WO2022123836A1 - 小児の近視進行抑制用点眼剤及び小児の近視進行抑制剤のスクリーニング方法 - Google Patents
小児の近視進行抑制用点眼剤及び小児の近視進行抑制剤のスクリーニング方法 Download PDFInfo
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Definitions
- the present invention relates to an eye drop used for suppressing the progression of myopia in children and a screening method for an agent for suppressing the progression of myopia in children. More specifically, the present invention "normalizes" the normal eye growth of a child ("normal eye growth of a child” by suppressing ATF6 and / or PERK, which are the causative genes of the progression of myopia in a child.
- Non-Patent Document 1 The latest research on myopia and severe myopia predicts a significant increase in the world's myopia population, with about 5 billion myopia and about 1 billion severe myopia in 2050. (See Non-Patent Document 1).
- the human eye has hyperopia immediately after birth, and the degree of hyperopia decreases due to the extension of the optical axis due to the extension of the optical axis in the anterior-posterior direction during the growth period (up to 8 years old). By becoming, it becomes hypermetropic. This is called “physiological axis extension", and if this physiological axis extension is impaired for some reason, hyperopia remains due to insufficient eye axis extension, and the QOL (Quality of Life) of children is significantly deteriorated. ..
- the present inventors have involved the degree of involvement of the signal transduction system (pathway) of endoplasmic reticulum stress response genes (PERK, ATF6, IRE1) in pathological axial elongation, and the contribution rate to the suppression of axial elongation by suppressing each pathway. , Or a synergistic effect when suppressed in combination was examined. As a result, it was found that the effect of suppressing pathological axial elongation is enhanced by suppressing the PERK pathway and / or the ATF6 pathway.
- PERK endoplasmic reticulum stress response genes
- An object of the present invention is to provide a screening method for searching for a component that suppresses the PERK pathway and / or the ATF6 pathway. Another object of the present invention is to obtain an active ingredient that suppresses the progression of myopia without inhibiting the normal growth (emmetropia) of a child's eyeball by the screening method, and to provide an eye drop containing the active ingredient.
- various components considered to be effective for myopia are the components safe for children with pathological axial elongation and physiological axial elongation at the same time, that is, for hyperopia due to insufficient elongation or myopia due to excessive elongation? It is to provide a way to verify that it does not happen.
- the present invention [1] An eye drop for suppressing the progression of myopia in children, which comprises an inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient.
- PERK PSR-like endoplasmic reticulum kinase
- ATF6 Activating transcription factor 6
- a method for screening a pediatric myopia progression inhibitor including.
- the present invention it is possible to provide a screening method for searching for a component that suppresses the signal transduction system of PERK and / or ATF6.
- a screening method for searching for a component that suppresses the signal transduction system of PERK and / or ATF6.
- FIG. 1 It is explanatory drawing of the myopia induction in a young mouse.
- A is a schematic structural diagram of myopia induction
- (b) is a photograph of a myopia-induced juvenile mouse. It is a graph which shows that myopia induction induces axial elongation and endoplasmic reticulum stress in the sclera.
- FIG. 3 is a graph showing changes in axial elongation and refraction (myopia) due to instillation of various inhibitors of the PERK pathway, ATF6 pathway, and IRE1 pathway to mice.
- STF STF080310
- GSK GSK2656157
- NFV Nerphinavir
- Is. It is a graph which shows the change (myopia) of the axial extension and refraction by instillation of various inhibitors of the PERK pathway, the ATF6 pathway, and the IRE1 pathway to a mouse in the inhibitor different from FIG.
- 3 is a graph evaluating the involvement of the ATF6 pathway in suppressing the progression of myopia in children in Test Example 4. It is a graph which showed the influence by the difference of the administration form on the lens thickening by myopia induction in Test Example 5.
- the eye drop for suppressing the progression of myopia in children contains an inhibitor of the PERK (PKR-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient.
- PERK PSR-like endoplasmic reticulum kinase
- ATF6 Activating transcription factor 6
- the inhibitor of the PERK pathway and / or the ATF6 pathway is a substance having an inhibitory effect on the signal transduction system of PERK (PERK pathway) and / or the signal transduction system of ATF6 (ATF6 pathway).
- PERK pathway signal transduction system of PERK
- ATF6 pathway signal transduction system of ATF6
- the inhibitory effect on these signal transduction systems can be evaluated by a known method using changes in genes and / or proteins involved in these signal transduction systems as an index, as in the examples described later.
- a substance having an inhibitory effect on both the PERK pathway and the ATF6 pathway can be an active ingredient for suppressing the progression of myopia in children.
- a compound that targets and reduces genes and proteins involved in PERK and / or ATF6 signal transduction and nucleic acids such as antisense oligonucleotides and siRNA that reduce protein expression in the PERK pathway and / or ATF6 pathway. It can be added to eye drops as an effective ingredient for suppressing the progression of myopia in children.
- the inhibitor of the PERK pathway or the ATF6 pathway means a substance having an inhibitory effect on the signal transduction system of PERK or the signal transduction system of ATF6 in the endoplasmic reticulum.
- the inhibitory effect on these signal transduction systems should be evaluated by the method described in the experimental examples described later or by a known method, using changes in genes and / or proteins involved in these signal transduction systems as indicators. Can be done.
- the evaluation is made by changing the expression of the factor by at least 1% depending on the candidate substance as compared with the control in which the candidate substance is not added. It is possible.
- the expression of the factor fluctuates by at least 1% depending on the candidate substance as compared with the control in which the candidate substance is not added. It is possible to evaluate.
- PERK is an endoplasmic reticulum transmembrane kinase, and as factors involved in its signal transduction, for example, eIF2 ⁇ (eucaryotic initiation factor 2 ⁇ ), ATF4 (Activating protein factor 4), CHOP (C / EBPhomo) Growth arrest DNA and damage protein 34) and the like can be mentioned.
