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Updated: Nov 14, 2025
Inducement and Evaluation of a Murine Model of Experimental Myopia
Published on: January 22, 2019
Stepwise candidate drug screening for myopia control by using zebrafish, mouse, and Golden Syrian Hamster myopia
Meng-Yin Lin1, I-Tsen Lin2, Yu-Ching Wu3
1Department of Ophthalmology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan; Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Ophthalmology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Background:
We developed a preclinical protocol for the screening of candidate drugs able to control myopia and prevent its progression. The protocol uses zebrafish, C57BL/6 mice, and golden Syrian hamster models of myopia.
Methods:
A morpholino (MO) targeting the zebrafish lumican gene (zlum) was injected into single-cell zebrafish embryos, causing excessive expansion of the sclera. A library of 640 compounds with 2 matrix metalloproteinase (MMP) inhibitors (marimastat and batimastat), which have the potential to modulate scleral remodelling, was screened to identify candidates for mitigating scleral diameter expansion in zlum-MO-injected embryos. The myopia-prevention ability of compounds discovered to have superior potency to inhibit scleral expansion was validated over 4 weeks in 4-week-old C57BL/6 mice and 3-week-old golden Syrian hamsters with form-deprivation myopia (FDM). Changes in the refractive error and axial length were investigated. Scleral thickness, morphology of collagen fibrils in the posterior sclera, messenger RNA (mRNA) expressions, and protein levels of transforming growth factor-β2 (TGF-β2), tissue inhibitor of metalloproteinase-2 (TIMP-2), MMP-2, MMP-7, MMP-9, and collagen, type I, alpha 1 (collagen Iα1) were investigated in C57BL/6 mice, and MMP-2, MMP-9, and MMP activity assays were conducted in these mice.
Findings:
In the zebrafish experiment, atropine, marimastat, batimastat, doxycycline, and minocycline were the drugs that most effectively reduced expansion of scleral equatorial diameter. After 28-day treatment in diffuser-wearing mice and 21-day treatment in lid-sutured hamsters, myopic shift and axial elongation were significantly mitigated by eye drops containing 1% atropine, 50 µM marimastat, 5 µM batimastat, or 200 µM doxycycline. MMP-2 mRNA expression in mouse sclera was lower after treatment with atropine, marimastat, batimastat, or doxycycline. The protein levels and activity of MMP-2 and MMP-7 were significantly reduced after treatment with atropine, marimastat, batimastat, doxycycline, and minocycline. Furthermore, scleral thickness and collagen fibril diameter were not lower after treatment with atropine, marimastat, batimastat, or doxycycline than those of occluded eyes.
Interpretation:
Stepwise drug screening in a range of models from zlum-MO-injected zebrafish to rodent FDM models identified effective compounds for preclinical myopia control or prevention. On the basis of the 640 compounds that were screened, MMP inhibitors may offer alternatives for clinical trials.
Funding:
This research was supported by grants from Taiwan's Ministry of Science and Technology and Ministry of Health and Welfare.
Insights
This study screened 640 compounds to find myopia control drugs, identifying atropine, doxycycline, and MMP inhibitors as effective in zebrafish and rodent models for preventing myopia progression.
Area of Science:
- Ophthalmology
- Pharmacology
- Genetics
Background:
- A novel preclinical protocol was established for screening myopia control drugs.
- The protocol utilizes zebrafish, C57BL/6 mice, and golden Syrian hamster models.
Purpose of the Study:
- To screen a library of 640 compounds for myopia control and prevention.
- To identify drug candidates that mitigate scleral expansion and myopic shift.
Main Methods:
- Zebrafish embryos with lumican gene morpholino (zlum-MO) were used to induce myopia.
- A compound library, including matrix metalloproteinase (MMP) inhibitors, was screened.
- Promising compounds were validated in mouse and hamster models of form-deprivation myopia (FDM).
Main Results:
- Atropine, marimastat, batimastat, doxycycline, and minocycline showed efficacy in zebrafish.
- These drugs significantly mitigated myopic shift and axial elongation in mice and hamsters.
- MMP-2 and MMP-7 expression and activity were reduced by the tested drugs.
Conclusions:
- Stepwise drug screening across multiple models identified effective preclinical myopia control agents.
- Matrix metalloproteinase (MMP) inhibitors show potential as alternatives for myopia control clinical trials.
