WO2018199287A1 - Procédé de traitement prophylactique et/ou thérapeutique de la rétinopathie cristalline - Google Patents

Procédé de traitement prophylactique et/ou thérapeutique de la rétinopathie cristalline Download PDF

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WO2018199287A1
WO2018199287A1 PCT/JP2018/017183 JP2018017183W WO2018199287A1 WO 2018199287 A1 WO2018199287 A1 WO 2018199287A1 JP 2018017183 W JP2018017183 W JP 2018017183W WO 2018199287 A1 WO2018199287 A1 WO 2018199287A1
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ips
cells
bcd
rpe
rpe cells
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PCT/JP2018/017183
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Japanese (ja)
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匡侑 畑
華子 池田
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国立大学法人京都大学
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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • Crystalline retinopathy is an autosomal recessive retinal degenerative disease reported by Bietti in 1937 and accounts for about 10% of autosomal recessive retinal degenerative diseases (Non-patent Document 1). Many Asians, including Japanese, usually develop progressive visual field and visual impairment after the 20s, and lose vision after the 60s. Crystalline retinopathy is characterized by progressive atrophy of retinal photoreceptor cells and retinal pigment epithelium (RPE) cells, and crystal-like deposits found in the fundus. Due to the development of inspection equipment such as optical coherence tomography (OCT), it has been reported that crystal-like deposits are often observed in RPE cells, and that RPE cell atrophy precedes retinal atrophy. (Non-patent Document 2).
  • OCT optical coherence tomography
  • Non-patent Document 3 An association between crystallin retinopathy and a mutation in the CYP4V2 gene (4q35) was reported in 2004 (Non-patent Document 3). Although CYP4V2 is strongly expressed in RPE cells and assumed to be an enzyme involved in lipid metabolism, its detailed function has not been clarified (Non-patent Document 4). There is a need to elucidate the pathophysiology of crystallin retinopathy and to establish a treatment based on the pathophysiology.
  • the present application aims to provide a method for the treatment and / or prevention of crystallin retinopathy.
  • the present inventors have studied the pathophysiology of crystallin retinopathy using iPS cells, and have found for the first time a relationship between crystallin retinopathy and free cholesterol accumulation in RPE cells. Furthermore, it was shown that cholesterol accumulation inhibitors reduce the abnormalities of RPE cells characteristic of crystallin retinopathy.
  • the present application provides a composition for the treatment and / or prevention of crystallin retinopathy comprising a cholesterol accumulation inhibitor.
  • the present application provides a method for the treatment and / or prevention of crystallin retinopathy comprising administering to a subject a cholesterol accumulation inhibitor.
  • the present application provides the use of a cholesterol accumulation inhibitor for the treatment and / or prevention of crystallin retinopathy.
  • the present application provides the use of a cholesterol accumulation inhibitor for the manufacture of a medicament for the treatment and / or prevention of crystallin retinopathy.
  • crystallin retinopathy can be treated and / or prevented.
  • FIG. 6 shows the expression of CYP4V2 protein in undifferentiated iPS cells derived from healthy individuals (WT) or crystallin retinopathy patients (BCD) and iPS-RPE cells differentiated from them. Shown are bright field microscopic images of WT iPS-RPE cells and BCD iPS-RPE cells. Electron microscopic images of WT iPS-RPE cells and BCD iPS-RPE cells are shown. The proliferative ability of WT iPS-RPE progenitor cells and BCD iPS-RPE progenitors measured by cell number is shown. BCD vs.
  • FIG. 3 shows autophagy-related protein expression in the presence or absence of bafilomycin A in WT iPS-RPE cells and BCD ⁇ iPS-RPE cells. NOR Tx- vs.
  • BCD vs. NOR; Student's t-test; n 3 for each cell line
  • the amount of sugar ceramide in the cells of WT iPS-RPE cells and BCD iPS-RPE cells is shown.
  • BCD; Student's t-test; n 10 The amount of cholesterol ester in the cells of WT iPS-RPE cells and BCD iPS-RPE cells is shown.