- eIF2 ⁇ eucaryotic initiation factor 2 ⁇
- ATF4 Activating protein factor 4
- CHOP C / EBPhomo Growth arrest DNA and damage protein 34
- ATF6 is a membrane-bound transcription factor belonging to the CREB / ATF family, and examples of factors involved in its signal transduction include BiP (Binding immunoglobulin protein, also referred to as “GRP78”) and Txndc12 (thioredoxin dominant proteining). 12, (also referred to as "ERp18"), S1P (site-1 protease), S2P (site-2 protease) and the like.
- the present invention is not limited to these, and at least a component specified as a component that suppresses the ATF6 pathway and a component newly specified as a component that suppresses the PERK pathway and the ATF6 pathway can also be used.
- the inhibitor of the ATF6 pathway is not limited, but sodium phenylbutyrate is preferable from the viewpoint of solubility in eye drops.
- sodium phenylbutyrate is preferable because it can inhibit the PERK pathway in addition to the ATF6 pathway.
- Inhibitors of the PERK pathway and / or the ATF6 pathway may be synthesized and used by a known method, or commercially available products may be obtained and used.
- the "pharmaceutically acceptable salt” is not particularly limited, and specific examples thereof include organic acid salts, inorganic acid salts, organic bases, and inorganic bases.
- organic acid salt include monocarboxylates such as acetate, trifluoroacetate, butyrate, palmitate and stearate; fumarate, maleate, succinate, malonate and the like.
- Examples of the inorganic acid salt include hydrochloride, sulfate, nitrate, hydrobromide, and phosphate.
- Examples of the salt with an organic base include salts with organic amines such as methylamine, triethylamine, triethanolamine, diethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picolin and ethylenediamine.
- Examples of the salt with an inorganic base include ammonium salts; alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, and various salts such as salts with metals such as aluminum. These salts may be used alone or in any combination of two or more.
- the "pharmaceutically acceptable salt” may include a solvate or hydrate of the salt.
- the content of the inhibitor of the PERK pathway and / or the ATF6 pathway can be appropriately changed depending on the usage, dosage, type of additive and the like. For example, 0.01% by mass or more is preferable, 0.05% by mass or more is more preferable, and 0.1% by mass or more is further preferable with respect to the total amount of eye drops (total mass; the same applies in the present specification). , 0.2% by mass or more is particularly preferable.
- the content of the inhibitor of the PERK pathway and / or the ATF6 pathway is, for example, preferably 5% by mass or less, more preferably 4% by mass or less, still more preferably 3% by mass or less, based on the total amount of the eye drops. Mass% or less is particularly preferable.
- the content of the inhibitor of the PERK pathway and / or the ATF6 pathway is, for example, preferably 0.01 to 5% by mass, more preferably 0.05 to 4% by mass, and 0.1 to 0.1% by mass, based on the total amount of eye drops. It is more preferably to 3% by mass, and particularly preferably 0.2 to 2% by mass.
- the content thereof is, for example, relative to the total amount of eye drops. Therefore, 0.01 to 5% by mass is preferable, 0.05 to 4% by mass is more preferable, 0.1 to 3% by mass is further preferable, and 0.2 to 2% by mass is particularly preferable.
- the eye drops according to the present invention are used for suppressing the progression of myopia in children.
- a child is a child between the ages of 7 and 15 years.
- the degree of refraction of the eye is mild hyperopia after birth, and the axis of the eye extends until it becomes almost emmetropic by school age.
- Axial length grows rapidly from birth to about 2 years old, and then gradually grows.
- the extension of the eye axis to the emmetropia accompanying such growth is called “physiological extension of the eye axis” and is an indispensable phenomenon for the normal growth of the eye.
- physiological extension of the eye axis is an indispensable phenomenon for the normal growth of the eye.
- continued elongation of the axial length even after school age is considered to be “pathological axial elongation” because it leads to the progression of myopia.
- pathological axial extension an extension of 1 mm axial length in an adult eye leads to an increase in myopia of about 3.0D, and the axial extension is irreversible.
- the composition according to the present invention is used as an eye drop.
- the dosage form of the eye drop for suppressing the progression of myopia in children is not limited, and examples thereof include an aqueous eye drop, a time-dissolving eye drop, a suspension eye drop, an oil-based eye drop, and an eye ointment. Be done. Among these, an aqueous eye drop is preferable from the viewpoint of remarkably exerting the effect of the present invention.
- active ingredients can be added to the eye drops.
- active ingredients are not particularly limited, and are, for example, decongestion components, eye muscle regulator components, anti-inflammatory drug components, astringent drug components, antihistamine drug components, antiallergic drug components, vitamins, amino acids, and antibacterial components.
- examples thereof include drug components, sugars, polymer compounds or derivatives thereof, cellulose or derivatives thereof, local anesthetic components and the like.
- various ingredients and additives are appropriately selected according to a conventional method according to the use and form thereof, as long as the effects of the present invention are not impaired, and one or two or more of them are contained in combination.
- those components or additives for example, carriers, fragrances or refreshing agents, preservatives, bactericides or antibacterial agents, pH regulators, chelating agents, stabilizers, etc., which are generally used for preparing liquids and the like, etc.
- examples thereof include various additives such as a tensioning agent, a buffering agent, and a thickening agent.
- the following are examples of typical ingredients used in eye drops, but are not limited thereto.
- the carrier examples include an aqueous solvent such as water and hydrous ethanol.
- a solubilizer may be used.
- the solubilizer include polyoxyethylene hydrogenated castor oil, polyoxyl 40 stearate, povidone, polysorbate 80 and the like.
