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WO2025089394A1 - Procédé et composition pour prévenir ou traiter la myopie - Google Patents

Procédé et composition pour prévenir ou traiter la myopie Download PDF

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Publication number
WO2025089394A1
WO2025089394A1 PCT/JP2024/038132 JP2024038132W WO2025089394A1 WO 2025089394 A1 WO2025089394 A1 WO 2025089394A1 JP 2024038132 W JP2024038132 W JP 2024038132W WO 2025089394 A1 WO2025089394 A1 WO 2025089394A1
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myopia
choroidal
group
macrophages
administration
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Japanese (ja)
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一男 坪田
俊英 栗原
真一 池田
靖 侯
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Tsubota Laboratory Inc
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Tsubota Laboratory Inc
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the present invention relates to methods and compositions for preventing or treating myopia, more particularly to compositions that act on immune cells in the choroid to inhibit the progression of myopia, more particularly by inducing polarization to M2 macrophages or modulating the function of choroidal resident immune cells, such as by administering a mast cell stabilizer, a chemical mediator release inhibitor, or lactic acid bacteria.
  • the present invention also relates to methods and compositions for preventing or treating myopia by administering berberine, taurine, or lipoic acid, or salts thereof, or derivatives thereof.
  • Myopia is a condition in which the light focus is in front of the retina due to axial elongation, and the longer the axial length, the stronger the myopia.
  • myopia As the prevalence of myopia increases, there has been growing interest in the factors involved in the development of myopia and the methods of preventing and controlling myopia progression.
  • Recent studies have suggested that the choroid is important in regulating eye growth and the development of myopia, and choroidal thinning has been shown to be a structural characteristic of myopia.
  • the negative correlation between choroidal thickness and axial length suggests that changes in choroidal thickness may be a predictive biomarker for axial elongation.
  • the detailed mechanism by which the choroid is involved in the development and progression of myopia remains unclear.
  • the choroid is a tissue that covers the outside of the retina and is rich in fine blood vessels. In addition to supplying oxygen and nutrients to retinal cells, it also supplies growth factors involved in tissue remodeling of the sclera on the outside of the eyeball and regulating eye growth. It is thought that a decrease in choroidal thickness or a decrease in blood flow contributes to scleral ischemia and hypoxia, and affects changes in scleral structure that lead to elongation of the axial length. Therefore, maintaining and increasing choroidal thickness and blood flow is attracting attention as a new target in the prevention and treatment of myopia.
  • Non-Patent Document 1 Methods have been proposed to inhibit the progression of myopia by maintaining or increasing the thickness of the choroid, such as taking crocetin (see Non-Patent Document 1) and irradiating it with violet light (Non-Patent Document 2).
  • Crocetin is known to have anti-inflammatory and immunomodulatory effects, and is known to exert its effects by adjusting the balance of Th1/Th2 and Th17/Treg in T cells and suppressing the NF- ⁇ B pathway in cells that produce inflammatory mediators (TNF- ⁇ , IL-6, IFN- ⁇ , etc.), such as macrophages (Non-patent Documents 3-5).
  • the choroid contains 13 types of cells, 4 of which are immune cells. Tissue-resident immune cells are responsible for maintaining tissue homeostasis and structure in addition to immune responses. For example, it has been reported that the choroid thins in mice lacking macrophages and mice in which degranulation of mast cells is induced (Non-Patent Documents 6-7).
  • Patent Document 1 describes that lipoic acid and its derivatives are effective in treating presbyopia and cataracts.
  • Patent Document 2 also describes that lipoic acid choline ester is effective in treating presbyopia.
  • Patent Documents 1 and 2 do not describe or suggest the relationship between lipoic acid and its derivatives and myopia.
  • the present disclosure aims to provide a method for preventing or treating myopia and a composition for use therein, in particular a composition that targets resident immune cells in the choroid, particularly macrophages and mast cells.
  • Myopia is a major cause of visual impairment and has emerged as a global public health concern.
  • One of the main structural features of myopia is the corresponding reduction in choroidal thickness, and evidence indicates that choroidal macrophages play an important role in maintaining choroidal thickness. Nevertheless, the influence of choroidal macrophages on myopia remains unclear.
  • continuous intraperitoneal injection of clodronate liposomes depletes choroidal macrophages and causes myopia, confirming that choroidal macrophages play an important role in the development of myopia.
  • experiments were designed to study the effects of different polarization directions of macrophages on the development of myopia.
  • LPS lipopolysaccharide
  • IL-4 or IL-13 induces polarization of choroidal M2 macrophages, thickening the choroid and inhibiting myopia progression.
  • M1 and M2 macrophages may be related to their influence on choroidal thickness, inflammation, and oxidative stress responses.
  • the inventors have found that administration of berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof, is effective in preventing and treating myopia.
  • the inventors also discovered that polarization of choroidal macrophages into M2 macrophages suppresses choroidal thinning and is effective in preventing and treating myopia.
  • mast cells are distributed in large numbers around small blood vessels, and their presence has also been observed in the choroid, a tissue made up of blood vessels, suggesting their involvement in maintaining the morphology of the choroid.
  • the present inventors have found that the progression of myopia is suppressed by instilling a drug (mast cell stabilizer) that inhibits the degranulation of mast cells.
  • a drug mass cell stabilizer
  • the present inventors have found that the progression of myopia is suppressed by instilling a mast cell stabilizer (sodium cromoglycate, pemirolast potassium), a type of antiallergic drug, into a mouse model of myopia induced by wearing minus lenses.
  • a mast cell stabilizer sodium cromoglycate, pemirolast potassium
  • the inhibition of myopia progression was not observed when another antiallergic drug, an antihistamine (levocabastine), was instilled into mice undergoing myopia induction by wearing minus lenses.
  • compositions that targets immune cells present in the choroid, such as macrophages and mast cells, and induces the properties of each cell to an appropriate state will have an inhibitory effect on the progression of myopia.
  • the present invention is based on such findings and includes the following aspects.
  • a composition for use in preventing or treating myopia comprising an M2 macrophage polarization inducer and/or a mast cell stabilizer.
  • the M2 macrophage polarization inducer comprises at least one selected from the group consisting of berberine, taurine, and salts thereof and derivatives thereof;
  • the composition of aspect A-1, wherein the mast cell stabilizer comprises at least one selected from the group consisting of azulene sulfonic acid, taurine, and salts and derivatives thereof.
  • A-3 The composition of aspect A-1 or A-2, wherein the inhibition or treatment of myopia is based on inhibiting at least one selected from the group consisting of a decrease in refractive value, axial elongation, and choroidal thinning.
  • A-4 The composition according to aspect A-1 or A-2, wherein the dosage form is an eye drop.
  • A-5 A method for inhibiting or treating myopia, comprising administering to a subject in need of treatment a therapeutically effective amount of an M2 macrophage polarization inducer and/or a mast cell stabilizer.
  • A-6 Use of an M2 macrophage polarization inducer and/or a mast cell stabilizer in the manufacture of a medicament for inhibiting or treating myopia.
  • [Aspect B-1] A method for inhibiting, ameliorating or treating myopia, comprising administering to a subject in need of treatment a therapeutically effective amount of berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • Aspect B-2] The method of embodiment 1, wherein berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof, is contained in a pharmaceutical composition, a supplement, or a food product.
  • [Aspect B-3] The method of embodiment 1, wherein refractive loss, axial elongation, and/or choroidal thinning is inhibited.
  • a composition for inhibiting or treating myopia comprising a therapeutically effective amount of berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • a supplement for inhibiting or improving myopia comprising an effective amount of berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • a food for inhibiting or improving myopia comprising an effective amount of berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • Aspect B-7 1.
  • a composition for use in preventing or treating myopia comprising an M2 macrophage polarization inducer and/or a mast cell stabilizer.
  • the M2 macrophage polarization inducer comprises at least one selected from the group consisting of berberine, taurine, and salts thereof and derivatives thereof;
  • the composition of embodiment 9, wherein the mast cell stabilizer comprises at least one selected from the group consisting of azulene sulfonic acid, taurine, and salts and derivatives thereof.
  • the composition according to embodiment 9 or 10, wherein the effect is based on inhibiting at least one selected from the group consisting of a decrease in refractive value, axial elongation, and choroidal thinning.
  • Aspect B-12 The composition of any one of aspects 9 to 11, wherein the dosage form is an eye drop.
  • a method for inhibiting or treating myopia comprising administering to a subject in need of treatment a therapeutically effective amount of an M2 macrophage polarization inducer and/or a mast cell stabilizer.
