WO2024143309A1 - Agent prophylactique/thérapeutique pour la maladie de gaucher neuronale - Google Patents

Agent prophylactique/thérapeutique pour la maladie de gaucher neuronale Download PDF

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WO2024143309A1
WO2024143309A1 PCT/JP2023/046520 JP2023046520W WO2024143309A1 WO 2024143309 A1 WO2024143309 A1 WO 2024143309A1 JP 2023046520 W JP2023046520 W JP 2023046520W WO 2024143309 A1 WO2024143309 A1 WO 2024143309A1
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tnf
microglia
inhibitor
neuronal
mice
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晶 山▲崎▼
隆 清水
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国立大学法人大阪大学
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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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a preventive and/or therapeutic agent for neuronal Gaucher disease (hereinafter, sometimes abbreviated as "prophylactic/therapeutic agent”). More specifically, the present invention relates to a preventive/therapeutic agent for neuronal Gaucher disease, which is a combination of a microglial activation inhibitor (e.g., minocycline) and a tumor necrosis factor (TNF) inhibitor (e.g., etanercept).
  • a microglial activation inhibitor e.g., minocycline
  • TNF tumor necrosis factor
  • Gaucher disease is a congenital metabolic disorder in which ⁇ -glucosylceramide (GlcCer) accumulates throughout the body due to reduced or absent activity of glucocerebrosidase (GCase) caused by a mutation in the GBA gene (Non-Patent Document 1).
  • GlcCer ⁇ -glucosylceramide
  • GCase glucocerebrosidase
  • Non-Patent Document 3 GlcCer synthesis inhibitors that can cross the BBB, GCase chaperone therapy, and gene therapy are all in the research and development stage (Non-Patent Document 4), and there is a need for rapid development of treatments based on a detailed understanding of the pathology.
  • the object of the present invention is therefore to elucidate the pathological mechanism of neuronal GD and to provide a new and effective agent for preventing and treating neuronal GD by suppressing said mechanism.
  • the present inventors investigated the pathological mechanism using a neuronal GD model mouse (Gba flox/flox ⁇ Nestin-Cre; Gba ⁇ Nes ).
  • ⁇ -GlcCer accumulated in the brain directly activates microglia, which produces tumor necrosis factor (TNF), which causes necroptotic stress in neurons, inducing the exposure of phagocytosis signal phosphatidylserine (PS) on the neuronal cell surface, and that microglia that recognize PS phagocytose neurons, promoting neuronal cell death.
  • TNF tumor necrosis factor
  • microglia that recognize PS phagocytose neurons, promoting neuronal cell death.
  • microglial activation and the resulting TNF production were observed in the brain tissue of patients with neuronal GD.
  • Minocycline was used to suppress microglial activation.
  • Mino is a tetracycline antibiotic preparation that is applicable to bacterial infections, but it is said to have anti-inflammatory effects in addition to antibacterial effects. It can also pass through the BBB and is widely used in experimental medicine to suppress microglial activation (Griffin, Pharmacal. Res. 2011).
  • Etanercept was used to neutralize TNF.
  • ETN is a fully human soluble TNF receptor preparation that is applicable to rheumatoid arthritis and also has a neutralizing effect on mouse TNF (Mohler, J. Immunol. 1993).
  • microglial activation inhibitors and/or TNF inhibitors can be used safely and effectively for the prevention and treatment of neuronal GD, and thus completed the present invention. That is, the present invention provides the following.
  • a microglial activation inhibitor comprising a combination of a microglia activation inhibitor and a TNF inhibitor.
  • TNF tumor necrosis factor
  • Item 3 Item 3. The agent according to Item 1 or 2, wherein the microglia activation inhibitor is a tetracycline antibiotic or a derivative thereof having an anti-inflammatory effect.
  • Item 4 Item 4.
  • TNF inhibitor is selected from the group consisting of a soluble TNF receptor (sTNFR), an antibody against TNF, an antagonist that binds to TNF, a mutant or fragment of TNF, an antibody against the TNF receptor, and a substance that inhibits the expression of TNF.