- fragrance or refreshing agent examples include terpenes (specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, ryuno, etc., which may be d-form, l-form or dl-form. Good), essential oils (eucalyptol oil, cool mint oil, kehi oil, spear mint oil, sardine water, sardine oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.) and the like.
- terpenes specifically, anethole, eugenol, camphor, geraniol, cineole, borneol, menthol, limonene, ryuno, etc.
- essential oils eucalyptol oil, cool mint oil, kehi oil, spear mint oil, sardine water, sardine oil, peppermint oil, berga
- preservatives, bactericides or antibacterial agents examples include polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, etc.
- pH adjusting agent examples include hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.
- chelating agent examples include ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.
- the stabilizer examples include sodium edetate hydrate, povidone, polysorbate 80, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium pyrosulfate, monoethanolamine, aluminum monostearate, and the like. Examples thereof include glycerin monostearate.
- tonicity agent examples include potassium chloride, sodium chloride, concentrated glycerin, glucose, D-mannitol and the like.
- buffering agent examples include sodium citrate hydrate, sodium acetate hydrate, sodium hydrogen carbonate, trometamol, boric acid, borosand, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate and the like.
- thickening agent examples include carboxyvinyl polymer, povidone, polyvinyl alcohol (partially saponified product), hydroxyethyl cellulose, hypromellose, methyl cellulose, glycerin and the like.
- the additive can be blended in the range where the effect of the present invention is expected or the effect of the present invention is not impaired.
- the content thereof is not particularly limited, but is preferably about 0.001 to 1% by mass with respect to the total amount of eye drops.
- the pH of the eye drops may be 3 to 10, preferably 4 to 9 from the viewpoint of usability, and more preferably 5 to 8.5 from the viewpoint of usability.
- a known eye drop container can be used without limitation.
- the eye drop container a container having a shape that allows the eye drop to be dropped onto the eye, for example, a shape having a nozzle and a container mouth at the tip of the nozzle can be used.
- the instillation container has a structure in which a nozzle separately molded is attached to the container, and a container in which the nozzle portion (liquid pouring portion) and the container body are integrally molded (for example,). It may be any of the single-use type instillation containers, etc.).
- the eye drop container may usually be a plastic container.
- the constituent materials of the plastic container are not particularly limited, but for example, one of polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, and polyimide, copolymers thereof, or two or more thereof. Can be mentioned.
- polyethylene terephthalate, polyarylate, polyethylene naphthalate, a copolymer thereof, or a mixture of two or more thereof is preferable from the viewpoint that the effect of the present invention can be easily exerted by adjusting the extrusion or the like.
- the eye drops may be filled in a transparent container (a container having transparency enough to observe foreign substances) containing such a material as a main material, or may be filled in a light-shielded container. good.
- the light shielding may be performed, for example, by adding a colorant to the transparent container material, or by covering the container with a shrink film, an outer box, or the like.
- the capacity of the container is preferably about 0.5 to 50 mL, more preferably about 3 to 20 mL, in order to further facilitate the effect of the present invention by adjusting the extrusion or the like.
- the structure and constituent materials of the nozzle provided in the eye drop container are not particularly limited.
- the structure of the nozzle may be any structure generally adopted as the nozzle of the eye drop container.
- the constituent material of the nozzle for example, the same material as the constituent material of the plastic container is exemplified. From the viewpoint of further improving the drainage of the eye drops and suppressing the variation in the dropping amount, a nozzle containing polyethylene or polypropylene as a constituent material is suitable.
- Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene, and among them, a nozzle containing low-density polyethylene as a constituent material is preferable.
- the eye drops according to the present invention can be prepared by a method commonly used or known to those skilled in the art. For example, after each component is dispersed on a carrier such as water, a solubilizer is added if necessary, heated as necessary, homogenized, dissolved or emulsified using a homomixer or the like to adjust the pH. It may be prepared by adjusting the pH with an agent. Further, as a method for sterilizing the preparation, a method such as electron beam sterilization, autoclave sterilization, or filtration sterilization can be selected.
- the usage and dosage of the eye drops according to the present invention vary depending on the patient's symptoms and the like, but usually, about 1 to 6 times a day, about 1 to 2 drops may be instilled.
- the eye drops according to the present invention can be applied to children.
- an eye drop containing at least one selected from the group consisting of phenylbutyric acid and a pharmaceutically acceptable salt thereof, for example, as an inhibitor of the PERK pathway and / or the ATF6 pathway without limitation. It is possible to instill the eye drops once or twice a day with one or two drops at a time, and it is preferable to instill one drop once a day.
- the eye drops according to the present invention can be used for children, for example, before taking a nap, before going to bed, or other times when the activity is not active.
- the method for screening a pediatric myopia progression inhibitor is a step of contacting a candidate substance with cells derived from the eye, and a protein and / or gene of the signal transduction system of PERK and / or ATF6 in the cells. It includes a step of selecting a candidate substance using a change as an index.
- cells are contacted in the presence or absence of a candidate substance, and changes in PERK and / or ATF6 signaling system proteins and / or genes due to the candidate substance are measured and compared. This can lead to screening of candidate substances.
- the cells derived from the eye are not limited, but are preferably cells in the sclera, and more preferably scleral fibroblasts, from the viewpoint of remarkably exerting the effect of the present invention.
- the cells derived from the eye are preferably cells derived from the animal model that induced myopia.
- a myopia induction model a known animal model can be used.
- examples of the myopia-inducing model include an animal model in which a minus lens is worn to induce myopia, and an animal model in which a myopia-inducing agent is administered to induce myopia.
- a negative lens As such a negative lens, a -20 to -40 diopter (D) can be used, and a -25 to -35 diopter (D) is preferable.