  • Aspect B-14 Use of an M2 macrophage polarization inducer and/or a mast cell stabilizer in the manufacture of a medicament for inhibiting or treating myopia.
  • a new method for preventing and treating myopia can be provided by administering berberine, taurine, or lipoic acid, or a salt or derivative thereof.
  • a new method for preventing and treating myopia can be provided by adjusting the function of choroidal resident immune cells, more specifically, by inducing polarization to M2 macrophages in the choroid, or by administering a mast cell stabilizer, a chemical mediator release inhibitor, or lactic acid bacteria.
  • Myopia is associated with a persistent decrease in macrophages present in the choroid of 3- and 8-week-old mice.
  • B Compared to the control group, the clodronate liposome (Clolip)-injected group showed greater refractive change (P ⁇ 0.001), axial ocular growth (P ⁇ 0.01), and thinner choroid (P ⁇ 0.001).
  • Macrophages in the H3-UR region were shown as CD11b + and F4/80 + .
  • the percentage of macrophages was significantly increased after IL-4 injection (P ⁇ 0.001).
  • M2 macrophages in the Q2-UR were identified as CD206 + .
  • 48 h after IL-4 injection M2 macrophages were dramatically polarized (P ⁇ 0.05).
  • B Real-time PCR results showed that the mRNA expression levels of Mrc1 and CD163 were significantly increased 48 h after IL-4 injection.
  • C Three-week-old wild-type C57BL/6JJc1 mice were divided into two groups and injected with 0.1 ⁇ g/100 ⁇ l IL-4 or PBS every other day to induce myopia (four times per group unless otherwise indicated). Refraction, axial length, and choroidal thickness were measured using an infrared photorefractive and SD-OCT system at the early (3 weeks) and final (6 weeks) stages of myopia induction.
  • D Eyes treated with -30D lenses showed significantly greater refractive change (P ⁇ 0.01), greater axial length elongation (P ⁇ 0.05), and increased choroidal thickness (P ⁇ 0.001) compared with eyes treated with 0D lenses from PBS-injected mice.
  • mice injected with 0.1 ⁇ g/100 ⁇ l IL-4 showed significantly smaller refractive changes (P ⁇ 0.05), smaller changes in axial length (P ⁇ 0.05), and positive changes in choroidal thickness with statistical significance (P ⁇ 0.001). Bars represent the mean +/- standard deviation.
  • E To evaluate changes in choroidal blood perfusion, 3-week-old mice were divided into three groups: both eyes fitted with 0D lenses (control-0D group), binocular myopia induction (control-30D group), and binocular myopia induction by IL-4 injection once every 2 days (IL-4-30D group). Choroidal blood perfusion was evaluated at the early (3 weeks of age) and end (6 weeks of age) stages of myopia induction using OCTA.
  • mice used for measuring choroidal blood perfusion were euthanized at 6 weeks of age, and choroids were collected for flow cytometry. The results showed that mice treated with -30D lenses and injected with IL-4 had a significant proportion of M2 macrophages compared with mice treated with -30D lenses and injected with PBS. P values correspond to comparisons made using one-way ANOVA. *P ⁇ 0.05. **P ⁇ 0.01. ***P ⁇ 0.001. Effect of macrophage polarization direction on oxidative stress response.
  • mice Three-week-old mice were divided into three groups: a group fitted with 0D lenses in both eyes (control 0D group), a group in which binocular myopia was induced (control-30D group), and a group in which binocular myopia was induced and injected with IL-13 (IL-13-30D group). The frequency of IL-13 injection was once every two days. Refraction, axial length, and choroidal thickness were measured using an infrared photorefractive and SD-OCT system at the early (3 weeks of age) and end (6 weeks of age) stages of myopia induction.
  • the Control-30D group showed significantly greater refractive change (P ⁇ 0.001), greater axial length elongation (P ⁇ 0.05), and thinner choroid (P ⁇ 0.001) compared to the Control 0D group.
  • the IL-13-30D group showed significantly smaller refractive change (P ⁇ 0.001), smaller axial length change (P ⁇ 0.05), and a positive change in choroidal thickness with statistical significance (P ⁇ 0.001). Bars represent the mean +/- standard deviation.
  • Choroidal blood perfusion was measured using OCTA. Choroidal blood perfusion was significantly decreased in the Control-30D group compared to the Control 0D group. Correspondingly, choroidal blood perfusion was significantly improved in the IL-13-30D group compared with the Control-30D group.
  • choroidal thickness was improved in the berberine-30D group compared with the 2% DMSO-30D group (P ⁇ 0.001). P values indicate comparison with control using one-way ANOVA. *P ⁇ 0.05. **P ⁇ 0.01. ***P ⁇ 0.001.
  • A shows the experimental schedule
  • B shows graphs indicating changes in refractive index (left), axial length (center), and choroidal thickness (right).
  • 1 is a graph showing changes in the expression of M1 macrophage marker genes and oxidative stress-related genes by LPS administration. 1 shows the results of M2 macrophage polarization induction by IL-4 administration.
  • A A diagram showing the experimental schedule.
  • FIG. 1 A graph showing changes in the expression of CD206 protein and phosphorylated STAT6 in the choroid by IL-4 administration.
  • C A graph showing changes in the expression of CD163 and CD206 mRNA by IL-4 administration. 1 is a graph showing changes in the expression of M2 macrophage marker genes and oxidative stress-related genes by administration of IL-4. 1 shows the results of an experiment to suppress myopia progression by administration of IL-4.
  • A A diagram showing the experimental schedule.
  • FIG. 1 A diagram showing changes in refraction (left), axial length (center), and choroidal thickness (right) by administration of IL-4 during the myopia induction period. IL-13 administration suppresses myopia and induces M2 macrophage polarization.
  • A Experimental schedule.
  • (B) Graphs showing changes in refraction (upper left), axial length (upper right), choroidal thickness (lower left), and blood flow (lower right) due to IL-13 administration during the myopia induction period.
  • (C) Graphs showing changes in macrophage number and M2 macrophage ratio due to myopia induction and IL-13 administration. These results show the myopia suppression effect of instilling mast cell stabilizer.
  • (A) Graph showing the change in axial length.
  • (B) Graph showing the change in refractive index.
  • (C) Graph showing the change in choroidal thickness. The left graph shows the control group vs. the pemirolast potassium instillation group, and the right graph shows the control group vs. the cromoglycic acid instillation group.
  • A A graph showing the change in axial length.
  • B A graph showing the change in refractive index.
  • C A graph showing the change in choroidal thickness. The left side shows the control group, and the right side shows the group administered Lactobacillus paracasei. Graphs showing the myopia suppression effect of administration of berberine chloride once a day or three times a day.
  • A A diagram showing the experimental schedule.
  • B A graph showing the refractive index and its change in the group with and without myopia induction.
  • C A graph showing the axial length and its change in the group with and without myopia induction. Graphs showing the myopia suppression effect of administration of berberine chloride, sodium azulene sulfonate, or taurine.
  • A A diagram showing the experimental schedule.
  • B A graph showing the change in refractive value and the difference between groups with and without myopia induction.
  • C A graph showing the change in axial length and the difference between groups with and without myopia induction.
  • D A graph showing the change in choroidal thickness and the difference between groups with and without myopia induction. Graphs showing the myopia suppression effect of administration of berberine chloride and sodium azulene sulfonate.
  • A A diagram showing the experimental schedule.
  • B A graph showing the change in refractive value in the group with and without myopia induction.
  • C A graph showing the change in axial length in the group with and without myopia induction.
  • (D) A graph showing the change in choroidal thickness in the group with and without myopia induction. Graphs showing the myopia suppression effect of administration of berberine chloride and sodium azulenesulfonate, administration of berberine chloride and taurine, or administration of berberine chloride, sodium azulenesulfonate and taurine.
  • (A) A diagram showing the experimental schedule.
  • (B) A graph showing the change in refractive value in the group with and without myopia induction.
  • (C) A graph showing the change in axial length in the group with and without myopia induction.
  • M1 macrophages are mainly involved in the initiation of inflammation, whereas M2 macrophages act antagonistically to terminate and suppress inflammation.
  • the present inventors have found that choroidal thinning and myopia progression are observed by inducing polarization to M1 macrophages in the choroid, while choroidal thinning and myopia progression are suppressed by inducing polarization to M2 macrophages.
  • mast cells are distributed in large numbers around small blood vessels, and their presence is also observed in the choroid, which is a tissue made of blood vessels, suggesting their involvement in maintaining the morphology of the choroid.