  • sTNFR soluble TNF receptor
  • the microglia activation inhibitor is minocycline and the TNF inhibitor is etanercept.
  • a method for preventing and/or treating neuronal Gaucher disease in a subject comprising administering to the subject an effective amount of a microglia activation inhibitor and/or a TNF inhibitor.
  • [Item 7] Use of a microglia activation inhibitor, a tumor necrosis factor (TNF) inhibitor, or a combination thereof in the manufacture of an agent for the prevention and/or treatment of neuronal Gaucher disease.
  • TNF tumor necrosis factor
  • the present invention can suppress microglial activation caused by ⁇ -GlcCer and can also suppress necroptotic stress in neurons induced by TNF, which is highly expressed in activated microglia, thereby improving the neurological symptoms in neuronal GD.
  • Microglia are highly activated in GD mice. Sections from brain tissues of wild-type (WT) and GD (Gba ⁇ Nes ) mice at postnatal day 21 were stained with NeuN (blue), FJC (green), and Iba1 (red) at the indicated areas. Iba1-positive cells were prominently detected in brain tissues of GD mice, indicating that microglia were activated.
  • MOp primary motor cortex
  • CP caudate putamen
  • HIP hippocampus
  • TH thalamus
  • MB midbrain
  • P pons
  • MY medulla
  • CB cerebellum
  • DH dorsal horn
  • VH ventral horn.
  • FIG. 1 ⁇ -GlcCer directly activates microglia.
  • Left Primary microglia from WT and Mincle -/- mice were stimulated with ⁇ -GlcCer d18:1/18:0 (10 nmol/well) or LPS (1 ⁇ g/mL) and immunostained for Iba1 (red). Representative staining images from three independent experiments are shown.
  • Right The size of Iba1-positive cells was calculated.
  • Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Tukey-Kramer test. *p ⁇ 0.05
  • PS phagocytosis signals
  • the present invention provides a preventive and/or therapeutic agent for neuronal Gaucher disease (GD) (hereinafter also referred to as the "preventive and therapeutic agent of the present invention”), which contains as an active ingredient a microglial activation inhibitor, a tumor necrosis factor (TNF) inhibitor, or a combination thereof.
  • GD neuronal Gaucher disease
  • TNF tumor necrosis factor
  • prevention and treatment of neurological GD is used to refer to the prevention or delay of the onset of neurological GD, improvement of the pathology of neurological GD, and prevention or delay of progression.
  • Microglia activation Inhibitor activation of microglia means that quiescent (M0) microglia are stimulated by ⁇ -GlcCer to become M1 type microglia that produce toxic molecules such as TNF. Therefore, in the present invention, “microglia activation inhibitor” refers to an agent that inhibits the transformation (activation) of microglia into TNF-producing M1 type microglia.
  • the present invention is based, at least in part, on the discovery that ⁇ -GlcCer directly stimulates microglia, and the activated microglia produce high levels of TNF, causing necroptosis stress in neurons, exposing the phagocytosis signal PS to neurons, and microglia that recognize PS phagocytose neurons to promote neuronal death. Therefore, although it is desirable to simultaneously reduce the phagocytic and TNF-producing abilities of microglia, it is also possible to suppress neuronal death by changing microglia to the M2 type, which produces protective molecules such as IL-4, IL-10, and arginase 1, thereby reducing TNF production and reducing necroptosis stress on neurons.
  • Microglial activation inhibitors that can be used in the preventive and therapeutic agents of the present invention are not particularly limited as long as they can inhibit the transformation (activation) of microglia into the TNF-producing M1 type, and may also include drugs that can transform M0 microglia into the M2 type that produces protective molecules such as IL-4, IL-10, and arginase 1, and drugs that can shift M1 microglia to the M2 type.
  • the microglial activation inhibitor may be a tetracycline antibiotic having an anti-inflammatory effect, such as minocycline, doxycycline, tetracycline, oxytetracycline, or tigecycline.
  • Minocycline or doxycycline is preferable, and minocycline is more preferable.
