPs., Results: At P14, RE was correlated with thickness of the choroid (β = 0.06), sclera (β = 0.12), and retina (β = 0.27; all P < 0.001). P14 ChT was correlated with P28 RE both with (β = 0.06, P = 0.0007) and without FDM (β = 0.05, P = 0.008). Multivariate regression analysis, taking into account FDM (versus physiological growth) and strain, revealed that for every 10-µm greater ChT at P14, P28 RE was 0.50D more positive (P = 0.005, n = 70). En face images of choroidal sublayers showed that albino choroids were relatively underdeveloped, with frequent avascular regions. Consistent with this finding, proteomic analysis suggested abnormalities of the nitric oxide system in the albino GP choroid., Conclusions: Current results are consistent with the notion that greater ChT could protect from or delay the onset of myopia, while lower ChT is associated with greater susceptibility to myopia development. The underlying mechanism could be related to dysfunction of the choroidal vascular system.

Purpose: To investigate differences in sensitivity to myopia-inducing stimuli of two strains of pigmented guinea pigs., Methods: Eleven-day-old animals (New Zealand [NZ], n = 24 and Elm Hill strains [EH], n = 26) wore either a +2 or -2 diopter (D) lens over one eye and a plano lens over the fellow eye for 5 days; other 10-day-old EH (n = 9) and 7-day-old NZ (n = 9) animals were monocularly form-deprived (FD) for 28 days. Choroidal thickness and axial length were measured using A-scan ultrasonography at baseline and after 1 and 5 days for optical defocus treatments, and at baseline and after 28 days for the FD treatment. Refractive errors were measured by retinoscopy. Choroids of untreated animals were also evaluated using spectral-domain optical coherence tomography., Results: One day of optical defocus induced bidirectional (optical sign-dependent) choroidal responses in EH animals only (P < 0.01). Similar responses were detected in NZ animals after 5 days (P < 0.01), with concordant spherical equivalent refraction changes (P < 0.01). Compared with NZ animals, EH animals developed minimal myopia with FD after 28 days (-4.58 ± 0.97 vs. -0.69 ± 0.75 D for NZ versus EH, P < 0.001). Yet, EH animals showed paradoxical choroidal thickening, 20 ± 9 vs. -8 ± 8 μm for EH versus NZ, P < 0.001. Untreated EH animals also had significantly thicker choroids than NZ animals (147 ± 19 vs. 132 ± 16 μm, P < 0.05), with well-defined layering., Conclusions: As previously reported in chicks, guinea pigs show strain-related differences in response to myopia-inducing stimuli. The finding of a thicker, multilayered choroid in the strain showing decreased sensitivity to FD is provocative, suggesting a possible protective role of the choroid.