  • myopia progression is suppressed by instilling a drug (mast cell stabilizer) that inhibits degranulation of mast cells.
  • one aspect of the present disclosure relates to methods for inhibiting, ameliorating or treating myopia by modulating the function of choroidal resident immune cells, more specifically, by polarizing macrophages into M2 macrophages in the choroid, or by administering a mast cell stabilizer, a chemical mediator release inhibitor, or lactic acid bacteria.
  • One aspect of the present disclosure relates to a method for inhibiting, ameliorating, or treating myopia by modulating the function of choroid-resident immune cells, more specifically, by inducing polarization to M2 macrophages in the choroid using an M2 macrophage polarization inducer, or by administering a mast cell stabilizer, a chemical mediator release inhibitor, or lactic acid bacteria.
  • one aspect of the present disclosure also relates to a screening method for searching for a substance that regulates the function of choroidal resident immune cells, such as a component that promotes polarization into M2 macrophages, in order to control choroidal thinning, which is a mechanism for the development of myopia, and a screening method for searching for a component that is effective in the prevention and treatment of myopia.
  • a screening method for searching for a component that is effective in the prevention and treatment of myopia relates to a method for inhibiting, ameliorating or treating myopia by administering berberine, taurine, or lipoic acid, or salts thereof, or derivatives thereof.
  • the choroidal resident immune cell function regulator is a substance that regulates the function of the choroidal resident immune cells.
  • the substance that regulates the function of the choroidal resident immune cells preferably includes a substance that regulates to suppress inflammation in the choroid, and a substance that regulates to make the choroid an anti-inflammatory environment.
  • Examples of the choroidal resident immune cells include macrophages and mast cells.
  • Examples of the choroidal resident immune cell function regulator include M2 macrophage polarization inducers, mast cell stabilizers, chemical mediator release inhibitors, and lactic acid bacteria.
  • M2 macrophage polarization inducer Macrophages are classified into inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which have different functions, and are polarized in response to signals from cytokines and stimulatory components to express specific functions. Therefore, the M2 macrophage polarization inducer in the present disclosure includes various substances involved in signal transduction that induces polarization into M2 macrophages in the choroid, and proteins, peptides, nucleic acid drugs, low molecular weight compounds, high molecular weight compounds, etc. can be used without particular limitation.
  • M2 macrophage polarization inducers examples include cytokines such as IL-4 and IL-13 produced by Th2 cells, as well as the leucine zipper transcription factor c-Maf, the carbohydrate-binding lectin galectin-3, etc.
  • cytokines such as IL-4 and IL-13 produced by Th2 cells
  • the leucine zipper transcription factor c-Maf the carbohydrate-binding lectin galectin-3, etc.
  • M2 macrophage polarization inducers examples include cytokines such as IL-4 and IL-13 produced by Th2 cells, as well as the leucine zipper transcription factor c-Maf, the carbohydrate-binding lectin galectin-3, etc.
  • M2 macrophage polarization inducers examples include cytokines such as IL-4 and IL-13 produced by Th2 cells, as well as the leucine zipper transcription factor c-Maf, the carbohydrate-binding lectin galectin-3, etc.
  • examples of M2 macrophage polarization inducers in the present disclosure include various low molecular weight compounds, for example, bisantrene dihydrochloride, triptolide, lovastatin, QS11, regorafenib, sorafenib, ixazomib, GW-843682X, KW 2449, axitinib, JTE 013, purmorphamine, and alciliaflavin A ( Examples of such anti-inflammatory agents include arcyriaflavin A), dasatinib, NVP-LDE225, 1-naphthyl PP1, MGCD-265, bosutinib, berberine or a salt thereof, taurine or a salt thereof, retinol, tocopherol, cyanocobalamin, or derivatives thereof (e.g., retinol palmitate, tocopherol acetate), preferably berberine or a salt thereof, more preferably berberine chlor
  • M2 macrophage polarization inducers can also be used as M2 macrophage polarization inducers.
  • Those skilled in the art can obtain M2 macrophage polarization inducers suitable for use in the methods and compositions of the present disclosure, in addition to the M2 macrophage polarization inducers specifically described in this specification, by culturing cells such as monocytic cell lines, such as RAW264 cells, J774 cells, and U937 cells, mouse peritoneal macrophages, and bone marrow-derived macrophages in a medium containing the substance to be evaluated, and evaluating whether the substance has M2 macrophage polarization induction ability using an in vitro evaluation system for evaluating the expression of M2 macrophage markers.
  • monocytic cell lines such as RAW264 cells, J774 cells, and U937 cells
  • mouse peritoneal macrophages mouse peritoneal macrophages
  • bone marrow-derived macrophages induction ability using an in vitro evaluation
  • the M2 macrophage polarization inducer When the M2 macrophage polarization inducer is a protein or peptide, it may be administered to the subject in the form of DNA or RNA encoding the protein or peptide.
  • the nucleic acid encoding the M2 macrophage polarization inducer may be administered to the subject using a plasmid or an expression vector.
  • the expression vector may be, for example, a viral vector, particularly an adenoviral vector, but is not limited thereto.
  • Other usable viral vectors include, for example, retrovirus, adeno-associated virus, pox, baculovirus, vaccinia, herpes simplex, Epstein-Barr, geminivirus, and caulimovirus vectors.
  • the nucleic acid encoding the M2 macrophage polarization inducer may contain a regulatory element for expressing the protein specifically in the choroid or RPE. That is, the nucleic acid encoding the M2 macrophage polarization inducer may be operably linked to a regulatory element such as a promoter or enhancer.
  • Mast cell stabilizers are also called mast cell stabilizers or mast cell stabilizing drugs.
  • Mast cell stabilizers are, for example, drugs that suppress the release of allergens from mast cells, such as drugs that stabilize the cell membrane of mast cells to suppress the release of allergens from mast cells.
  • mast cell stabilizers examples include ashitazanolast hydrate solution (Zepelin), amlexanox (Elix), pemirolast or its salts (e.g., pemirolast potassium (Alegysal), pemirolast potassium (Pemilaston)), cromoglycic acid or its salts (e.g., sodium cromoglycate (Intal)), tranilast or its salts (e.g., tranilast (Rizaben), tranilast (Tramelas)), ibudilast (Ketas), ⁇ 2-adrenergic agonists, cromolyn sodium, ketothiol ...
  • ashitazanolast hydrate solution Zepelin
  • Amlexanox elix
  • pemirolast or its salts e.g., pemirolast potassium (Alegysal), pemirolast potassium (Pemilaston)
  • cromoglycic acid or its salts e.g., sodium cromog
  • Examples of such an inhibitor include phenanthrene, methylxanthine, omalizumab, quercetin, azulene sulfonic acid or a salt thereof, taurine or a salt thereof, pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride), tocopherol, or a derivative thereof (e.g., tocopherol acetate), of which preferred examples include cromoglycic acid or a salt thereof, tranilast or a salt thereof, pemirolast or a salt thereof, azulene sulfonic acid or a salt thereof, and taurine or a salt thereof, and more preferred examples include sodium azulene sulfonate and taurine.
  • pyridoxine or a salt thereof e.g., pyridoxine hydrochloride
  • tocopherol or a derivative thereof (e.g., tocopherol acetate)
  • preferred examples include cromoglycic acid or a
  • Chemical mediator release inhibitors are drugs that suppress allergic reactions by suppressing the release of chemical mediators from immune cells such as mast cells.
  • they are drugs that stabilize the cell membrane of mast cells to prevent histamine and other substances from being released, and they suppress the release of allergens (substances that cause allergic reactions), such as histamine, LTB4, LTC4, LTD4, PGD2, TXB2, and PAF, from mast cells.
  • Examples of chemical mediator release inhibitors include ashitazanolast hydrate solution (Zeperin), amlexanox (Elix), pemirolast potassium (Alegysal), pemirolast potassium (Pemilaston), cromoglycate sodium (Intal), tranilast (Rizaben), tranilast (Tramelas), ibudilast (Ketas), ⁇ 2-adrenergic agonists, cromolyn sodium, cromoglycic acid, ketotifen, methylxanthine, omalizumab, pemirolast, and quercetin, and preferably cromoglycic acid or pemirolast, or a salt thereof.
  • lactic acid bacteria examples include homolactic acid bacteria and heterolactic acid bacteria.
  • examples of lactic acid bacteria include coccus lactic acid bacteria and rod-shaped lactic acid bacteria.
  • Examples of lactic acid bacteria include gram-positive, rod-shaped or coccus bacteria, non-spore-forming, non-motile, 50% or more lactic acid produced from glucose consumed, and niacin (B3)-requiring fungi.