  • NOR vs. BCD; Student's t-test; n 8 The amount of free cholesterol in the cells of WT iPS-RPE cells and BCD iPS-RPE cells is shown.
  • NOR vs. BCD; Student's t-test; n 3 The amounts of intracellular free cholesterol and cholesterol esters in BCD iPS-RPE cells treated with NBDNJ, HPBCD, HPGCD, MBCD or ⁇ -T are shown.
  • each group n 4 The dead cell rate of BCD iPS-RPE progenitor cells treated with NBDNJ, HPBCD, HPGCD, MBCD or ⁇ -T is shown.
  • each group n 3 The percentage of LysoTracker positive cells in BCD iPS-RPE cells treated with NBDNJ, HPBCD or HPGCD is shown.
  • “Cholesterol accumulation inhibitor” means a substance that inhibits the accumulation of free cholesterol in cells by inhibiting the synthesis or uptake of free cholesterol or by promoting the extracellular excretion of free cholesterol.
  • examples of cholesterol accumulation inhibitors include HMG-CoA reductase inhibitors such as cyclodextrin compounds, vitamin E compounds, statins, histone deacetylase inhibitors, and lysosomal acid lipase inhibitors. Cholesterol accumulation inhibitors can be synthesized by methods known in the art or purchased.
  • cyclodextrin compounds include ⁇ -, ⁇ -, ⁇ -cyclodextrin, and derivatives in which a displaceable group of ⁇ -, ⁇ -, ⁇ -cyclodextrin is substituted, and pharmaceutically acceptable products thereof. Salts, esters, solvates and hydrates.
  • the cyclodextrin compound is a compound of formula (I) or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.
  • each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be substituted; or —C (O ) OR B , —OC (O) R B , —C (O) R B , or —C (O) NR A R B ;
  • Each R 1 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR B , —SR B , —SOR B , —SO 2 R B , —N (R B ) S (O 2 ) —R B ,
  • alkyl refers to a saturated, linear or branched hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl groups, and the like.
  • alkenyl means a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, containing one or more double bonds.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl means a straight or branched chain hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, containing one or more triple bonds.
  • Alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic compound.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and the like.
  • the term “carbocycle” or “carbocyclic” or “carbocyclyl” includes saturated (eg, “cycloalkyl”), partially saturated (eg, “cycloalkenyl” or cyclo) containing 0 heteroatoms as ring atoms.
  • a carbocyclyl may be, but is not limited to, a single ring, two or more fused rings, a bridge or a spiro ring.
  • Carbocyclyl can contain, for example, 3 to 10 member atoms.
  • the substituted carbocyclyl can have either a cis or trans configuration.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro- Indenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (known as “phenalenyl”), decalinyl And norpinanyl and the like.
  • a carbocyclyl group can be attached to the parent mo
  • aryl refers to an aromatic carbocyclyl containing 6 to 14 ring atoms.
  • Non-limiting examples of aryl include phenyl, naphthalenyl, anthracenyl, indenyl and the like.
  • the aryl group can be attached to the parent molecular moiety through any of the substitutable group's carbon atoms.
  • heteroaryl means an aromatic heterocyclyl generally containing from 5 to 18 ring member atoms, where at least one ring member atom is a heteroatom. Heteroaryl may be a single ring or two or more fused rings.
  • Non-limiting examples of 5-membered heteroaryl include thiazolyl; 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-oxadiozalyl; and isothiazolyl.
  • Non-limiting examples of 6-membered heteroaryl include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2,4- and 1,2,3-triazinyl.
  • Non-limiting examples of 6/5 membered fused ring heteroaryls include benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl.
  • Non-limiting examples of 6/6 membered fused ring heteroaryl include quinolinyl; isoquinolinyl; and benzoxazinyl (including cinnolinyl and quinazolinyl).
  • heterocycloalkyl denotes a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring, or a bicyclic or tricyclic fused system, wherein at least one ring atom is And (i) each 5-membered ring has 0-1 double bonds and each 6-membered ring has 0-2 double bonds, and (ii) Nitrogen and sulfur atoms may be oxidized, (iii) nitrogen heteroatoms may be quaternized, and (iv) any of the above rings may be fused to a benzene ring.