- a method of wearing the minus lens a known method can be used, and the method of wearing the minus lens is not limited, and examples thereof include fixing the minus lens in front of the eyes of an animal using a fixative.
- the wearing period of the minus lens can be, for example, at least one week, preferably two weeks or more, and more preferably three weeks or more.
- the myopia inducer a known substance can be used, but for example, as the myopia inducer, tunicamycin, thapsigargin and the like can be used as evaluated in the experimental examples described later. be.
- an activator of the PERK pathway and an activator of the ATF6 pathway can be used in combination.
- Examples of the PERK pathway activator include CCT020312 and the like, and examples of the ATF6 pathway activator include AA147 and the like, which can be administered alone or in combination, and these can be administered in combination. It is preferable to do so.
- Such myopia inducers are not limited, but can be administered as, for example, an injection or an eye drop from the viewpoint of acting on cells of the eye such as the sclera, and should be administered as an eye drop. Is preferable.
- tunicamycin When used as an eye drop, it can be, for example, 10 to 100 ⁇ g / mL, preferably 20 to 80 ⁇ g / mL, and more preferably 40 to 60 ⁇ g / mL.
- Thapsigargin When Thapsigargin is used as an eye drop, it can be, for example, 1 to 100 ⁇ M, preferably 2 to 60 ⁇ M, and more preferably 5 to 30 ⁇ M.
- mice it is preferable to use young-aged animals from the viewpoint of using an animal model assuming application to children.
- the mice it is preferable to start wearing a minus lens at the time of weaning, and it is more preferable that the mice are 3 weeks old.
- physiological axial elongation occurs from 3 to 6 weeks of age. Therefore, by inducing myopia from the age of 3 weeks, it is possible to promote excessive axial elongation in addition to physiological axial elongation, and thus it is possible to cause pathological axial elongation.
- the candidate substance it is preferable to apply the candidate substance to 3-week-old mice before and after myopia induction, or during the period during which myopia induction is performed. According to this method, it is possible to evaluate the effect of the candidate substance on physiological axial elongation and pathological axial elongation.
- white Leghorn it is preferable to use, for example, 5-day-old white Leghorn chicks from the viewpoint of making an animal model assuming application to children.
- the step of bringing the candidate substance into contact with cells derived from the eye is preferably administered by oral, intraperitoneal injection or eye drops, and more preferably by eye drops.
- the candidate substance can be contained in eye drops and administered.
- a known evaluation method can be used in the step of measuring the protein of the signal transduction system of PERK and / or ATF6 by the candidate substance and / or the gene change.
- gene expression and protein expression or secretion can be measured by known methods such as microarray, real-time PCR method, PCR method, Western blotting method, ELISA method, and immune tissue staining.
- RNA extraction method when measuring changes in genes in the signal transduction system of PERK or ATF6, it is possible to extract RNA from cultured cells using a known RNA extraction method and use it as a step for quantitative analysis of mRNA expression.
- the step of quantitatively analyzing the expression of mRNA is not limited, but it is preferable to use the real-time PCR method.
- the factor involved in signal transduction described above in the item inhibitor of PERK pathway and ATF6 pathway
- Examples of factors involved in the PERK pathway include CHOP, ATF4, GADD34 and the like.
- factors involved in the ATF6 pathway include GRP78, GRP94, PDI, Cnex, HYOU, ERdj3 and the like.
- the candidate substance is selected as an inhibitor of the PERK pathway and / or the ATF6 pathway, and myopia in children. It can be used as a progress inhibitor.
- the present invention may also have the following aspects.
- An eye drop for suppressing the progression of myopia in children which contains an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient; Eye drops containing an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6 (Activating transcription factor 6) pathway as an active ingredient for use in suppressing the progression of myopia in children; Use of PERK (PKRK-like endoplasmic reticulum kinase) and / or ATF6 (Activating transcription factor 6) pathway inhibitors for the manufacture of eye drops for the inhibition of myopia progression in children; A method for suppressing the progression of myopia in children, which comprises ingesting an inhibitor of the PERK (PKRK-like endoplasmic reticulum kinase) pathway and / or the ATF6
- the screening method according to the above, wherein the cells derived from the eye are cells derived from an animal model that induced myopia;
- the screening method according to the above, wherein the negative lens is a -20 to -40 diopter (D) lens;
- the screening method according to the above, wherein the wearing period of the minus lens is at least one week;
- the screening method according to the above, wherein the myopia inducer comprises tunicamycin and / or thapsigargin;
- the screening method according to the above, wherein the concentration of the tunicamycin in the case of eye drop administration is 10 to 100 ⁇ g / mL;
- the screening method according to the above, wherein the concentration of Thapsigargin in the case of eye drop administration is 1 to 100 ⁇ M;
- Non-Patent Document 3 the human eye has hyperopia immediately after birth, and then the axis of the eye extends (that is, myopia) and becomes emmetropic in school age (around 8 years old). Further, as described in Non-Patent Document 6, the eye axis is elongated with the growth of the mouse (C57BL6) during the period of 3 to 6 weeks of age. Therefore, this myopia-induced juvenile mouse corresponds to about 8 years of age in humans in terms of the dynamics of myopia progression, which corresponds to a real infant / child (school age). By using this animal model, it is possible to elucidate the mechanism of myopia progression in human children and to screen for therapeutic agents for myopia progression in children.
- Fig. 1 (a) schematically shows the mechanism by which axial myopia is induced by wearing a minus lens.
- Emmetropia is a state in which the image is clearly visible because the parallel rays that enter the eye form an image on the retina.
- axial myopia is a state in which parallel rays entering the eye form an image in front of the retina due to the long axial length of the eye, and therefore cannot be clearly seen.