  • Examples of lactic acid bacteria include intestinal lactic acid bacteria, animal lactic acid bacteria, vegetable lactic acid bacteria, and marine lactic acid bacteria.
  • Examples of lactic acid bacteria include lactobacilli and actinomycetes.
  • lactobacillus lactic acid bacteria examples include lactobacillus lactic acid bacteria, enterococcus lactic acid bacteria, lactococcus lactic acid bacteria, pediococcus lactic acid bacteria, leuconostoc lactic acid bacteria, streptococcus lactic acid bacteria, etc.
  • actinomycete lactic acid bacteria examples include bifidobacterium lactic acid bacteria.
  • Lactobacillus paracasei Lactobacillus plantarum
  • Lactobacillus brevis Lactobacillus delbrueckii
  • Lactobacillus acidophilus Lactobacillus casei
  • Lactobacillus bulgaricus Lactobacillus gasseri
  • Lactobacillus acidophilus Lactobacillus fructivorans
  • Lactobacillus hilgardii Lactobacillus rhamnosus
  • Lactobacillus plantarum Lactobacillus casei Shirota, etc.
  • Examples of lactic acid bacteria of the genus Enterococcus include Enterococcus faecalis and Enterococcus faecium, etc.
  • Examples of lactic acid bacteria of the Lactococcus genus include Lactococcus lactis and Lactococcus cremoris.
  • Examples of lactic acid bacteria of the Pediococcus genus include Pediococcus damnosus.
  • Examples of lactic acid bacteria of the Leuconostoc genus include Leuconostoc mesenteroides.
  • Examples of lactic acid bacteria of the Streptococcus genus include Streptococcus thermophiles and Streptococcus mutans.
  • Examples of lactic acid bacteria of the Bifidobacterium genus include Bifidobacterium bifidum and Bifidobacterium adolescentis. It is known that administration of Lactobacillus paracasei improves the symptoms of non-alcoholic steatohepatitis by shifting the liver's Kupffer cells (resident macrophages) to M2 (Sohn et al, Dig Dis Sci, 2015 Nov;60(11):3340-50). It is known that administration of Lactobacillus paracasei alleviates blue light-induced retinal degeneration by activating M2 macrophages (Morita et al, Nutrients, 2018 Dec15;10(12):1991).
  • Lactobacillus plantarum alleviates colitis by promoting polarization from M1 macrophages to M2 macrophages (Jang et al, Int Immunopharmacol, 2014 Jul;21(1):186-92). It is known that administration of Lactobacillus brevis bacteria alleviates colitis by promoting polarization from M1 macrophages to M2 macrophages (Jang et al, J Appl Microbiol, 2013 Sep;115(3):888-96). Thus, it is known that administration of lactic acid bacteria of the order Lactobacillales, such as the genus Lactobacillus, induces and activates polarization to M2 macrophages. Therefore, the lactic acid bacteria is preferably lactic acid bacteria of the order Lactobacillales, such as the genus Lactobacillus.
  • Berberine is a benzylisoquinoline alkaloid found in plants such as Phellodendron amurense (Rutaceae) and Coptis japonica (Ranunculaceae), and has the following formula: Examples of berberine, its salts, or its derivatives include berberine chloride, berberine sulfate, berberine tannate, and the like.
  • Taurine is a substance with the structural formula H2N - CH2 - CH2 - SO3H . Taurine is also called aminoethylsulfonic acid. The IUPAC name for taurine is 2-aminoethanesulfonic acid. Taurine has the following formula: Examples of taurine, a salt thereof, or a derivative thereof include tauroursodeoxycholic acid, hypotaurine, phosphorylated tau protein, taurocholic acid (TCA), and thiotaurine (TTAU).
  • Lipoic acid is an optically active organic compound that is an essential cofactor for many enzymes, an antioxidant, and contains a carboxyl group and a cyclic disulfide.
  • the oxidized form of lipoic acid is ⁇ -lipoic acid, and the reduced form is dihydrolipoic acid.
  • Lipoic acid or a salt or derivative thereof, includes ⁇ -lipoic acid, ⁇ -lipoic acid, dihydrolipoic acid, dextrolipoic acid, lipoic acid choline ester, and (R)-(+)-(7-hydroxy-2-oxo-2H-chromen-4-yl)methyl 5-(1,2-dithiolan-3-yl)pentanoate, which is represented by the following formula:
  • a DDS may be used to deliver a substance that modulates the function of choroid-resident immune cells, such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor, to the subject's choroid.
  • a substance that modulates the function of choroid-resident immune cells such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor
  • the choroidal resident immune cell function regulator such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor
  • a DDS such as a liposome.
  • choroidal resident immune cell function regulator such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor, may be administered to a subject in the form of a protein. The administration may be performed, for example, by local administration to the choroid.
  • a choroidal resident immune cell function regulator such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor
  • Delivery of a choroidal resident immune cell function regulator, such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator release inhibitor, to the subject's choroid may be performed by transplanting into the subject cells that secrete choroidal resident immune cell function regulators, such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator, or berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • M2 macrophage polarization inducer such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator, or berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • Cells that secrete choroidal resident immune cell function regulators such as an M2 macrophage polarization inducer, a mast cell stabilizer, or a chemical mediator, or berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof, may be, for example, retinal pigment epithelial cells (RPE).
  • RPE retinal pigment epithelial cells
  • the cells may be genetically engineered to secrete M2 macrophage polarization inducers, mast cell stabilizers, chemical mediators, or other substances that regulate the function of immune cells resident in the choroid, or berberine, taurine, or lipoic acid, or salts or derivatives thereof.
  • composition for inhibiting or treating myopia (hereinafter also referred to as "composition for use in inhibiting or treating myopia")]
  • composition for use in inhibiting or treating myopia One aspect of the present disclosure relates to a composition for suppressing, improving or treating myopia using an M2 macrophage polarization inducer, a mast cell stabilizer, a choroidal resident immune cell function regulator such as a chemical mediator release inhibitor, lactic acid bacteria, berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • one aspect of the present disclosure relates to a composition for suppressing or treating myopia, comprising a therapeutically effective amount of an M2 macrophage polarization inducer, a mast cell stabilizer, a choroidal resident immune cell function regulator such as a chemical mediator release inhibitor, lactic acid bacteria, berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • a composition for suppressing or treating myopia comprising a therapeutically effective amount of an M2 macrophage polarization inducer, a mast cell stabilizer, a choroidal resident immune cell function regulator such as a chemical mediator release inhibitor, lactic acid bacteria, berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof.
  • Such compositions can be used to deliver M2 macrophage polarization inducers, mast cell stabilizers, choroidal resident immune cell function regulators such as chemical mediator release inhibitors, lactic acid bacteria, berberine, taurine, or lipoic acid, or salt
  • the pharmaceutical composition according to the present disclosure is administered, for example, locally to the eye.
  • the administration form of the composition include eye drops (including application of eye ointment and eye washing), subconjunctival administration, intraconjunctival sac administration, sub-Tenon administration, etc.
  • the dosage form of the composition is not particularly limited, but examples include eye drops, eye ointments, injections, patches, gels, and inserts, with eye drops being preferred. These can be prepared using conventional techniques commonly used in the field.
  • Ophthalmic solutions can be prepared using isotonic agents such as sodium chloride, potassium chloride, and concentrated glycerin; buffering agents such as sodium phosphate, sodium acetate, and epsilon-aminocaproic acid; surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; and preservatives such as parabens, as required.
  • the pH should be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4 to 8. Eye ointments can be prepared using commonly used bases such as white petrolatum and liquid paraffin.
  • the pharmaceutical composition according to the present disclosure is not limited to administration to the eye, but can be administered by any administration route such as enteral administration (oral, tube feeding, infusion, etc.), parenteral administration (intravenous, intraarterial, transdermal, intramuscular injection, etc.) etc.
  • the dosage form of the composition used for these administration forms can be appropriately selected, and can be, for example, a solid preparation such as a tablet, granule, powder, capsule, chewable agent, or a liquid preparation such as a liquid, syrup, injection, drip, etc.
  • the pharmaceutical composition according to the present disclosure may contain other ingredients in appropriate amounts within the scope of not impairing the effects of the present invention.
  • ingredients include any carrier, buffer, diluent, excipient, suspending agent, lubricant, adjuvant, medium, delivery system, emulsifier, tablet disintegrant, absorbent, preservative, surfactant, colorant, flavoring, or sweetener. These ingredients may be used alone or in appropriate combination of two or more.