Purpose: Disruption of dopaminergic signaling has been implicated in the abnormalities of ocular development in albinism, and many experiments have shown that retinal dopamine is a major regulator of postnatal eye growth and myopia in animal models. Therefore, in the present study we investigated whether progressive myopia, which can occur in albino guinea pigs without experimental manipulation of visual conditions, is affected by dopaminergic agents., Methods: Two-week-old albino guinea pigs, selected for being myopic (range refractive error [RE], -2 to -10 diopters [D]), received unilateral peribulbar injections of apomorphine (nonselective dopamine receptor agonist; 0, 7.5, 25, 75, 250, 750, and 2500 ng; n = 112), SKF38393 (D1-like agonist; 0, 10, 100, 1000 ng; n = 63), SCH23390 (D1-like antagonist; 0, 2500 ng; n = 27), quinpirole (D2-like agonist; 0, 10, 100, 1000 ng; n = 58), or sulpiride (D2-like antagonist; 0, 2500 ng; n = 24) once a day for four weeks. One noninjected group (n = 19) served as untreated control. Refractive states and axial dimensions of the eyes were measured without cycloplegia or general anesthetic, using eccentric infrared photoretinoscopy and A-scan ultrasonography, respectively, before treatment, and after 2 and 4 weeks of treatment. The main drug effects were analyzed by paired t-test or 2-way repeated measures ANOVA, as required., Results: The naturally occurring progression of myopic RE was inhibited by apomorphine at relatively high doses (250 and 750 ng), SKF38393 at 100 ng (D1-like agonist), and sulpiride at 2500 ng (D2-like antagonist), but promoted by apomorphine at a lower dose (25 ng), quinpirole at 100 ng (D2-like agonist), and SCH23390 at 2500 ng (D1-like antagonist). All drugs affected primarily vitreous chamber depth, rather than anterior segment dimensions., Conclusions: Our data suggest that the activation of D1-like receptors inhibits, whereas activation of D2-like receptors promotes, progressive myopia in this animal model. The robust effects of antagonists suggest that ocular dopamine receptors in these albinos may be in a chronic state of partial excitation. The precise location and identity of the receptors responsible for these effects remain to be determined., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To compare emmetropization in albino and pigmented guinea pigs., Methods: Distributions of refractive state were examined in 214 albino and 234 pigmented guinea pigs. Albino (A) and pigmented (P) guinea pigs were divided into two groups, hyperopic (H) and myopic (M). Eye development was separately followed in 10 randomly selected animals from each group (AH, AM, PH, PM) from 2 to 10 weeks of age. In addition, deprivation myopia was induced in 36 age-matched albino (18 AH and 18 AM) and 36 pigmented (18 PH and 18 PM) guinea pigs by diffusers that were worn from 2 to 6 weeks of age. Finally, sclera fibril diameters were measured using transmission electron microscopy., Results: Strikingly, the distributions of refractive errors were bimodal at 2 weeks of age, both in albino and pigmented animals, with clearly different averages (-2.86 ± 5.60 diopters [D] vs. 2.13 ± 5.27 D respectively; t = 9.712; P < 0.001). Spontaneous myopia was more common in albino animals: 70.1% were myopic (AM) and 29.9% hyperopic (AH), whereas only 28.6% were myopic (PM) and 71.4% hyperopic (PH) in pigmented guinea pigs. Different from PM and AM did not show any recovery from myopia. With diffusers, AH became more myopic (-7.61 ± 2.71 D and -11.17 ± 2.55 D) than PH (-4.48 ± 1.46 D and -8.28 ± 2.13 D) after 2 and 4 weeks, respectively. Deprivation myopia could still be induced in PM (-1.64 ± 1.44 D and -5.17 ± 1.88 D after 2 and 4 weeks, respectively; P < 0.01) but not in AM. Scleral fibril diameters were smaller in myopic animals, both albino and pigmented., Conclusions: Deprivation myopia could not be induced in spontaneously myopic but only in hyperopic albino guinea pigs, where it was even higher than in pigmented animals. The distinct effects of albinism on emmetropization will help to elucidate the mechanisms underlying the emmetropization.