- the axis of the eye extends to the position where the image is formed when the minus lens is worn, that is, the state where the image is clearly visible when the minus lens is worn.
- the axis of the eye is elongated, and it is possible to create an eye condition similar to that of axial myopia.
- a myopia-induced juvenile mouse is prepared as follows.
- myopia guidance, axial length and refraction were measured by the same method as in Non-Patent Documents 4 and 5.
- male C57BL6J mice were housed in standard clear cages in a temperature controlled clean room under a 12 hour light-dark cycle. Animals were allowed free intake of standard feed and high pressure steam sterilized tap water.
- mice Immediately after weaning, 3-week-old mice are anesthetized with a three-kind mixed anesthesia of Domitor (Nippon Zenyaku Kogyo Co., Ltd.), Betorfar (Meiji Seika Pharma Co., Ltd.), and Midazolam (Sand Co., Ltd.), and the skull is exposed with scissors.
- a support is erected on the skull and fixed with dental cement (Super-Bond, Sun Medical Co., Ltd.).
- the stanchion is provided with a thread so that the adjustment device described later can be fixed with a nut.
- a -30 diopter (D) minus lens (Rainbow Contact, Rainbow Optical Laboratory Co., Ltd.) as the right eye (myopia-guided eye), and use a 0D lens as a control, or only the frame as the left eye. Attach it to (control eye).
- D diopter
- a protector having a shape protruding laterally is adhered to the frame portion at the bottom of the lens so that the mouse is not damaged by the front legs or the like.
- the protector prevents the mouse from touching the lens and does not scratch the lens.
- the protector used here is one that is glued to the frame and integrated, but it is not necessary that the protector is integrated with the lens as long as the action of the mouse does not damage the lens. For example, it may be shaped like an Elizabethan collar worn by a traumatized animal.
- An adjustment device for adjusting the width and angle of the attached lens is adhered to the frame above the lens as the mouse grows.
- the adjuster is bent into a dogleg shape, one with a lens glued on it and the other with a slotted hole for attachment to a strut erected on the head.
- the mouse By passing a long hole through a support and screwing it with a nut, the mouse can be firmly attached to the skin and fixed without pressing the periphery of both eyes.
- a three-point adjustment mechanism consisting of a support, a nut, and an adjustment device, the width and angle can be adjusted according to the growth of the mouse, and the lens can be adjusted so that it is at the position of the mouse's eyes. Further, since the lens can be removed, it is possible to measure changes in the axial length and the refraction value with time.
- Quantitative real-time PCR was performed on PowerUp SYBR Green Master Mix (Applied Biosystems, CA, USA) using the StepOnePlus real-time PCR system. Expression levels were standardized by ⁇ -actin.
- FIG. 2 shows the axial elongation (a) and the refractive change (b) after myopia induction for 3 weeks
- FIG. 3 shows the gene expression change in the sclera at that time.
- the pathway of the endoplasmic reticulum stress response gene is shown in FIG.
- FIG. 4 shows the expression of genes downstream of PERK, ATF6, and IRE1, which are the major genes for endoplasmic reticulum stress response
- FIGS. 6-a and 6-b show axial extension (a) and inflection (b) after instillation of 60 ⁇ M STF, 100 ⁇ M GSK, and 100 ⁇ M NFV once daily for 10 days during the period of myopia induction in mice. ..
- FIGS. 6-c and d show axial elongation (c) and inflection change (d) after similarly instilling a combination of these inhibitors (STF + GSK: S + G, GSK + NFV: G + N, NFV + STF: N + S, STF + GSK + NTF: S + G + N).
- FIG. 7 shows the axial extension (a) and the refractive change (b) after similarly instilling 100 ⁇ M GSK2606414, Ceapin-A7, and 4 ⁇ 8C, respectively.
- the axial length is significantly suppressed only when at least two types of PERK inhibitor and ATF6 inhibitor are present (G + N, S + G + N), myopia of refraction is suppressed, and single instillation is performed. No axial extension of the control eye was observed (Fig. 6-c, d). Furthermore, the changes in axial length and refraction due to single instillation of the inhibitors GSK2606414, Ceapin-A7, 4 ⁇ 8C, which are different from those in FIG. 6, are exactly the same as the results in FIG. 6, and neither axial elongation nor refraction myopia is suppressed. With single instillation other than 4 ⁇ 8C, it extended to the axis of the control eye (Fig. 7).
- Test Example 3 4-Inhibition of endoplasmic reticulum stress pathway by PBA and TUDCA> In Test Example 2, it was considered effective to search for a component that suppresses both the PERK pathway and the ATF6 pathway in order to search for an agent for suppressing the progression of myopia in children.
- the inhibition profile of the endoplasmic reticulum stress pathway was evaluated for components known to inhibit elongation (sodium phenylbutyrate ⁇ 4-PBA ⁇ , tauroursodeoxycholic acid ⁇ TUDCA ⁇ ).
- FIG. 8 shows changes in gene expression after daily intraperitoneal injection of 4-PBA throughout the period of myopia induction in mice.
- FIG. 9 shows the axial extension (a) and the refractive change (b) at the first week and the third week of myopia induction by 4-PBA administration.
- FIG. 10 shows axial extension (a) and refractive change (b) after instillation of 0.2% and 2% 4-PBA into mice undergoing myopia induction.
- FIG. 11 shows axial extension (b) and inflection (a) after daily intraperitoneal injection of TUDCA throughout the myopia induction period.
- 4-PBA and TUDCA suppress the PERK pathway and ATF6 pathway, which are the mechanisms of suppression of myopia progression in children, in the endoplasmic reticulum stress pathway (Fig. 12), and are physiologically associated with normal eye growth. It was confirmed that the axial elongation was not suppressed, but only the pathological axial elongation was suppressed. That is, components that suppress both PERK and ATF6, such as 4-PBA, TUDCA, and combinations of PERK and ATF6 inhibitors, do not inhibit or exceed the normal inflection of children from hyperopia to emmetropia. It was confirmed that only the progression of myopia was suppressed.