  • the content of M2 macrophage polarization inducers, mast cell stabilizers, choroidal resident immune cell function regulators such as chemical mediator release inhibitors, lactic acid bacteria, berberine, taurine, or lipoic acid, or salts or derivatives thereof in 100% by weight of the pharmaceutical composition can be appropriately set within the range of, for example, 0.001 to 99.99% by weight.
  • the dosage of the pharmaceutical composition according to the present disclosure is not particularly limited and can be appropriately selected depending on the dosage form, age, weight, and desired degree of effect of the subject.
  • the dosage of M2 macrophage polarization inducers, mast cell stabilizers, choroid-resident immune cell function regulators such as chemical mediator release inhibitors, lactic acid bacteria, berberine, taurine, or lipoic acid, or salts thereof, or derivatives thereof can be, for example, 100 to 1,000,000 nmol, preferably 150 to 100,000 nmol, per day, and the frequency of administration can be, for example, 1 to 100 times per month.
  • the composition for use in the suppression or treatment of myopia preferably contains an M2 macrophage polarization inducer and/or a mast cell stabilizer, and more preferably contains an M2 macrophage polarization inducer and a mast cell stabilizer.
  • an M2 macrophage polarization inducer and a mast cell stabilizer a single component that functions as both an M2 macrophage polarization inducer and a mast cell stabilizer may be combined, or different components may be combined.
  • the content of berberine, or a salt thereof, or a derivative thereof in the above composition is preferably 0.005-0.025 (w/v)%, more preferably 0.012-0.025 (w/v)%, and even more preferably 0.025 (w/v)%, from the viewpoint of more effectively suppressing or treating myopia.
  • the content of azulene, its derivative, or a salt of said derivative in 100 (w/v)% of the composition is preferably 0.04-0.02 (w/v)%, more preferably 0.01-0.02 (w/v)%, and even more preferably 0.02 (w/v)%, from the viewpoint of more effectively suppressing or treating myopia.
  • the content of taurine, or a salt thereof, or a derivative thereof in the above composition is preferably 0.1-1 (w/v)%, more preferably 0.5-1 (w/v)%, and even more preferably 1 (w/v)%, from the viewpoint of more effectively suppressing or treating myopia.
  • the content of cromoglycic acid, its derivative, or its salt in the above composition is preferably 1-2 (w/v)% from the viewpoint of more effectively suppressing or treating myopia.
  • the content of tranilast, its salt, or its derivative as a mast cell stabilizer is preferably 0.25-0.5 (w/v)% from the viewpoint of more effectively suppressing or treating myopia.
  • the content of pyridoxine, its salt, or its derivative in the above composition is preferably 0.01-0.1 (w/v)% from the viewpoint of more effectively suppressing or treating myopia.
  • the content of tocopherol, its derivative, or its salt in the above composition is preferably 0.005 to 0.05 (w/v)% from the viewpoint of more effectively suppressing or treating myopia.
  • the content of retinol, its derivative, or its salt in 100 (w/v)% of the composition is preferably 10,000 to 50,000 I.U./100mL from the viewpoint of more effectively suppressing or treating myopia.
  • the composition according to the present disclosure contains an M2 macrophage polarization inducer and/or a mast cell stabilizer
  • the composition is preferably in the form of eye drops.
  • the eye drop is preferably administered at least once a day, and more preferably 1 to 6 times a day.
  • the composition according to the present disclosure is an eye drop containing an M2 macrophage polarization inducer and/or a mast cell stabilizer, from the viewpoint of more effectively suppressing or treating myopia, it is preferable that the eye drop be administered at one or more drops at a time, and more preferably at one to three drops at a time.
  • composition according to the present disclosure is an eye drop containing an M2 macrophage polarization inducer and/or a mast cell stabilizer, it is preferable to administer it for three weeks or more in order to more effectively suppress or treat myopia.
  • composition disclosed herein is preferably administered during the period of normal axial length elongation that occurs with growth.
  • composition disclosed herein is preferably for use in children, from the viewpoint of more effectively suppressing or treating myopia.
  • children refers to children under the age of 15. In children, normal axial length elongation usually occurs as a result of growth.
  • the composition according to the present disclosure may be a food or a supplement.
  • the form of the food or supplement may be, for example, liquid, solid, tablet, granule, powder, capsule, paste, gel, or the like, and may be any of the above solid or liquid preparations.
  • Specific examples of foods include various general processed foods such as fruit juice drinks, vegetable juice, soft drinks, tea, soups, puddings, yogurt, cake premix products, confectioneries, cookies, candies, gummies, and chewing gum, as well as special purpose foods, foods for specified health uses, functional foods, functional foods, nutritional supplements, health supplements, nutritionally enhanced foods, nutritionally adjusted foods, and the like, such as supplements and drinks.
  • the food or supplement disclosed herein may contain any functional ingredients (vitamins, minerals, etc.), any excipients, any additives (flavoring agents, sweeteners, acidulants, colorants, thickeners, binders, strengthening agents, disintegrants, buffers, surfactants, solubilizers, resorption promoters, dispersants, stabilizers, gelling agents, emulsifiers, antioxidants, surfactants, preservatives, moisture-proofing agents, pH adjusters, colorants, soothing agents, isotonic agents, etc.).
  • any additives flavoring agents, sweeteners, acidulants, colorants, thickeners, binders, strengthening agents, disintegrants, buffers, surfactants, solubilizers, resorption promoters, dispersants, stabilizers, gelling agents, emulsifiers, antioxidants, surfactants, preservatives, moisture-proofing agents, pH adjusters, colorants, soothing agents, isotonic agents, etc.
  • One aspect of the present disclosure relates to the use of an M2 macrophage polarization inducer, a mast cell stabilizer, a choroidal resident immune cell function regulator such as a chemical mediator release inhibitor, lactic acid bacteria, berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof, for suppressing or treating myopia. Furthermore, another aspect of the present disclosure relates to the use of an M2 macrophage polarization inducer, a mast cell stabilizer, a choroidal resident immune cell function regulator such as a chemical mediator release inhibitor, lactic acid bacteria, berberine, taurine, or lipoic acid, or a salt thereof, or a derivative thereof, in the manufacture of a medicament for suppressing or treating myopia.
  • Screening method One aspect of the present disclosure relates to a screening method for searching for a component that promotes polarization of macrophages into M2 macrophages in order to control choroidal thinning, which is a mechanism for the development of myopia, and a screening method for searching for a component that is effective in the prevention and treatment of myopia.
  • the screening method includes (i) administering a candidate substance to a model animal, and (ii) measuring the axial length, choroidal thickness, and refractive index of the model animal.
  • the screening method includes (i) administering a candidate substance to a model animal, and (ii) measuring the expression of a choroidal resident immune cell marker, such as an M2 macrophage marker, in a sample derived from the model animal. In some embodiments, the screening method further includes (iii) measuring the expression of a choroidal resident immune cell marker, such as an M1 macrophage marker.
  • choroid-resident immune cells such as mouse peritoneal macrophages and bone marrow-derived macrophages
  • the model animal can be an animal undergoing a myopia-inducing procedure.
  • the choroidal resident immune cell marker such as the M2 macrophage marker
  • the choroidal resident immune cell marker may be CD163, CD206, arginase, or IL-10.
  • Methods for measuring choroidal resident immune cell markers, such as macrophage markers include quantitative PCR, flow cytometry, immunostaining, luciferase assay, arginase activity staining, and the like.
  • Substances identified by such screening methods can be used to prevent or treat myopia.
  • mice The Ethics Committee for Animal Research at Keio University School of Medicine approved all procedures, which followed the Association for Research in Vision and Ophthalmology statement on the use of animals in ophthalmic and vision research, the Keio University Institutional Guidelines for Animal Experimentation, and the Reporting of Animal Experiments: In Vivo Experiments (ARRIVE) guidelines. Furthermore, the principle of random allocation was implemented in this study. Wild-type male C57BL/6J mice were provided by CLEA Japan Co., Ltd.
  • mice were housed in standard transparent mouse cages (29 ⁇ 18 ⁇ 13 cm), four or five per cage, in a pathogen-free environment maintained at 23 ⁇ 3 °C, under background fluorescent lighting of approximately 50 lux (color temperature: 5000 K), with a diurnal cycle of 12 h, and with regular chow (MF, Oriental Yeast Co., Ltd., Tokyo, Japan) and tap water available at all times. All animals were randomly assigned.