  • these anti-inflammatory tetracycline antibiotics may be derivatives thereof as long as they retain the effect of suppressing microglial activation, and the derivatives may not have antibacterial activity. Examples of such derivatives include, but are not limited to, incyclinide (COL-3).
  • the tetracycline antibiotic or its derivative that can be used in the present invention may be a compound represented by the following general formula:
  • the carbons at positions 4, 5, 6, 7 and 9 may have one or two substituents, and when they have a substituent, each substituent may be independently selected from hydroxy, C 1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3 alkoxy (e.g., methoxy, ethoxy, propyloxy, isopropynoxy), monoalkylamino (e.g., methylamino, ethylamino), dialkylamino (e.g., dimethylamino, diethylamino), halogen (e.g., fluorine, chlorine, bromine, iodine).)
  • C 1-3 alkyl e.g., methyl, ethyl, propyl, isopropyl
  • C 1-3 alkoxy e.g., methoxy, ethoxy, propyloxy, isopropynoxy
  • monoalkylamino
  • These drugs may be in the free form or in the form of a salt (unless otherwise specified in this specification).
  • Such salts include salts with physiologically acceptable acids (e.g., inorganic acids, organic acids) and bases (e.g., alkali metals, alkaline earth metals), and physiologically acceptable acid addition salts are particularly preferred.
  • salts include salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).
  • inorganic acids e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid
  • organic acids e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid.
  • these drugs may be in the form of a hydrate.
  • Tetracycline antibiotics such as minocycline and doxycycline are known to cross the BBB and can act on the central nervous system when administered systemically (e.g., orally).
  • Tetracycline antibiotics such as minocycline and doxycycline can be produced by known methods. These drugs are also commercially available.
  • examples of microglial activation inhibitors that can be used in the preventive and therapeutic agents of the present invention include existing antipsychotics and antidepressants. These drugs have been believed to act exclusively on the nervous and synaptic systems, but in recent years, it has been reported that they may act directly on microglia and have a brain-protecting effect. Examples of such antipsychotics and antidepressants include, but are not limited to, COX-2 inhibitors (e.g., celecoxib), risperidone, fluvoxamine, reboxetine, imipramine, perospirone, ziprasidone, quetiapine, paroxetine, sertraline, and aripiprazole.
  • COX-2 inhibitors e.g., celecoxib
  • risperidone fluvoxamine
  • reboxetine imipramine
  • perospirone ziprasidone
  • quetiapine paroxetine
  • sertraline aripiprazole
  • These drugs may be in the free form or as a salt. Alternatively, these drugs may be in the form of a hydrate.
  • a “substance that inhibits the function of TNF” may be any substance as long as it suppresses the function of TNF (necroptosis stress) on nerve cells once it has been functionally produced, and examples of such substances include substances that bind to TNF and inhibit the function, and substances that bind to TNF receptors (e.g., TNFR1, TNFR2) and inhibit the binding of TNF to the receptor.
  • the antibody against TNF is used as a pharmaceutical intended for administration to humans, and therefore the antibody (preferably a monoclonal antibody) is an antibody with a reduced risk of exhibiting antigenicity when administered to humans, specifically a fully human antibody, a humanized antibody, a mouse-human chimeric antibody, etc., and is particularly preferably a fully human antibody.
  • Humanized antibodies and chimeric antibodies can be produced by genetic engineering according to standard methods. Although fully human antibodies can also be produced from human-human (or mouse) hybridomas, in order to stably provide large amounts of antibodies at low cost, it is desirable to produce them using human antibody-producing mice or phage display methods.
  • pharmaceuticals containing anti-human TNF antibodies as the active ingredient are commercially available (e.g., infliximab, adamlimab, golimumab, and certolizumab), and these can also be used.
  • microglia activation inhibitor Only one type of microglia activation inhibitor may be used, or two or more types may be used in combination. Two or more types of microglia activation inhibitors may be formulated as separate pharmaceuticals, or may be combined in the same pharmaceutical composition. When two or more types of microglia activation inhibitors are formulated as separate pharmaceuticals, the respective preparations may be administered simultaneously or at different times. The administration route may be the same or different.