Purpose: To investigate changes in protein profiles of posterior sclera in guinea pigs during development of form deprivation myopia and recovery., Methods: Three groups of guinea pigs (developing form deprivation myopia, recovering from the myopia and normal control) were evaluated for protein profiles of the posterior sclera using two-dimensional gel electrophoresis. Protein spots with a different intensity of at least threefold among the 3 groups were further identified with mass spectrometry. Key proteins associated with ocular growth (crystallins) were examined at mRNA levels using RT-PCR., Results: Moderate myopia was induced at 7 weeks of monocular deprivation and then more gradually recovered toward the previous refractive status 4 days after re-exposure of the eye to normal visual conditions. The profile of all protein spots at the posterior sclera was similar for both the deprived and the recovery eyes but distinct between either of the 2 experimental eyes and the normal control eyes. Twenty-six and 33 protein spots were differentially expressed in the deprived and the recovery eyes, respectively, compared to the normal control eyes. In contrast, the number of proteins differentially expressed between the deprived and the recovery eyes was only 5. Among the different subtypes of crystallins, βB2-crystallin was down-regulated and βA4-crystallin was upregulated in the deprived eyes at both protein and mRNA levels compared to the normal control eyes. The trend of expression for βA3/A1-crystallin was also similar at both mRNA and protein levels for the deprived eyes. However, αA-crystallin mRNA in the recovery eyes was upregulated while αA-crystallin itself was down-regulated. A similar inconsistency in expression of βA3/A1-, βA4-, and βB2-crystallins between the protein and mRNA levels also occurred in the recovery eyes., Conclusions: Proteomic analysis provides a useful survey of the number of proteins whose levels change during form deprivation myopia and the subsequent recovery. In particular, the crystallins changed during the development of form deprivation myopia and recovery. The changes in crystallin protein levels were consistent with that in mRNA levels during the development stage of form-deprivation myopia (FDM). However, the changes of most crystallin protein levels were mismatched with mRNA levels during the recovery stage.

Purpose: To critically evaluate whether the adenosine A2A receptor (A2AR) plays a role in postnatal refractive development in mice., Methods: Custom-built biometric systems specifically designed for mice were used to assess the development of relative myopia by examining refraction and biometrics in A2AR knockout (KO) mice and wild-type (WT) littermates between postnatal days (P)28 and P56. Ocular dimensions were measured by customized optical coherence tomography (OCT), refractive state by eccentric infrared photorefraction (EIR), and corneal radius of curvature by modified keratometry. Scleral collagen diameter and density were examined by electron microscopy on P35. The effect of A2AR activation on collagen mRNA expression and on soluble collagen production was examined in cultured human scleral fibroblasts by real-time RT-PCR and a collagen assay kit., Results: Compared with WT littermates, the A2AR KO mice displayed relative myopia (average difference, 5.1 D between P28 and P35) and associated increases in VC depth and axial length from P28 to P56. Furthermore, the myopic shift in A2AR KO mice was associated with ultrastructural changes in the sclera: Electron microscopy revealed denser collagen fibrils with reduced diameter in A2AR KO compared with WT. Last, A2AR activation induced expression of mRNAs for collagens I, III, and V and increased production of soluble collagen in cultured human scleral fibroblasts., Conclusions: Genetic deletion of the A2AR promotes development of relative myopia with increased axial length and altered scleral collagen fiber structure during postnatal development in mice. Thus, the A2AR may be important in normal refractive development.

Ambient lighting is essential for ocular development in many species, however, disruption in diurnal lighting cycle can affect the development in refraction and axial growth of the eye. This study investigated the effects of prolonged daily lighting on refraction and various optical components of the eye by raising C57BL/6 mice under three different light/dark cycles (18/6, 12/12 and 6/18). Egr-1 mRNA expression, apoptosis and histology of the retina and size of the scleral fibrils were evaluated in these three lighting cycles. Results showed that there was a trend of myopic development, increasing vitreous chamber depth and thinning of the retina in eyes from 6/18 to 18/6 groups. Retinal Egr-1 mRNA expression and diameter of scleral fibrils were reduced with the prolongation of daily lighting from 6/18 to 18/6. However, retinal apoptosis was not detected in all the groups. These results suggest that prolonged lighting can induce axial myopia in inbred mice. This model, which uses mice with similar genetic backgrounds, provides an alternative to the currently available models and therefore is useful for evaluation of refractive errors caused by changes in environmental illumination.