  • mice were placed under general anesthesia using a mixture of midazolam (Sandoz KK, Tokyo, Japan), medetomidine (Domitor®, Orion Corporation, Espoo, Finland), and butorphanol tartrate (MMB) (Meiji Seika Pharma Co., Ltd., Tokyo, Japan). Eyeglass frames were designed to fit the contours of the mouse head and printed with a 3D printer. For myopia induction, a negative 30D lens was constructed using polymethyl methacrylate (PMMA).
  • PMMA polymethyl methacrylate
  • the left and right eyes of the glasses were screwed onto a stick, a joint that was adjusted to the shape of the frame on the mouse skull and could be removed for repositioning the left and right frames or for cleaning.
  • the stick was subsequently glued to the mouse skull using a self-curing dental adhesive system. Induction began once the mice had fully recovered from anesthesia, and the lenses were removed for cleaning at least twice weekly.
  • mice were treated with mydriatic eye drops containing 0.5% tropicamide and 0.5% phenylephrine (Santen Pharmaceutical Co., Ltd., Osaka, Japan) to ensure pupil dilation and cycloplegia. After pupil dilation, mice were subjected to general anesthesia using MMB. It is important to prevent the occurrence of corneal damage during the measurements. Axial length was measured as the perpendicular distance from the anterior corneal surface to the retinal pigment epithelium layer near the optic nerve [Jiang, X. et al. A highly efficient murine model of experimental myopia. Scientific reports 8, 1-12 (2018)].
  • Choroidal thickness was determined by quantifying the circular area of the disc at the posterior surface of the choroid using ImageJ software [Dysli, C., Enzmann, V., Sznitman, R. & Zinkernagel, M. S. Quantitative analysis of mouse retinal layers using automated segmentation of spectral domain optical coherence tomography images. Translational vision science & technology 4, 9-9 (2015)].
  • Choroidal blood perfusion was measured at the beginning (3 weeks after birth) and end (6 weeks after birth) stages of myopia induction using a SS-OCT/OCTA device (XEPHILIO OCT-S1, Canon Medical Systems, Tokyo, Japan). The measurement method was described in a previous report [Hou, J. et al. Ginkgo biloba extracts improve choroidal circulation leading to suppression of myopia in mice. Scientific Reports 13, 3772 (2023)]. Briefly, mice were dilated under general anesthesia before measurement, as in the case of refraction measurement. Choroidal blood perfusion was measured using en face angiography to identify the optic nerve as the central region.
  • Choroidal blood perfusion signals were obtained from B-scan images at the corresponding positions. In the B-scan images, the areas covered by red noise points were areas without blood perfusion. ImageJ quantitative analysis was used to calculate the non-blood perfused area in the choroid and evaluate the percentage of the area with blood perfusion in the choroid.
  • Flow cytometry Mice were administered an overdose of MMB to induce deep anesthesia before being euthanized by cervical dislocation. Eyes were immediately enucleated, and the anterior segment, vitreous, and retina were discarded. Choroidal tissues were carefully scraped off from the sclera-choroid complex and collected in tubes (10 choroidal tissues/tube), then treated with digestion buffer (0.75 mg/ml collagenase A, Fujifilm, Tokyo, Japan) in complete Dulbecco's Modified Eagle Medium (DMEM) solution at 37°C for 45 min.
  • DMEM Dulbecco's Modified Eagle Medium
  • the digested choroidal mixture was transferred onto a cell strainer, and 5 ml of cold complete DMEM was added to pass the cells into a new 50 ml tube under the strainer, while the undigested choroidal pieces were crushed using the end of a syringe plunger.
  • the aggregated choroidal cells were dissociated into a single cell suspension by differential centrifugation.
  • the cells were washed by adding 700 ⁇ l of flow cytometry staining (FACS) buffer (80 ⁇ l of 0.5 mol/L ethylenediaminetetraacetic acid (EDTA) and 0.1 g of bovine serum albumin (BSA) in 20 ml of PBS (pH 7.4) solution) to the cell suspension.
  • FACS flow cytometry staining
  • Fc-block solution (1:10 Fc-block) (BD Biosciences, NJ, USA) for 10 min and stained with a mixture of fluorochrome-conjugated antibodies (1:200 FITC anti-mouse/human CD11b M1/70, BioLegend, CA, USA) (1:200 APC/Cyanine7 anti-mouse F4/80, BioLegend, CA, USA), (1:200 CD206, AbD Serotec, Kidlington, near Oxford, UK) for at least 45 min and finally covered with 0.1 mg/ml Hoechst (DOJINDO, Amsterdam, Netherlands) for 10 min. All incubations were performed on ice and protected from light. Data were acquired on a CytoFLEX S flow cytometer using CytExpert software (Beckman Coulter Life Sciences, Inc., IN, USA) and offline data analysis was performed using CyExpert software.
  • Clodronate Liposome Treatment Clodronate liposomes (Liposoma BV, Amsterdam, The Netherlands) were injected intraperitoneally at a dose of 0.10 ml/10 g (once every 2 days) into C57BL/6J mice from P21 to P28 or from P56 to P63. Control groups were injected with an equal volume of PBS liposomes as above. Refraction, axial length, and choroidal thickness were measured before and after the four injections. Mice were then euthanized and choroidal samples were collected.
  • LPS treatment Lipopolysaccharide from Escherichia coli O111:B4 (Merck, Tokyo, Japan) was dissolved in PBS and injected intraperitoneally to induce systemic M1 macrophage polarization.
  • concentration of LPS was 10 mg/ml, and the injection dose was increased proportionally to the mouse body weight, giving 10 ⁇ g of LPS per gram of mouse. Because LPS injections caused a significant decrease in mouse body weight, the body weight of the mice was monitored and recorded before each injection. In addition, a corresponding volume of PBS was injected intraperitoneally as a vehicle control.
  • EPA-supplemented diet containing 5% EPA EPADEL®, Mochida Pharmaceutical Co., Ltd., Tokyo, Japan
  • normal diet 5% EPA
  • EPADEL® Mochida Pharmaceutical Co., Ltd., Tokyo, Japan
  • normal diet normal diet
  • EPA ethyl ester was mixed with powdered normal diet and tap water was added. The mixture was formed into small cylindrical shapes, dried and consumed. Feeding with the EPA-mixed diet began with the induction of myopia and ended with the induction of myopia.
  • IL-4/IL-13 treatment To induce systemic M2 macrophage polarization, recombinant mouse IL-4 (214-14) and IL-13 (210-13) (PeproTech, New Jersey, USA) were dissolved in PBS at the same concentration of 0.1 ⁇ g/100 ⁇ l and injected intraperitoneally into mice once every 2 days. The control group received the same volume of PBS intraperitoneally. Injections were administered during the induction of myopia. Body weight was measured and recorded before each injection to ensure that the mice were growing normally.
  • Berberine chloride eye drops Berberine chloride hydrate (TCI, Tokyo, Japan) solution was freshly prepared in DMSO. The concentration of berberine chloride eye drops was measured and found to be insoluble in water at room temperature. Dissolution was attempted using 100% DMSO and found to be approximately 13mg/ml in 100% DMSO at room temperature. Currently, the concentration of berberine chloride eye drops is 0.26mg/ml. In addition, DMSO, a dissolution vector, has been reported to exert cytotoxic effects at certain concentrations. Therefore, to check for solvent toxicity, an untreated control group should be included along with the DMSO solvent control [Galvao, J. et al. Unexpected low ⁇ dose toxicity of the universal solvent DMSO.
  • qPCR Real-time quantitative PCR
  • RNA samples were dissolved in RNase-free water (TAKARA HOLDINGS Inc., Kyoto, Japan, 9012) and measured with a spectrophotometer (NanoDrop; Thermo Fisher Scientific, Waltham, MA, USA).
  • the extracted RNA was converted to cDNA via RNA denaturation, DNase reaction, and reverse transcription according to the manufacturer's instructions.
  • mRNA gene expression was determined using SYBR Green RT-PCR on cDNA templates, and PCR was performed using a StepOnePlus real-time PCR system (Applied Biosystems, Waltham, MA, USA).
  • 8-OHdG ELISA To evaluate oxidative stress, the levels of 8-oxo-2'-deoxyguanosine (8-OHdG) in choroidal tissues were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions (Uscn Life Science, Wuhan, China). Because this assay uses a competitive inhibition enzyme immunoassay technique, the concentration of 8-OHdG in the samples and the assay signal intensity were inversely correlated. The concentration of 8-OHdG in each sample was calculated using a standard curve generated from standard proteins and was calculated and analyzed using Boster's ELISA Online Calculator.
