期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 63, 期 12, 页码 -出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.63.12.11
关键词
microRNA-328; myopia; axial length; oligonucleotide; eye drops
资金
- Ministry of Science and Technology (Taiwan, R.O.C.) [106-3114-8-039-002, MOST 107-2823-8-039-002, MOST 108-2314-B-039049-MY3, MOST 111-2314-B-039-057]
- Drug Development Center, China Medical University from The Featured Areas Research Center Program by the Ministry of Education (MOE) in Taiwan
This study investigated the role of miR-328-3p in controlling myopia. The results showed that anti-miR-328-3p could reduce the expression of fibromodulin and collagen1A1 in myopic eyes, and it exerted its effects by regulating the expression of TGF-beta 1 and phosphorylation levels of p38-MAPK and JNK. Additionally, retinoic acid was found to up-regulate the expression of miR-328-3p. Animal studies demonstrated that anti-miR-328-3p effectively suppressed axial elongation. The toxicity study showed that anti-miR-328-3p had no adverse effects.
PURPOSE. We previously reported miR-328-3p as a novel risk factor for myopia through a genetic association study of the PAX6 gene. In the present study, we first explored the effects of miR-328-3p on other myopia-related genes, and then tested whether anti-miR-328-3p may be used for myopia control. METHODS. The luciferase report assay and transient transfection were used to confirm miR-328-3p target genes. The chromatin immunoprecipitation (ChIP) assay was used to investigate retinoic acid receptor on the miR-328-3p promoter. Mice and pigmented rabbits were induced to have myopia by the form deprivation method, and then anti-miR-328-3p oligonucleotide was topically instilled to the myopic eyes. The axial length was measured to assess the therapeutic effect of anti-miR-328-3p. A toxicity study using much higher doses was conducted to assess the safety and ocular irritation of anti-miR-328-3p. RESULTS. The report assay and transfection of miR-328-3p mimic confirmed that miR-328-3p dose-dependently decreased both mRNA and protein expression of fibromodulin (FMOD) and collagen1A1 (COL1A1). We subsequently showed that FMOD promoted TGF-beta 1 expression, and overexpression of FMOD increased the phosphorylation levels of p38-MAPK and JNK. The ChIP study showed that retinoic acid binds to miR-328-3p promoter and up-regulates miR-328-3p expression. In myopic animal studies, anti-miR-328-3p was as effective as 1% atropine and had a dose-dependent effect on suppressing axial elongation. In the toxicity study, anti-miR-328-3p did not cause any unwanted effects in the eyes or other organs. CONCLUSIONS. Micro (mi)R-328-3p affects myopia development via multiple routes. anti-miR-328-3p possesses a potential as a novel therapy for myopia control.
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