  • heterocycloalkyl groups include, but are not limited to, [1.3] dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazo Includes lysinyl, tetrahydrofuryl and the like.
  • each R is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be substituted.
  • Well preferably optionally substituted with hydroxy; or with —C (O) OR B , —OC (O) R B , —C (O) R B , or —C (O) NR A R B is there.
  • each R is independently H, optionally substituted alkyl, —C (O) OR B , —OC (O) R B , —C (O) R. B , or —C (O) NR A R B.
  • each R is independently H, alkyl optionally substituted with hydroxy, —C (O) OR B , —OC (O) R B , —C (O ) R B , or —C (O) NR A R B.
  • each R is independently H or alkyl optionally substituted with hydroxy.
  • each R is independently H, methyl, ethyl, propyl, or hydroxypropyl.
  • each R 1 is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR B , —SR B , —SOR B , —SO 2 R B , —N (R B ) S (O 2 ) —R B , —N (R B ) S (O 2 ) NR A R B , —NR A R B , —C (O) OR B , —OC (O) R B , —C (O) R B , —C (O) NR A R B , or N (R B ) C (O) R B.
  • n is 1, 2, or 3. In certain embodiments, in Formula (I), n is 2 or 3. In certain embodiments, in Formula (I), m is 0.
  • the cyclodextrin compound is ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin, derivatives thereof, such as derivatives in which at least one hydroxyl group is alkylated or hydroxyalkylated, or These pharmaceutically acceptable salts, esters, solvates or hydrates.
  • the cyclodextrin compound is ⁇ -cyclodextrin or ⁇ -cyclodextrin, derivatives thereof, such as derivatives in which at least one hydroxyl group is alkylated or hydroxyalkylated, or pharmaceutically thereof. It is an acceptable salt, ester, solvate or hydrate.
  • the cyclodextrin compound is methyl- ⁇ -cyclodextrin (MBCD), 2-hydroxyethyl- ⁇ -cyclodextrin (HPBCD) or 2-hydroxypropyl- ⁇ -cyclodextrin (HPGCD), or a pharmaceutical thereof Acceptable salts, esters, solvates or hydrates.
  • the cyclodextrin compound is HPBCD or HPGCD, or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.
  • the cyclodextrin compound is HPGCD or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.
  • the cholesterol accumulation inhibitor is a vitamin E compound.
  • Vitamin E compounds include tocopherols or tocotrienols such as ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol and ⁇ -tocotrienol and their pharmaceutically Acceptable salts, esters, solvates and hydrates are included.
  • tocopherol esters include tocopherol acetate, tocopherol phosphate, tocopherol succinate, tocopherol nicotinate and the like.
  • the cholesterol accumulation inhibitor is ⁇ -tocopherol or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.
  • pharmaceutically acceptable salt as used herein is within the scope of sound medical judgment and is in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, etc. Indicates a salt of a compound that is suitable for use and has a reasonable benefit / risk ratio balanced.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge and et al describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • salts include, but are not limited to, non-toxic acid addition salts, or inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, maleic acid Salts formed with organic acids such as tartaric acid, citric acid, succinic acid, malonic acid, or by other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid
  • maleic acid Salts formed with organic acids such as tartaric acid, citric acid, succinic acid, malonic acid, or by other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyric acid Salt, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate , Hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, Mymate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like.
  • Further pharmaceutically acceptable salts are, if appropriate, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and Includes ammonium, quaternary ammonium, and amine cations formed using counterions, such as aryl sulfonates.
  • ester as used herein includes those that are hydrolyzed in vivo and readily degraded in the human or animal body, leaving the parent compound or salt thereof, The ester of the compound is shown.
  • Suitable ester groups are, for example, pharmaceutically acceptable fatty acids, in particular alkanoic acids, alkenoic acids, cycloalkanoic acids and those in which the respective alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Includes those derived from alkanedioic acid. Examples of specific esters include, but are not limited to, formate, acetate, phosphate, propionate, butyrate, acrylate, nicotinate and succinate.