  • ELISA enzyme-linked immunosorbent assay
  • Example 1 Chronic intraperitoneal injection of clodronate liposomes may deplete choroidal macrophages and induce myopia: It has previously been reported that choroid-resident macrophages positively influence choroidal thickness and maintain vascular integrity [Yang, X. et al. CSF1R blockade induces macrophage ablation and results in mouse choroidal vascular atrophy and RPE disorganization. Elife 9, e55564 (2020)]. In contrast, a series of animal models have demonstrated that choroidal thinning is an inevitable change in the development of experimental myopia and a prominent feature in the development of myopia [Liu, Y., Wang, L., Xu, Y., Pang, Z. & Mu, G.
  • the clodronate liposomes In the clodronate liposome group, after being taken up by macrophages, the clodronate liposomes were degraded by lysosomal phospholipase, releasing clodronate into macrophages to induce apoptosis, thereby promoting macrophage depletion [Weisser, S. B., van Rooijen, N. & Sly, L. M. Depletion and reconstitution of macrophages in mice. JoVE (Journal of Visualized Experiments), e4105 (2012)].
  • the injection volume of clodronate liposomes was 0.1 ml per 10 g of mouse, and the injection frequency was once every two days.
  • the change in axial length was expressed using the ratio of axial length to body weight.
  • the clodronate liposome-injected group showed a larger refractive shift (-7.52 ⁇ 2.57D vs. +1.52 ⁇ 4.91D, P ⁇ 0.01), a larger axial length/weight (0.168 ⁇ 0.015mm/g vs. 0.155 ⁇ 0.002mm/g, P ⁇ 0.05), and a thinner choroid (-2.39 ⁇ 1.33mm vs.
  • Example 2 Continuous intraperitoneal injections of LPS stimulate polarization of choroidal M1 macrophages and induce myopia in a mouse model: Based on their activation status and function, macrophages are classified into two categories, M1 type (classically activated macrophages) and M2 type (alternatively activated macrophages), which exhibit pro-inflammatory and anti-inflammatory properties, respectively [Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature reviews immunology 8, 958-969 (2008)]. Because upregulation of allergic inflammation is related to the progression of myopia in animal models [Wei, C.-C. et al. Allergic conjunctivitis-induced retinal inflammation promotes myopia progression.
  • mice were divided into LPS (10 mg/ml)-injected and PBS-injected groups for daily intraperitoneal injection. To determine whether myopia had progressed, refraction, axial length, and choroidal thickness were measured using SD-OCT before injection, 1 week after injection, and 2 weeks after injection (Figure 2A).
  • LPS-injected mice showed refractive changes (-9.21 ⁇ 5.91D vs. +2.91 ⁇ 3.91D, P ⁇ 0.001), increased axial length/weight (0.28 ⁇ 0.01mm/g vs.
  • mice injected with LPS maintained a significantly greater refractive change (-7.23 ⁇ 4.36D vs. +8.41 ⁇ 7.01D, P ⁇ 0.001), an increased ratio of axial length to mouse weight (0.20 ⁇ 0.005mm/g vs. 0.17 ⁇ 0.004mm/g, P ⁇ 0.01), and choroidal thinning (-1.77 ⁇ 1.02mm vs.
  • the expression levels of the proinflammatory cytokines Tnf and Il6 were significantly upregulated in LPS-injected choroidal samples compared with PBS-injected choroidal samples (Fig. 2D). These data indicate that intraperitoneal injection of LPS polarizes choroidal M1 macrophages, promotes the release of inflammatory cytokines, and induces myopia in mouse models. As reported in LPS-treated macrophages, the secretion of proinflammatory cytokines (TNFA and IL6) was significantly attenuated by eicosapentaenoic acid (EPA), which inhibits myopia progression [Mullen, A., Loscher, C. E. & Roche, H. M.
  • EPA eicosapentaenoic acid
  • Example 3 Continuous intraperitoneal injection of IL-4/IL-13 promoted polarization of choroidal M2 macrophages and inhibited myopia progression in a mouse model of LIM: We found that intraperitoneal injection of LPS enhanced the expression of proinflammatory cytokines in the choroid and promoted myopia progression. Conversely, polarization of choroidal M2 macrophages should suppress myopia progression.
  • Previous studies have demonstrated that IL-4 and IL-13, as anti-inflammatory interleukins, can directly activate M2 macrophages, which can be identified by the expression of M2 macrophage markers such as CD206 and mannose receptor 1 (Mrc1), also known as CD163 [Yao, Y., Xu, X.-H. & Jin, L.
  • mice were divided into three groups: control 0D group (both eyes treated with 0D lenses), control -30D group (bilateral myopia induction), and IL-4-30D group (bilateral myopia induction by IL-4 injection once every 2 days).
  • control 0D group both eyes treated with 0D lenses
  • control -30D group bilateral myopia induction
  • IL-4-30D group bilateral myopia induction by IL-4 injection once every 2 days.
  • OCTA we measured choroidal blood perfusion at the beginning (3 weeks of age) and end (6 weeks of age) of myopia induction. The results showed that 3 weeks after myopia induction, choroidal blood perfusion was lower in the IL4-30D group compared with the control 0D group (8.59 ⁇ 5.90% area vs. -6.29 ⁇ 8.73% area, P ⁇ 0.01).
  • Example 4 Berberine eye drops polarize M2 macrophages and inhibit myopia progression with chronic use: Realizing that M2 macrophage polarization may suppress myopia progression, we used an M2 macrophage activator as an eye drop to examine its effect on myopia progression.
  • M2 macrophage activator as an eye drop to examine its effect on myopia progression.
  • Berberine promotes M1 proinflammatory phenotype to M2 anti-inflammatory phenotype polarization in macrophage cell line RAW264. 7. Basic & Clinical Medicine 39, 646 (2019)].
  • berberine eye drops we examined and compared the changes in refraction, axial length, and choroidal thickness after 3 weeks of myopia induction and administration of either berberine or dimethyl sulfoxide (DMSO) eye drops in 3-week-old C57BL/6J mice.
  • the control-30D group wearing -30D lenses in both eyes
  • the 2% DMSO-30D group inducing bilateral myopia by daily application of 2% DMSO eye drops
  • showed greater refractive changes P ⁇ 0.001
  • increased axial length elongation P ⁇ 0.05
  • decreased choroidal thickness P ⁇ 0.001 compared with the control 0D group (wearing 0D lenses in both eyes).
  • the berberine-30D group (bilateral myopia induced by daily 0.26 mg/ml eye drops) had smaller refractive index changes (2.12 ⁇ 1.63 D vs. -5.25 ⁇ 2.89 D, P ⁇ 0.001), smaller axial elongation (0.19 ⁇ 0.02 mm vs. 0.22 ⁇ 0.04 mm/g, P ⁇ 0.05), and a relatively thicker choroid (0.79 ⁇ 0.64 mm vs. -1.56 ⁇ 0.76 mm, P ⁇ 0.001) compared with the 2% DMSO-30D group.
  • Example 5 Effects of LPS and IL-4 injection on Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidation Activity: We speculated that the direction of macrophage polarization may affect the development or suppression of myopia through its pro- or anti-inflammatory properties. However, other mechanisms underlying this association remain largely unknown. LPS-treated M1 macrophages are associated with high levels of reactive oxygen and nitrogen species (ROS and RNS, respectively) and matrix metalloproteinase (MMP) activity, and ROS production is important for M1 macrophage activation and function [Virag, L., Jaen, R. I., Regdon, Z., Bosca, L. & Prieto, P.
  • ROS reactive oxygen and nitrogen species
  • MMP matrix metalloproteinase
  • Example 6 Choroidal thinning and myopia caused by LPS administration To confirm whether polarization into M1 macrophages is involved in choroidal thinning and myopia, we measured the expression of polarization marker genes in the choroid after LPS administration and the choroidal thickness, axial length, and refractive index.
  • LPS solution was administered intraperitoneally every day at a dose of 10 mg/kg BW.
  • PBS was administered instead of the LPS solution.
  • the LPS-administered group showed a decrease in refraction (Fig. 8B, left), axial elongation (Fig. 8B, center), and choroidal thinning (Fig. 8B, right) in both the 1-week and 2-week administration periods.
  • Example 7 Polarization into M2 macrophages and myopia suppression effect by administration of IL-4 and IL-13 M1 macrophages are primarily involved in the initiation of inflammation, while M2 macrophages have antagonistic functions, such as being involved in the termination and suppression of inflammation. Since M1 macrophages have a myopia-inducing effect, it is thought that M2 macrophages have an inhibitory effect on myopia and its progression. Therefore, we administered IL-4, a cytokine required for polarization into M2 macrophages, to mice and examined whether polarization into M2 occurred in the choroid by analyzing the expression levels of M2 macrophage markers CD163 and CD206 ( Figures 10A and 10B).