- the method of instilling a single inhibitor of each of PERK, ATF6, and IRE1 in the sclera of a myopia-induced juvenile mouse, or the method of instilling an instillation using a combination of inhibitors, and the like are based on the description of Test Example 2.
- ATF6-N The value obtained by dividing the amount of ATF6 activation form (ATF6-N) by the amount of ATF6 precosor form (ATF6-P) is shown in FIG. 13 as an index of activation.
- the value obtained by dividing the amount of ATF6-N of ATF6 by the amount of ATF6-P of ATF6 showed significantly higher values in some groups.
- the group in which the active ATF6 value was high was consistent with the group in which the pathological axial elongation and the decrease in the refractive value shown in FIGS. 6c and 6d were observed, respectively.
- STF indicates an IRE1 inhibitor
- G indicates a PERK inhibitor
- NFV or "N” indicates an ATF6 inhibitor. It is the same as the previous test examples.
- the results summarized in Table 1 show that in the sclera of the myopic eye, activation of the ATF6 pathway triggers a decrease in the refractive index associated with axial elongation, and conversely, inactivation of the ATF6 pathway causes the axial axis. It is shown that the decrease in the refraction value due to the elongation is suppressed.
- a drug (4-PBA) having this medicinal effect and pharmacology is effective for the treatment / prevention of myopia progression in children.
- FIG. 14 (B) when 4-PBA was administered by eye drops, no thickening of the crystalline lens was observed in the -30D lens wearing group. That is, it was shown that eye drops are suitable as a method for administering 4-PBA in terms of reachability to the target tissue.
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Abstract
Description
[1]PERK(PKR-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を有効成分として含有する、小児の近視進行抑制用点眼剤。
本発明に係る小児の近視進行抑制用点眼剤は、PERK(PKR-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を有効成分として含有する。
上述のとおり、小児の近視進行(病的眼軸伸長)に関する因子として、小胞体中の異常蛋白質である折りたたみ不全蛋白質に応答する遺伝子経路が病的眼軸伸長に関与している。この遺伝子経路には、PERK経路、ATF6経路及びIRE1経路の三つが知られているが、後述の実験例にて示されているように、少なくともATF6経路を抑制することが近視抑制に必須であることが新たに見出された。また、これら三つの経路のうち、PERK経路とATF6経路とを抑制することで小児の近視進行抑制効果が更に高まることが新たに見出された。PERK経路又はATF6経路のいずれかのみを抑制した場合には、他方の経路を代償的に活性化してしまう場合があることも確認された。よって、限定はされないが、一つの実施形態においては、PERK経路とATF6経路のいずれに対しても阻害効果を有する物質が小児の近視進行抑制の有効成分となり得る。
本発明に係る点眼剤は、小児の近視進行抑制用として用いられる。本明細書において、小児とは、7歳以上、15歳未満の児をいう。眼の屈折の程度は、出生後は軽度の遠視であり、学童期までにほぼ正視になるまで眼軸が伸長する。
本発明に係る組成物は、点眼剤として用いられる。本発明において、小児の近視進行抑制用点眼剤の剤形は、限定はされないが、例えば、水性点眼剤、用時溶解点眼剤、懸濁性点眼剤、油性点眼剤、眼軟膏剤等が挙げられる。これらの中でも、本発明の効果を顕著に奏する観点から、水性点眼剤であることが好ましい。
本発明に係る点眼剤は、当業者に慣用又は公知の方法で調製できる。例えば、各成分を水等の担体に分散させた後、必要であれば可溶化剤を添加し、必要に応じて加温し、ホモミキサー等を用いて均一化、溶解又は乳化させ、pH調整剤でpHを調整することにより調製すればよい。また、製剤の滅菌方法としては、電子線滅菌、オートクレーブ滅菌、ろ過滅菌等の方法を選択することができる。
本発明に係る点眼剤の用法及び用量は、患者の症状等により変動するが、通常、1日約1~6回、1回約1~2滴を点眼すればよい。