  • Crystallin retinopathy means a retinal degenerative disease caused by a mutation in the CYP4V2 gene. In general, crystallin retinopathy is diagnosed when deposits of crystallin granules (so-called “crystal-like deposits”), which are flashy crystal deposits, are observed in the retina and peripheral cornea surface layer. Presents with progressive visual field impairment and visual impairment, and prognosis varies from case to case.
  • treating is to reduce or eliminate the cause of crystallin retinopathy, delay or stop its progression in a subject suffering from crystallin retinopathy. And / or alleviating, alleviating, ameliorating or eliminating the symptoms.
  • prevent refers to a subject having a crystalline retinopathy, particularly in a subject who is likely to have, but has not yet suffered from, crystallin retinopathy. It means preventing or reducing the likelihood of suffering from crystal retinopathy.
  • Subjects who may be affected by crystallin retinopathy but have not yet suffered include, for example, subjects having a mutation in the CYP4V2 gene and subjects with a family history of crystallin retinopathy.
  • Subjects for treatment and / or prevention of crystallin retinopathy include animals, typically mammals (eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.), particularly humans. Can be mentioned. When applied to animals other than humans, the dose of the drug of the present invention may be appropriately adjusted depending on the body weight or size of the animal.
  • mammals eg, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
  • the dose of the drug of the present invention may be appropriately adjusted depending on the body weight or size of the animal.
  • composition disclosed herein can be a pharmaceutical composition.
  • the administration method of the pharmaceutical composition is not particularly limited, but can be administered through general administration routes such as oral administration, rectal administration, injection, infusion, eye drops, intravitreal injection, etc. It can be a suitable dosage form.
  • Oral dosage forms include granules, fine granules, powders, coated tablets, tablets, suppositories, powders, (micro) capsules, chewables, syrups, juices, liquids, suspensions, emulsions, etc. Is mentioned.
  • a dosage form for administration by injection general dosage forms of pharmaceutical preparations such as direct intravenous infusion, infusion administration, vitreous injection, a preparation for prolonging the release of an active substance and the like can be adopted.
  • dosage forms are manufactured by formulating in a conventional manner. Further, various pharmaceutically acceptable pharmaceutical substances can be blended as required in the preparation.
  • the substance for the preparation can be appropriately selected depending on the dosage form of the preparation.
  • the pharmaceutical substance examples include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol, and solvents, Examples include sterilized water and mono- or polyhydric alcohols such as glycerol.
  • the dose of the cholesterol accumulation inhibitor by the composition may vary depending on the age, weight or pathological condition of the subject patient, or the pharmaceutical dosage form or administration method.
  • the cyclodextrin compound can be administered in an amount of about 1 mg / kg body weight to 10 g / kg body weight, about 1 mg / kg body weight to 5 g / kg body weight, about 1 mg / kg body weight to 1 g / kg body weight per adult day.
  • the daily dose can be administered at once or in several divided doses.
  • Cholesterol accumulation inhibitors can be used alone or in combination with one or more additional active ingredients, in particular active ingredients for the treatment and / or prevention of crystallin retinopathy.
  • the pharmaceutical composition may comprise one or more additional active ingredients in addition to the cholesterol accumulation inhibitor.
  • “Combination” of the ingredients is not only for the use of dosage forms containing all ingredients and for the combination of dosage forms containing each ingredient separately, but also for the prevention and / or treatment of crystallin retinopathy. As long as it is used, it also means that each component is administered simultaneously or delayed. It is also possible to use two or more additional active ingredients in combination.
  • Active ingredients suitable for combined use include, for example, adaptinol, chocolate A, calcium blocker, valproic acid, vitamin A, DHA, taurine, lutein, isopropyl unoprostone, brimonidine and the like.
  • a therapeutic method for eye diseases other than drug therapy can also be performed.
  • Suitable therapies include, for example, surgery, photodynamic therapy, gene therapy, regenerative medicine, artificial retina transplantation, laser therapy.
  • a food for reducing the risk of crystallin retinopathy, or maintaining or improving eye function comprising a cholesterol accumulation inhibitor
  • the food may be any general food form containing a cholesterol accumulation inhibitor.
  • drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be eaten and eaten as juice, milk, confectionery, jelly, yogurt, rice cake, and the like.
  • This health functional food includes food for specified health use and food with nutritional function.
  • the food for specified health use is, for example, a food that can indicate that a specific health purpose can be expected, such as reducing the risk of crystallin retinopathy or maintaining or improving eye function.
  • functional nutritional food is a food that can indicate the function of the nutritional component when the amount of nutritional component included in the daily intake standard amount conforms to the national and national standards for upper and lower limits. is there.
  • Dietary supplements include so-called nutritional supplements or health supplements.
  • Specified health foods are foods that are labeled for use in applications such as reducing the risk of crystallin retinopathy or maintaining or improving eye function, and that they are used in such applications. Foods that include written documents (so-called Noh) as packages are also included.
  • a composition for treatment and / or prevention of crystallin retinopathy comprising a cholesterol accumulation inhibitor.
  • the cholesterol accumulation inhibitor is a cyclodextrin compound or a vitamin E compound.
  • the cholesterol accumulation inhibitor is a cyclodextrin compound.
  • the cholesterol accumulation inhibitor is a ⁇ -cyclodextrin or ⁇ -cyclodextrin in which at least one hydroxyl group may be alkylated or hydroxyalkylated, or a pharmaceutically acceptable salt, ester thereof, Item 4.
  • Items 1 to 4 wherein the cholesterol accumulation inhibitor is 2-hydroxypropyl- ⁇ -cyclodextrin (HPBCD), 2-hydroxypropyl- ⁇ -cyclodextrin (HPGCD) or methyl- ⁇ -cyclodextrin (MBCD) 5.
  • HPBCD 2-hydroxypropyl- ⁇ -cyclodextrin
  • HPGCD 2-hydroxypropyl- ⁇ -cyclodextrin
  • MBCD methyl- ⁇ -cyclodextrin
  • a composition according to 1. [10] The composition according to item 8, wherein in the formula (I), each R is independently H or alkyl optionally substituted with hydroxy. [11] The composition according to item 8 or 10, wherein in formula (I), each R is independently H, methyl, ethyl, propyl, or hydroxypropyl. [12] The composition according to any one of items 8 to 11, wherein n is 1, 2, or 3 in formula (I). [13] The composition according to any one of items 8 to 12, wherein n is 2 or 3 in formula (I).
  • the composition according to item 1 or 2 wherein the cholesterol accumulation inhibitor is a vitamin E compound.
  • the method according to item 18, wherein the cholesterol accumulation inhibitor is any one of items 2 to 17.
  • [20] Use of a cholesterol accumulation inhibitor for the treatment and / or prevention of crystallin retinopathy. [21] The use according to item 20, wherein the cholesterol accumulation inhibitor is one according to any one of items 2 to 17. [22] Use of a cholesterol accumulation inhibitor for the manufacture of a medicament for the treatment and / or prevention of crystallin retinopathy. [23] The use according to item 22, wherein the cholesterol accumulation inhibitor is any one of items 2 to 17.
  • P2-P3 cells WT iPS-RPE cells and BCD iPS-RPE cells
  • the lineage of cells derived from 3 healthy persons is divided into NOR-1, NOR-2 and NOR-3
  • the lineage of cells derived from 3 crystallin retinopathy patients is divided into BCD-1, BCD-2 and BCD. -3.
  • Experiment 2 Expression of CYP4V2 protein in iPS-RPE cells
  • the expression of CYP4V2 protein was analyzed by Western blotting. SDS- lysates of undifferentiated cells (WT iPS cells and BCD iPS cells) and P2 differentiated cells (WT iPS-RPE cells and BCDiPS-RPE cells) and human RPE cultured cells (ARPE19) (protein 20 ⁇ g / lane) They were separated by PAGE and transferred to a PVDF membrane.