  • mice undergoing myopia induction were intraperitoneally administered IL-4 solution at 0.1 ⁇ g/100 ⁇ l (10 ⁇ g/kg BW) for 3 weeks.
  • refraction, axial elongation, and choroidal thinning were measured in the same manner as in Example 6.
  • IL-4 increased the expression of M2 markers CD163 and CD206 in the choroid (Fig. 10B, C), confirming polarization to M2 macrophages. Furthermore, gene expression analysis revealed increased expression of M2 macrophage marker genes and suppressed expression of oxidative stress-related genes (Fig. 12). These results suggest that administration of IL-4 induces polarization to M2 macrophages, suppresses expression of oxidative stress-related genes, and inhibits the progression of myopia (Fig. 12).
  • IL-4 administered during the myopia induction period was confirmed to suppress the decrease in refraction (Fig. 12B, left), the elongation of the eye axis (Fig. 12B, center), and the thinning of the choroid (Fig. 12B, right).
  • IL-13 is a cytokine known to polarize macrophages to M2, similar to IL-4.
  • IL-13 is a cytokine known to polarize macrophages to M2, similar to IL-4.
  • the number of macrophages was measured by staining the choroid with F4/80 and CD11b antibodies after digestion and counting them with a flow cytometer (CytoFLEX S, Beckman Coulter). The number of M2 macrophages was measured in the same manner as for the measurement of macrophage number, except that a staining process with CD206 antibody was added.
  • Example 8 Suppression of myopia by instilling mast cell stabilizer
  • a lens-induced myopia model was used in which myopia was induced in mice by having them wear minus lenses, and cromoglycate solution (4% solution) or pemirolast potassium (0.1% solution) was administered as an instillation once daily during the myopia induction period.
  • Example 9 Comparison of myopia suppression effects between mast cell stabilizer eye drops and histamine receptor inhibitor eye drops
  • Antiallergic drugs are broadly divided into two types: mast cell stabilizers that inhibit the degranulation of mast cells, and histamine receptor inhibitors that inhibit the action of histamine secreted by the degranulation of mast cells.
  • mast cell stabilizers that inhibit the degranulation of mast cells
  • histamine receptor inhibitors that inhibit the action of histamine secreted by the degranulation of mast cells.
  • pemirolast potassium (0.1% solution) as a mast cell stabilizer
  • levocabastine solution 0.025% solution
  • the results were the same as in Example 8, and the pemirolast potassium group did not show the axial elongation, myopic refractive error, and choroidal thinning seen in the control group.
  • the levocabastine group showed axial elongation, myopic refractive error, and choroidal thinning, similar to the control group.
  • mast cell stabilizer among other anti-allergy drugs, is effective in suppressing myopia.
  • Example 10 Inhibition of myopia progression by administration of Lactobacillus paracasei Since induction of M2 macrophages can suppress the progression of myopia, Lactobacillus paracasei, a lactic acid bacterium contained in Yakult (Yakult Honsha Co., Ltd.), was cultured and grown and administered to myopic model mice, and the axial length, refractive index, and choroidal thickness were measured and the amount of change calculated as in Examples 8 to 9 ( Figure 16). As a result, it was confirmed that administration of lactic acid bacteria suppresses the progression of myopia ( Figure 16).
  • Example 11 Three times daily administration of berberine chloride significantly inhibited the progression of myopia: The effect of the number of administrations per day on the inhibitory effect of berberine on the progression of myopia was examined. Eye drops with the formulations shown in Table 2 below were prepared. A LIM mouse model was created from 3-week-old mice by the method described in the above "LIM mouse model:". However, a negative 30D lens was constructed in the right eye (-30D group), and no lens was constructed in the left eye (0D group). As shown in Figure 17A, the above LIM mouse model was administered placebo eye drops A (Control) once a day, or eye drops 1 once a day or three times a day (10:00, 14:00, and 18:00) until 6 weeks of age.
  • Example 12 Berberine chloride, sodium azulene sulfonate, or taurine inhibited the progression of myopia:
  • Eye drops containing 0.025 (w/v)% berberine chloride, 0.02 (w/v)% sodium azulene sulfonate, or 1 (w/v)% taurine could inhibit the progression of myopia.
  • Eye drops with the formulations shown in Table 3 below were prepared.
  • LIM mouse models were created from 3-week-old mice by the method described in the above "LIM mouse model:”. However, a negative 30D lens was constructed in the right eye (-30D group), and no lens was constructed in the left eye (0D group).
  • placebo eye drops B (Control) and eye drops 2 to 4 were administered once a day to the LIM mouse models until they were 6 weeks old. Thereafter, the refraction, axial length, and choroidal thickness of the -30D and 0D groups at 3 weeks of age before administration of the eye drops and at 6 weeks of age after administration of the eye drops were measured according to the above-mentioned "Measurement of refraction, axial length, and choroidal thickness:".
  • Example 13 The combination of berberine chloride and sodium azulene sulfonate significantly inhibited the progression of myopia:
  • Eye drops with the formulation shown in Table 4 below were prepared.
  • LIM mouse models were created from 3-week-old mice by the method described in the above "LIM mouse model:”. However, a negative 30D lens was constructed in the right eye (-30D group), and no lens was constructed in the left eye (0D group).
  • placebo eye drops C Control
  • eye drops 5 to 7 were administered once a day to the LIM mouse models until 6 weeks of age.
  • the refraction value, axial length, and choroidal thickness were measured in the -30D group and 0D group at 3 weeks of age before administration of various eye drops, and at 6 weeks of age after the end of administration of various eye drops, based on the above "Measurement of refraction, axial length, and choroidal thickness:".
  • the changes in refractive index, axial length, and choroidal thickness from 3 weeks of age before administration of each eye drop to 6 weeks of age after administration of each eye drop (Change in refraction, Change in AL, and Change in ChK, respectively) are shown in Figures 19B to D.
  • "*", "**”, “***”, and “****” indicate P values of P ⁇ 0.05, P ⁇ 0.01, P ⁇ 0.001, and P ⁇ 0.0001, respectively, in statistical analysis using a combination of one-way ANOVA and least significant difference (LSD).
  • Example 14 The combination of berberine chloride and sodium azulene sulfonate, the combination of berberine chloride and taurine, and the combination of berberine chloride, sodium azulene sulfonate, and taurine significantly inhibited the progression of myopia: We examined whether eye drops containing 0.012 (w/v)% berberine chloride and 0.01 (w/v)% sodium azulene sulfonate, eye drops containing 0.012 (w/v)% berberine chloride and 0.5 (w/v)% taurine, and eye drops containing 0.012 (w/v)% berberine chloride, 0.01 (w/v)% sodium azulene sulfonate and 0.5 (w/v)% taurine suppress the progression of myopia.
  • Eye drops with the formulations shown in Table 5 below were prepared.
  • a LIM mouse model was created from 3-week-old mice by the method described in "LIM Mouse Model:” above. However, a negative 30D lens was constructed in the right eye (-30D group), and no lens was constructed in the left eye (0D group).
  • the above LIM mouse model was administered placebo eye drops D (Control) and eye drops 8 to 10 once a day until 6 weeks of age. After that, the refraction and axial length of the -30D and 0D groups were measured according to the above "Measurements of refraction, axial length, and choroidal thickness:" at 3 weeks of age before administration of each eye drop and at 6 weeks of age after completion of administration of each eye drop.
  • the decrease in refractive value was suppressed in the following order: berberine chloride and azulene (eye drops 8), berberine chloride and taurine (eye drops 9), and berberine chloride, azulene, and taurine (eye drops 10).
  • the decrease was most suppressed when the three components berberine chloride, azulene, and taurine (eye drops 10) were administered, and myopia was almost completely eliminated.

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Abstract

Le but de la présente invention est de fournir un procédé de prévention ou de traitement de la myopie, et une composition qui est utilisée dans celui-ci. La présente invention concerne un procédé et une composition qui sont destinés à inhiber, réduire ou traiter la myopie par administration de berbérine, de taurine, d'acide lipoïque, d'un sel de l'un quelconque de ceux-ci, ou d'un dérivé de l'un quelconque de ceux-ci.
PCT/JP2024/038132 2023-10-25 2024-10-25 Procédé et composition pour prévenir ou traiter la myopie Pending WO2025089394A1 (fr)

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