  • the dosage described below indicates the dosage of one type of microglia activation inhibitor, but even when two or more substances are used in combination, the same dosage can be used for each drug within a range that does not have an undesirable effect on the subject.
  • the pharmaceutical of the present invention may contain other active ingredients as long as they do not cause undesirable interactions when combined with the microglia activation inhibitor.
  • active ingredients include various compounds that have an effect of improving or alleviating any pathological condition of GD, but are not limited to these.
  • compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc.
  • Such compositions are produced by known methods and may contain carriers, diluents, or excipients commonly used in the pharmaceutical field. Examples of carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.
  • the pharmaceutical of the present invention may contain other active ingredients as long as they do not cause undesirable interactions when combined with the TNF inhibitor.
  • active ingredients include various compounds that have an effect of improving or alleviating any pathological condition of GD.
  • other active ingredients include other active ingredients that can be used in combination with the microglia activation inhibitors described above.
  • the preventive/therapeutic agent of the present invention is a medicine comprising a combination of a microglia activation inhibitor and a TNF inhibitor.
  • the microglia activation inhibitor and the TNF inhibitor may be formulated as separate medicines, or may be combined in a single pharmaceutical composition as long as they can be formulated and the same administration route can be selected.
  • the respective preparations may be administered simultaneously or at different times.
  • the administration routes may be the same or different. Even when the microglia activation inhibitor and the TNF inhibitor are used in combination, the same dosages as described above can be used for each drug, as long as they do not have an undesirable effect on the subject.
  • mice Mincle-deficient mice were backcrossed with C57BL/6J (WT) mice (purchased from CLEA Japan, Inc.) for at least 23 generations.
  • Nestin-Cre mice were purchased from The Jackson Laboratory. Both male and female mice were used in all experiments.
  • Gba-floxed mice were generated by gene targeting.
  • Gba flox/flox mice were crossed with Gba flox/+ ⁇ Nestin-Cre mice to generate Gba flox/flox ⁇ Nestin-Cre (Gba ⁇ Nes ) mice. All mice were maintained in laminar flow cages under SPF conditions with filtered air, fed standard laboratory chow, and allowed free access to water. All animal experiments were performed with the approval of the Ethics Committee for Animal Experiments at the Institute for Microbial Diseases, Osaka University.
  • Sections were then incubated overnight at 4°C with rabbit anti-Iba1 (1:1,000, EPR16588), guinea pig anti-IBA1 (1:500; Synaptic Systems, 234 004), mouse anti-NeuN (1:1,000, 1B7) and/or rabbit anti-TNF (1:500; Cell Signaling Technology, 3707) diluted in 1% (w/v) BSA in PBS.
  • the dissociated cells were suspended in Dulbecco's modified Eagle's medium (DMEM, Sigma-Aldrich, D5796) supplemented with 0.1% penicillin (Sigma-Aldrich, P3032)/streptomycin (MP Biochemicals, 194541) and 10% heat-inactivated fetal bovine serum (Sigma-Aldrich, 175012).
  • DMEM Dulbecco's modified Eagle's medium
  • P3032 penicillin
  • streptomycin MP Biochemicals, 194541
  • heat-inactivated fetal bovine serum Sigma-Aldrich, 175012
  • the cells were then seeded onto poly-D-lysine-coated T-75 flasks (Corning, 354537) and cultured at 37°C in a 5% CO2 incubator for 2–3 weeks.
  • microglia were harvested by shaking the flasks at 180 rpm for 2 h.
  • the tissue was washed with papain inhibitor buffer containing 1 mg/mL BSA and 1 mg/mL ovomucoid, and then the tissue was physically dissociated by gentle pipetting. Finally, dissociated cells were resuspended in 20% (v/v) Percoll (Cytiva, 17089101) in PBS and centrifuged at 400 ⁇ g for 25 min at 4 °C to remove myelin and debris.