  • CYP4V2 and ⁇ -actin were detected with anti-cyp4v2 antibody (sigma, rabbit polyclonal, 1: 100) and anti- ⁇ -actin antibody (Millipore, mouse monoclonal, 1: 10000). The results are shown in FIG. Expression of CYP4V2 protein was not observed in undifferentiated cells. In differentiated cells, expression of CYP4V2 protein was observed in WT iPS-RPE cells derived from healthy subjects, but not in BCD iPS-RPE cells derived from patients with crystal retinopathy.
  • WT iPS-RPE cells had a typical RPE cell morphology, namely polygonal shape and pigment granules.
  • BCD iPS-RPE cells showed vacuolar degeneration, enlargement and pigment granule excess.
  • WTiPS-RPE was a monolayer of highly polarized cubic cells with abundant apical microvilli and pigment granules.
  • BCD iPS-RPE cells showed accumulation and cytopathicity of melanosomes, lysosomes and autophagosomes.
  • Experiment 5 Proliferation ability of iPS-RPE cells
  • a 24-well plate (Costar) was coated with CELLstat TM (Gibco) at 4 ° C overnight, and then the coating solution was removed.
  • 2.1 ⁇ 10 4 iPS-RPE cells were seeded in each well in an RPE culture medium (DMEM / F12 medium, B27 (Invitrogen) and penicillin / streptomycin added) to obtain iPS-RPE progenitor cells.
  • RPE culture medium DMEM / F12 medium, B27 (Invitrogen) and penicillin / streptomycin added
  • the proliferative ability was evaluated. At the end of the culture on days 1, 2 and 3, 25 ⁇ l of Cell Count Reagent SF (Nacalai Tesque) was added to 225 ⁇ l of culture and incubated for 0.5 hours. The absorbance at 450 nm (reference 650 nm) of each well was measured with a microplate reader (ARVO), and the number of cells was calculated. The results are shown in FIG. BCD iPS-RPE progenitor cells were less proliferative than WT iPS-RPE progenitor cells.
  • P2 WT iPS-RPE progenitor cells (NOR-1) and BCD iPS-RPE progenitor cells (BCD-1) were cultured for 3 days and immunized with anti-Ki67 antibody (DAKO, mouse monoclonal, 1: 100) and DAPI Histochemical staining was performed. The ratio of the number of Ki67 positive cells to the number of DAPI positive cells was calculated. The results are shown in FIG. The ratio of BCD ⁇ iPS-RPE cells to Ki67 positive cells was lower than that of WT iPS-RPE cells.
  • Ki67 is a cell cycle-related nuclear protein, and is expressed in proliferating cells in the G1, S, G2, and M phases, but not in the G0 phase where growth is paused. Therefore, the expression level of Ki67 reflects the number of proliferating cells. This result indicates that BCD iPS-RPE cells are less proliferative than WT iPS-RPE cells. When the cells were observed with a bright field microscope, the number of BCDBiPS-RPE cells was clearly smaller than that of WT iPS-RPE cells.
  • Experiment 7 Change in proliferation ability of iPS-RPE cells by introduction of CYP4V2 gene Adenovirus vector construction pIRES-EGFP-CYP4V2 (WT) containing wild type CYP4V2 gene and pIRES-EGFP containing mutant CYP4V2 gene in cosmid DNA (pAxcwit2DNA) -CYP4V2 (mut) or pIRES-EGFP (control) was ligated to generate cosmid DNA. This was transfected into 293 cells to obtain recombinant adenovirus. As in Experiment 5, iPS-RPE cells were seeded in 24-well plates. However, the above three kinds of recombinant adenoviruses were infected two days before sowing.
  • FIG. 7 shows the results of evaluating cell proliferation ability in the same manner as in Experiment 5.
  • BCD + CYP4V2 (WT) vs. BCD + GFP
  • day 5 p 0.024
  • day 7 p 0.006.
  • the proliferation ability of BCDBiPS-RPE progenitor cells introduced with the wild-type CYP4V2 gene was significantly higher than that of BCD iPS-RPE progenitor cells introduced with the mutant or control gene. This result shows that the phenotype of cells derived from patients with crystal retinopathy was restored by the wild-type CYP4V2 gene.