This study investigated whether adolescent guinea pigs can develop myopia induced by negative lenses, and whether they can recover from the induced myopia. Forty-nine pigmented guinea pigs (age of 3 weeks) were randomly assigned to 4 groups: 2-week defocus (n=16), 4-week defocus (n=9), 2-week control (n=15) and 4-week control (n=9). A -4.00D lens was worn in the defocus groups and a plano lens worn in the control groups monocularly. The lenses were worn from 3 weeks to 5 weeks of age in the 2-week treatment groups with the biometry measured at 2, 4, 6, 10 and 14 days of lens wear. The lenses were worn from 3 weeks to 7 weeks of age in the 4-week treatment groups with the biometry measured immediately and at 2, 4, 6, 10 and 14 days after lens removal. Refractions in the defocused eyes developed towards myopia rapidly within 2 days of lens wear, followed by a slower development. The defocused eyes were at least 3.00D more myopic with a greater increase in vitreous length by 0.08 mm compared to the fellow eyes at 14 days (p<0.05). The estimated choroidal thickness of the defocused eyes decreased rapidly within 2 days of lens wear, followed by a slower decrease over the next 4 days. Relative myopia induced by 4 weeks of negative-lens treatment declined rapidly following lens removal. A complete recovery occurred 14 days after lens removal when compared to the fellow controls. The refractive changes during the recovery corresponded to a slower vitreous lengthening and a rapid thickening of the choroid. The plano-lens wearing eyes showed a slight but significant myopic shift (<-0.80D) with no associated biometrical changes. Guinea pigs aged 3 weeks can still develop negative lens induced myopia and this myopia is reversible after removal of the lens. The myopia and recovery are mainly due to changes in vitreous length and choroidal thickness.

Purpose: To describe a wild-type guinea pig strain with an incidence of spontaneous axial myopia, minimal pupil responses, lack of accommodation, and apparently normal spatial vision. Such a strain is of interest because it may permit the exploration of defective emmetropization and mapping of the underlying quantitative trait loci., Methods: Twenty-eight guinea pigs were selected from 220 animals based on binocular myopia (exceeding -1.50 diopter [D]) or anisometropia (difference between both eyes exceeding 10 D) at 4 weeks of age. Refractions and pupil responses were measured with eccentric infrared photoretinoscopy, corneal curvature by modified conventional keratometer, and axial lengths by A-scan ultrasonography once a week. Twenty-one guinea pigs were raised under a normal 12-hour light/12-hour dark cycle. From a sample of 18 anisometropic guinea pigs, 11 were raised under normal light cycle and 7 were raised in the dark to determine the extent to which visual input guides emmetropization. Spatial vision was tested in an automated optomotor drum., Results: In 10 guinea pigs with myopia in both eyes, refractive errors ranged from -15.67 D to -1.50 D at 3 weeks with a high interocular correlation (R = 0.82); axial length and corneal curvature grew almost linearly over time. Strikingly, two patterns of recovery were observed in anisometropic guinea pigs: in 12 (67%) anisometropia persisted, and in 6 (33%) it declined over time. These ratios remained similar in dark-reared guinea pigs. Unlike published strains, all guinea pigs of this strain showed weak pupil responses and no signs of accommodation but up to 3 cyc/deg of spatial resolution., Conclusions: This strain of guinea pigs has spontaneous axial refractive errors that may be genetically or epigenetically determined. Interestingly, it differs from other published strains that show no refractive errors, vivid accommodation, or pupil responses.