  • Isolated microglia and neurons were prepared as previously described with some modifications. Briefly, single-cell suspensions of brain tissue were incubated with anti-mouse CD16/CD32 (1:100, 2.4G2) for 20 min at 4°C. Next, cells were labeled with anti-CD11b APC (1:200, M1/70; BioLegend, 101212) for 10 min at 4°C, and further incubated with anti-APC microbeads (1:5; Miltenyi Biotec, 130-090-855) for 10 min at 4°C.
  • Cells were then loaded into an MS column (Miltenyi Biotec, 130-042-201) and placed on a MACS separator (Miltenyi Biotec, 130-042-501).
  • the CD11b-labeled cell fraction was collected as microglia.
  • the unlabeled (negative) cell fraction was further incubated with non-neuronal cell biotin antibody cocktail for 5 min at 4°C and labeled with anti-biotin microbeads (Miltenyi Biotec, 130-090-485) for 10 min at 4°C.
  • the cells were then loaded into the MS column and placed in the MACS separation device.
  • the unlabeled flow-through cell fraction was collected as neurons.
  • RNA sequencing Single-cell suspensions (containing approximately 1 ⁇ 104 cells) from postnatal day 14 mouse brains were loaded onto the Chromium Next GEM Chip G Single Cell Kit (10x Genomics, PN-1000127) and barcoding and cDNA synthesis were performed using the Chromium Controller.
  • cDNA was amplified using the Chromium Next GEM Single Cell 3' Kit v3.1 (10x Genomics, PN-1000269) to construct cDNA libraries that were sequenced in paired-end mode (read 1, 28 bp; read 2, 91 bp) on an Illumina NovaSeq 6000 System. Data analysis and visualization were handled by BBrowser v2.10.48 software (BioTuring).
  • TNF levels in brain tissue lysates were quantified using the LEGENDplex Mouse Inflammation Panel (13-plex) (BioLegend, 740150) according to the manufacturer's instructions. After analysis using a Gallios flow cytometer, the data were analyzed using LEGENDplex v8.0 software (BioLegend).
  • Neurons isolated from mice were sonicated and suspended in lysis buffer containing 1% Nonidet P-40 (Nacalai Tesque, 23640-94), 1 mM phenylmethylsulfonyl fluoride (Nacalai Tesque, 27327-52), and a protease inhibitor cocktail containing 10 ⁇ g/mL aprotinin (Sigma-Aldrich, A6012), 12.5 ⁇ g/mL antipain dihydrochloride (Sigma-Aldrich, A6191), 12.5 ⁇ g/mL chymostatin (Sigma-Aldrich, C7268), 50 ⁇ g/mL leupeptin trifluoroacetate (Sigma-Aldrich, L2023), and 25 ⁇ g/mL pepstatin A (Sigma-Aldrich, P4265).
  • aprotinin Sigma-Aldrich, A6012
  • antipain dihydrochloride Sigma-Ald
  • PS labeling In vivo PS labeling was performed as previously described. Briefly, 1 ⁇ L of 1 mM PSVue 643 (Molecular Targeting Technologies, P-1006) was injected into the right lateral ventricle of mice using a 33-gauge Neuros syringe (Hamilton Company, 4015-63014). Mice were then killed by CO2 asphyxiation 24 h after injection and cardiac perfusion with PBS. Brain cells from the left cerebral cortex were stained with a non-neuronal biotin antibody cocktail and streptavidin PE, then resuspended in PI and analyzed on a Gallios flow cytometer. The obtained data were evaluated using FlowJo software.
  • Minocycline (Sigma-Aldrich, M9511) was dissolved in PBS and administered intraperitoneally to mice at 100 mg/kg daily from postnatal day 10.
  • Etanercept (Pfizer) was dissolved in PBS and administered intracerebroventricularly at 5 mg/kg (2 ⁇ L) using a 33-gauge Neuros syringe every other day from postnatal day 10.
  • Phenotypic Evaluation Righting reflex was measured as the time it took for mice to return to a standing position after being placed on their back. Loss of righting reflex was defined as the inability to right themselves within 60 s.