  • Experiment 8 Changes in modified cells caused by CYP4V2 gene transfer P2 WT iPS-RPE cells (NOR-2) and BCD iPS-RPE cells (BCD-2) were further cultured for 3 months. Infected with recombinant adenovirus. Furthermore, it culture
  • the percentage of degenerated cells in BCD iPS-RPE cells introduced with the wild-type CYP4V2 gene was significantly lower than BCD iPS-RPE cells introduced with the mutant or control gene. This result shows that the phenotype of cells derived from patients with crystal retinopathy was restored by the wild-type CYP4V2 gene.
  • BCD iPS-RPE cells In the absence of bafilomycin A (Tx-), BCD iPS-RPE cells have higher levels of LC3 and p62 compared to WT iPS-RPE cells, suggesting that autophagy is inhibited .
  • bafilomycin A Baf A1
  • LC3 and p62 Increase in WT iPS-RPE cells compared to Tx-, but no effect of bafilomycin A was seen in BCD iPS-RPE cells.
  • Autophagy was inhibited by lysosome inhibitors in WT iPS-RPE cells, but autophagy was always inhibited in BCD iPS-RPE cells, so it is considered that they were not affected by lysosome inhibitors.
  • P2 WT iPS-RPE cells and BCD iPS-RPE cells were further cultured for 3 months, and anti-p62 (BD (610932), mouse monoclonal, 1:50), anti-lamp2 (abcam (ab25631), mouse IgG1, 1: 100). ) And DAPI. Immunostaining also confirmed increased expression of Lamp2, a lysosomal protein, and increased p62 expression in BCD iPS-RPE cells, suggesting that autophagy flow is impaired along with lysosomal accumulation in BCD PS-RPE cells. It was done.
  • Experiment 15 Effect of Cholesterol Accumulation Inhibitor on Cell Degeneration in BCD iPS-RPE Cells
  • BCD-1 BCD iPS-RPE cells
  • Experiment 18 Effect of cholesterol accumulation inhibitor on lysosomal function of BCD iPS-RPE cells
  • P2 BCD iPS-RPE cells (BCD-1-3) were further cultured for 3 months, 50 ⁇ M NBDNJ, 1 mM HPBCD or 1 mM HPGCD And cultured for 14 days.
  • the HPBCD and HPGCD treated groups had improved lysosomal function compared to the untreated group.
  • Experiment 20 Effect of cholesterol accumulation inhibitor on autophagy damage of BCD iPS-RPE cells
  • P2 BCD iPS-RPE cells (BCD-1-3) were further cultured for 3 months and then cultured with 1 mM HPBCD for 14 days.
  • the results are shown in FIG.
  • the levels of LC3-II and p62 were low compared to the untreated group (Tx ( ⁇ ) group). This suggests that autophagy disorder was improved by HPBCD treatment.

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Abstract

La présente invention concerne : une composition destinée au traitement prophylactique et/ou thérapeutique d'une rétinopathie cristalline, la composition contenant un inhibiteur d'accumulation de cholestérol ; un procédé de traitement prophylactique et/ou thérapeutique de la rétinopathie cristalline, le procédé comprenant l'administration d'un inhibiteur d'accumulation de cholestérol à un sujet ; et l'utilisation d'un inhibiteur d'accumulation de cholestérol dans le traitement prophylactique et/ou thérapeutique d'une rétinopathie cristalline.
PCT/JP2018/017183 2017-04-28 2018-04-27 Procédé de traitement prophylactique et/ou thérapeutique de la rétinopathie cristalline WO2018199287A1 (fr)

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JP7495756B2 (ja) 2019-12-09 2024-06-05 北京中因科技有限公司 医薬の製造におけるＣＹＰ４Ｖ２およびＲｄＣＶＦの使用

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JP2023506458A (ja) * 2019-12-09 2023-02-16 北京中因科技有限公司 医薬の製造におけるＣＹＰ４Ｖ２およびＲｄＣＶＦの使用
JP7495756B2 (ja) 2019-12-09 2024-06-05 北京中因科技有限公司 医薬の製造におけるＣＹＰ４Ｖ２およびＲｄＣＶＦの使用

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