Purpose: Guinea pigs have been increasingly used as an animal model for experimental myopia. Infant guinea pigs are susceptible to recovery from myopia within 2 weeks of form deprivation. This study investigated whether adolescent guinea pigs are susceptible to recovery from myopia after a longer period of form deprivation., Method: Twenty-two guinea pigs (age of 3 weeks) were randomly assigned to two groups: MDF (monocularly deprived facemask, n=11) and normal control (free of form deprivation, n=11). All animals underwent biometric measurement (refraction, corneal curvature and axial length) prior to the experiment. Animals in the MDF group wore a facemask that covered the right eye for 4 weeks. The MDF was then removed and biometric measurement was performed immediately and at 2, 6, 10 and 14 days. The same measurement was performed in the normal control group at time-points matching those of the MDF group., Results: The MDF eyes were approximately 4D more myopic with a greater increase in vitreous length by 0.12 mm compared to either the fellow or the normal control eyes after form deprivation (p<0.01). This relative myopia shifted rapidly towards hyperopia within 2 days after removal of the MDF, followed by a more gradual recovery. A complete recovery occurred by 6 days after removal of the MDF compared to the fellow and normal control eyes (p>0.05). Vitreous length in the MDF eyes slightly reduced within 2 days after removal of the MDF and then remained steady. The MDF eyes were similar to both the fellow and normal control eyes in vitreous length (p>0.05) 6 days after removal of the MDF. There was no significant difference between the MDF, fellow and normal control eyes in the other axial components during the form deprivation and recovery period., Conclusion: Adolescent guinea pigs are susceptible to recovery from MDF-induced myopia. The refractive recovery is mainly correlated to the inhibited axial elongation of the vitreous chamber of the previously deprived eyes.

This study evaluated the efficacy of a facemask, a non-invasive and potentially more reliable method, in inducing axial myopia in guinea pigs. Thirty-six animals were randomly assigned to 3 groups: MDF (monocularly-deprived facemask, n=6), lid-suture (eyelids sutured monocularly, n=24) and normal control (free of form deprivation, n=6). All the groups underwent biometric measurement (refraction, corneal curvature and axial length) prior to the experiment. All animals in the MDF group underwent biometric measurement at each of the 4 timepoints (2, 4, 6 and 8 weeks of form deprivation). In the lid-sutured group, the animals were randomly assigned to 4 subgroups (n=6 each) and each subgroup underwent biometric measurement at one of the timepoints matching those of the MDF group. In the normal control group, all animals underwent biometric measurement at each of the timepoints matching those of the 2 experimental groups. Placement of a facemask on an animal took approximately 10 sec and all the facemasks remained in place at all timepoints. The procedure of lid-suture took at least 20 min for an animal and rupture of the sutures occurred in 50% of the animals after 4 weeks. The MDF eyes developed myopia from -2.21+/-2.11D (Mean+/-s.d.) at 2 weeks to -4.38+/-2.14 at 8 weeks (p<0.05 at all timepoints, compared to the contralateral eyes) with a lengthening of the vitreous chamber from 0.17+/-0.05 mm at 2 weeks to 0.29+/-0.12 mm at 8 weeks (p<0.01 at all timepoints, compared to the contralateral eyes). The lid-sutured eyes developed myopia from -2.38+/-1.21D at 2 weeks to -4.75+/-1.39D at 8 weeks (p<0.05 at all timepoints, compared to the contralateral eyes) with a lengthening of the vitreous chamber from 0.13+/-0.02 mm at 2 weeks to 0.30+/-0.10 mm at 8 weeks (p<0.05 at 2, 4, 8 weeks, but >0.05 at 6 weeks, compared to the contralateral eyes) and an increase in the radius of the corneal curvature (0.20+/-0.07 mm at 4 weeks, p<0.01; 0.17+/-0.05 mm at 8 weeks, p<0.05; compared to the contralateral eyes). Both the MDF and lid-sutured groups had a similar development in myopia and vitreous length (MDF vs lid-suturing: p>0.05 at all timepoints, one-way ANOVA with Bonferroni correction). This development was significantly faster than in the normal control group (MDF or lid-suture vs normal control: p<0.05 to <0.01 from 2 to 8 weeks, one-way ANOVA with Bonferroni correction). The radius of corneal curvature in the lid-sutured group was significantly greater than in either the MDF group or the normal control group since 4 weeks of form deprivation (p<0.05, one-way ANOVA with Bonferroni correction). Treatment with MDFs is as effective as the lid-suture in inducing axial myopia in guinea pigs. This method is non-invasive and allows evaluation of the same group of animals at different timepoints so that the number of animals required could be minimized without affecting the accuracy of the results.