  • the mouse was placed on the wire mesh of a Wire Hanging Test Chamber (O'HARA & CO., LTD. WH-3002) and turned over. The time it took to fall was recorded three times, and the longest time was used.
  • mice were placed on a wire mesh and stimulated with von Frey filaments (Neuroscience, inc. 514000-20C) on the midplantar surface of the hind paw until the mouse withdrew its hind paw in response to the physical stimulus. The 50% threshold was determined using the up-down stimulation method.
  • ⁇ -GlcCer directly activates microglia>
  • ⁇ -GlcCer which accumulates due to enzyme deficiency in GD, directly activates microglia
  • primary microglia prepared from WT mice and mice lacking Mincle
  • an immunoreceptor of ⁇ -GlcCer in microglia (Mincle -/- ) were stimulated with ⁇ -GlcCer and their size was measured by visualization using Iba1 positivity as an indicator. The results are shown in Figure 2. The increase in microglia size was Mincle-dependent, demonstrating that ⁇ -GlcCer directly activates microglia.
  • PS phosphatidylserine
  • Minocycline is an antibacterial drug used for various infections and is known to suppress the activation of microglia.
  • Etanercept is a TNF inhibitor that is applicable to rheumatoid arthritis.
  • the medicine using the microglia activation inhibitor and/or TNF inhibitor of the present invention is useful for improving the neurological symptoms of neurological GD, which has had no effective treatment and a very poor prognosis until now.
  • the use of existing drugs minocycline and etanercept will enable early clinical application.

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Abstract

L'invention concerne un agent prophylactique/thérapeutique pour la maladie de Gaucher neuronale selon la présente invention contient en tant que principe actif un inhibiteur de l'activation microgliale, un inhibiteur de facteur de nécrose tumorale ou une combinaison de ceux-ci (de préférence la minocycline et l'étanercept).
PCT/JP2023/046520 2022-12-26 2023-12-25 Agent prophylactique/thérapeutique pour la maladie de gaucher neuronale WO2024143309A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016005748A1 (fr) * 2014-07-11 2016-01-14 Isis Innovation Limited Traitement de troubles lysosomaux (traitement anti-tnf)
JP2022547169A (ja) * 2019-09-09 2022-11-10 フィジーン、エルエルシー 線維芽細胞による外傷性脳症の治療と治療補助薬

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016005748A1 (fr) * 2014-07-11 2016-01-14 Isis Innovation Limited Traitement de troubles lysosomaux (traitement anti-tnf)
JP2022547169A (ja) * 2019-09-09 2022-11-10 フィジーン、エルエルシー 線維芽細胞による外傷性脳症の治療と治療補助薬

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KOBAYASHI K, IMAGAMA S, OHGOMORI T, HIRANO K, UCHIMURA K, SAKAMOTO K, HIRAKAWA A, TAKEUCHI H, SUZUMURA A, ISHIGURO N, KADOMATSU K: "Minocycline selectively inhibits M1 polarization of microglia", CELL DEATH & DISEASE, NATURE PUBLISHING GROUP, GB, vol. 4, no. 3, 2013, GB , pages e525 - e525, XP093186627, ISSN: 2041-4889, DOI: 10.1038/cddis.2013.54 *
SHIMIZU TAKASHI, SCHUTT CHARLES R., IZUMI YOSHIHIRO, TOMIYASU NORIYUKI, OMAHDI ZAKARIA, KANO KUNIYUKI, TAKAMATSU HYOTA, AOKI JUNKE: "Direct activation of microglia by β-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease", IMMUNITY, CELL PRESS, AMSTERDAM, NL, vol. 56, no. 2, 1 February 2023 (2023-02-01), AMSTERDAM, NL , pages 307 - 319.e8, XP093186623, ISSN: 1074-7613, DOI: 10.1016/j.immuni.2023.01.008 *
SHIMIZU, TAKASHI ET AL.: "Novel molecular mechanism for induction of neuronal death in Gaucher disease", JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 283, no. 5, 29 October 2022 (2022-10-29), pages 380 - 384 *

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