本発明において、小児の近視進行抑制剤のスクリーニング方法は、眼由来の細胞に候補物質を接触させる工程と、前記細胞における、PERK及び/又はATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の変化を指標として候補物質を選択する工程とを含む。限定はされないが、例えば、候補物質の存在下又は不存在下で細胞に接触させ、候補物質によるPERK及び/又はATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の変化を測定して比較することによって候補物質のスクリーニングが行われ得る。
PERK(PKRK-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を有効成分として含有する、小児の近視進行抑制用点眼剤;
小児の近視進行抑制における使用のための、PERK(PKRK-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を有効成分として含有する点眼剤;
PERK(PKRK-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤の、小児の近視進行抑制用点眼剤の製造のための使用;
PERK(PKRK-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を、人に有効量摂取させることを含む、小児の近視進行抑制方法;
前記阻害剤が、少なくともATF6経路を選択的に抑制することを含む、上記に記載の点眼剤、使用、又は方法;
前記阻害剤が、PERK経路及びATF6経路の両経路の阻害剤である、上記に記載の点眼剤、使用、又は方法;
前記阻害剤が、フェニル酪酸及びその薬理学的に許容される塩からなる群より選択される少なくとも1種である、上記に記載の点眼剤、使用、又は方法;
前記阻害剤が、フェニル酪酸ナトリウムである、上記に記載の点眼剤、使用、又は方法;
前記阻害剤の含有量が、点眼剤全量に対して、0.01~5質量%である、上記に記載の点眼剤、使用、又は方法;
前記阻害剤の含有量が、点眼剤全量に対して、0.1~3質量%である、上記に記載の点眼剤、使用、又は方法;
前記阻害剤の含有量が、点眼剤全量に対して、0.2~2質量%である、上記に記載の点眼剤、使用、又は方法;
前記小児の近視進行抑制が、生理的眼軸伸長を抑制しないものである、上記に記載の点眼剤、使用、又は方法;
前記小児の近視進行抑制が、病的眼軸伸長を抑制するものである、上記に記載の点眼剤、使用、又は方法;
前記小児が、7歳以上、15歳未満の児を含む、上記に記載の点眼剤、使用、又は方法;
前記点眼剤が、水性点眼剤である、上記に記載の点眼剤、使用、又は方法;
前記点眼剤が、1日1~2回の点眼で用いられるものである、上記に記載の点眼剤、使用、又は方法;
前記点眼剤が、1日1~2回の点眼で用いられるものである、上記に記載の点眼剤、使用、又は方法;
前記点眼剤が、昼寝前、又は、就寝前に用いられるものである、上記に記載の点眼剤、使用、又は方法;
眼由来の細胞に候補物質を接触させる工程と、前記細胞における、PERK及び/又はATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の変化を指標として候補物質を選択する工程とを含む、小児の近視進行抑制剤のスクリーニング方法;
前記眼由来の細胞が、近視を誘導した動物モデルに由来する細胞である、上記に記載のスクリーニング方法;
前記動物モデルが、マイナスレンズを装用させて近視を誘導した動物モデル、又は、近視誘導剤を投与することにより近視誘導した動物モデルである、上記に記載のスクリーニング方法;
前記マイナスレンズが、-20~-40ディオプター(D)のレンズである、上記に記載のスクリーニング方法;
前記マイナスレンズの装用期間が、少なくとも1週間である、上記に記載のスクリーニング方法;
前記近視誘導剤が、ツニカマイシン、及び/又は、タプシガルギンを含む、上記に記載のスクリーニング方法;
前記ツニカマイシンの点眼投与の場合の濃度が、10~100μg/mLである、上記に記載のスクリーニング方法;
前記タプシガルギンの点眼投与の場合の濃度が、1~100μMである、上記に記載のスクリーニング方法;
前記動物モデルが、離乳時期にマイナスレンズを装用開始するものである、上記に記載のスクリーニング方法;
前記眼由来の細胞に候補物質を接触させる工程が、前記候補物質を経口、腹腔内注射又は点眼により投与することを含む、上記に記載のスクリーニング方法;
候補物質によるPERK及び/又はATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の発現が抑制されている場合、当該候補物質を小児の近視進行抑制剤として選択することを含む、上記に記載のスクリーニング方法;
候補物質によるPERK及びATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の発現が抑制されている場合、当該候補物質を小児の近視進行抑制剤として選択することを含む、上記に記載のスクリーニング方法。
本実験におけるすべての動物実験は、慶応義塾大学動物実験委員会の承認を受け、慶応義塾大学動物実験に関する施設ガイドライン、眼科・視覚研究における動物の使用に関するARVO声明、動物研究:研究における動物の使用に関するin vivo実験の報告(ARRIVE)ガイドラインを遵守した。
非特許文献3に記載されているように、ヒトの眼は出生直後は遠視であり、その後に眼軸が伸長(つまり近視化)し、学童期(8歳ごろ)に正視化する。また、非特許文献6に記載されているように、マウス(C57BL6)の3から6週齢の期間も成長に伴い眼軸が伸長している。したがって、この近視誘導幼若マウスは、近視進行の動態という点でヒトの8歳前後に相当し、それは実質幼児・小児(学童期)に相当する。この動物モデルを用いることで、ヒト小児の近視進行におけるメカニズム解明と、小児の近視進行治療剤のスクリーニングが可能である。
具体的には以下のようにして近視誘導幼若マウスを作製する。なお、近視誘導、眼軸長及び屈折の計測は非特許文献4、5と同様の方法で行った。まず、雄性C57BL6Jマウスを、12時間の明暗サイクル下で温度制御クリーンルームで標準透明ケージに収容した。動物には、標準飼料と高圧蒸気滅菌した水道水を自由摂取させた。離乳直後の3週齢のマウスをドミトール(日本全薬工業株式会社)、ベトルファール(Meiji Seikaファルマ株式会社)、ミダゾラム(サンド株式会社)の3種混合麻酔で麻酔し、ハサミで頭蓋を露出させる。図1(b)に示すように、頭蓋に支柱を立設し、歯科用セメント(Super-Bond、サンメディカル株式会社)で固定する。支柱は、後述の調節器具をナットで固定できるようにねじ山が設けてある。
コントロール眼はフレームのみ、近視誘導眼は-30Dレンズを3週間装用させ、屈折値、眼軸長を測定し、装用前後の差を求めた。屈折値は屈折計(Infrared photorefractor for mice、Tubingen大学Schaeffel教授作製)、眼軸長はSD-OCT(Spectral-domain OCT、スペクトラルドメイン光干渉断層撮影、Envisu R4310、bioptigen Inc.)によって計測した。
フェニル酪酸ナトリウム(Cayman Chemical、MI、USA)及びタウロウルソデオキシコール酸(シグマ・アルドリッチ、東京、日本)はPBSに溶解した。IRE1阻害剤であるSTF080310(セレック・バイオテック、東京、日本)又は4μ8C(セルレック・バイオテック)、PERK阻害剤であるGSK2656157(セルレック・バイオテック)又はGSK2606414(セルレック・バイオテック)、ATF6阻害剤であるネルフィナビルメシステレイトハイドレート(東京化学工業、東京、日本)又はCeapin-A7(シグマ・アルドリッチ)はDMSOで溶解し、1:1000でPBSにより希釈し点眼試験に用いた。
0.2%又は2%のフェニル酪酸ナトリウムのPBS溶液(4-PBA)、60μMのSTF080312(STF)、100μMの4μ8C(4μ8C)、100μMのGSK2656157(GSK)、100μMのGSK2606414(GSK2606414)、100μMのネルフィナビルメシステレイトハイドレート(NFV)、100μMのCeapin-A7(Ceapin)を近視誘導中に、10日間、毎日、1日1回、夕方、両眼に点眼した。
フェニル酪酸ナトリウムPBS溶液(4-PBA;200mg/kg体重)又はタウロウルソデオキシコール酸(TUDCA;100mg/kg体重)を近視誘導期間を通して毎日腹腔内注射(i.p.)した。
強膜のタンパク質(10μg/ウェル)は、SDS-PAGEにより分離され、PVDF膜(米国MA州、Merck Millipore)に移され、Blocking One(東京、Nacalai Tesque)でブロックされ、抗ATF6(バイオアカデミア株式会社)、リン酸化-IRE1(Ser724、Abcam、Cambridge、UL)、IRE1、リン酸化-eIF2α、eIF2α、及びβ-アクチン(Cell Signaling Technologies Japan、東京、日本)抗体と共に4℃で一晩インキュベートされた。膜を適切なHRP結合二次抗体とインキュベートし、EzWestLumi plus (ATTA、東京日本)を用いて可視化した。SDS-PAGEは10%アクリルアミドゲルで蛋白サイズマーカー(MagicMark XP Western Protein Standard、ThermoFisher Scientific)を用いて行った。ImageJソフトウェアを用いて濃度測定分析を行った。
定量的real-time PCRは、StepOnePlusリアルタイムPCRシステムを用いてPowerUp SYBR Green Master Mix(Applied Biosystems、CA、USA)で行った。発現レベルはβ-アクチンにより標準化した。
実験で得たデータは、すべて平均値±標準偏差で表す。群間差は、Studentのt検定又は一元配置分散分析又は一般化推定方程式により解析した。ANOVAが有意差を示した場合、次にTukey HSDを行い、各平均値間の差の有意性を判定した。p値が0.05未満の場合は、統計学的有意差を示す。
<試験例1 近視誘導幼若マウスの強膜における小胞体ストレス応答遺伝子の発現変化>
小胞体ストレス応答遺伝子経路であるPERK経路、ATF6経路、IRE1経路の小児の近視進行への関与を評価するために、小児近視進行を模しているマウスの強膜における遺伝子発現を上記[実験方法]の記載に従って評価した。
試験例1において小児の近視進行にPERK、ATF6、及びIRE1が関与していることが示唆されたので、この試験例2では、これらの遺伝子の既知阻害剤によって近視進行という表現型がどう影響を受けるかを評価した。なお、PERK阻害剤としてGSK2656157(GSK)、GSK2606414、ATF6阻害剤としてネルフィナビルメシステレイトハイドレート(NFV)、Ceapin-A7、IRE1阻害剤としてSTF080312(STF)、4μ8Cを用いた(図5)。
試験例2において、小児の近視進行抑制剤探索には、PERK経路とATF6経路とを両方抑制する成分を探索することが有効があるものと考えられたので、この試験例3では、既に眼軸伸長を抑制することが知られている成分(フェニル酪酸ナトリウム{4-PBA}、タウロウルソデオキシコール酸{TUDCA})について、小胞体ストレス経路の抑制プロファイルを評価した。
小児の近視進行抑制において、PERK経路とATF6経路の両経路のうち、ATF6経路がどの程度関与しているかをさらに検討した。上記[実験方法]の記載にしたがってウエスタンブロット法での濃度測定分析を行い、ATF6の活性化form(ATF6-N)量、及び、ATF6のprecosor form(ATF6-P)量を求めた。近視誘導幼若マウスの強膜における、PERK、ATF6、IRE1の各々の阻害剤の単独点眼方法、又は、阻害剤の組合せによる点眼方法等は、試験例2の記載に準じる。
近視誘導(LIM)により、水晶体が僅かに厚くなる傾向が確認されている。4-PBAの投与形態の違いによって、水晶体の変化に影響があるか否かを検討した。上記[実験方法]の記載にしたがって、近視誘導幼若マウスに4-PBAを点眼、又は、腹腔内投与し、眼軸長の計測と同様に、SD-OCTを用いて水晶体の厚さを計測した。
Claims (7)
- PERK(PKRK-like endoplasmic reticulum kinase)経路及び/又はATF6(Activating transcription factor 6)経路の阻害剤を有効成分として含有する、小児の近視進行抑制用点眼剤。
- 前記阻害剤が、フェニル酪酸及びその薬理学的に許容される塩からなる群より選択される少なくとも1種である、請求項1に記載の点眼剤。
- 前記阻害剤が、フェニル酪酸ナトリウムである、請求項1又は2に記載の点眼剤。
- 前記阻害剤の含有量が、点眼剤全量に対して、0.01~5質量%である、請求項1~3のいずれか1項に記載の点眼剤。
- 前記小児の近視進行抑制が、生理的眼軸伸長を抑制しないものである、請求項1~4のいずれか1項に記載の点眼剤。
- 前記小児の近視進行抑制が、病的眼軸伸長を抑制するものである、請求項1~5のいずれか1項に記載の点眼剤。
- 眼由来の細胞に候補物質を接触させる工程と、前記細胞における、PERK及び/又はATF6のシグナル伝達系のタンパク質、及び/又は、遺伝子の変化を指標として候補物質を選択する工程とを含む、小児の近視進行抑制剤のスクリーニング方法。
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