WO2023171806A1 - Agent thérapeutique ou prophylactique pour des maladies associées à des dysfonctionnements mitochondriaux - Google Patents

Agent thérapeutique ou prophylactique pour des maladies associées à des dysfonctionnements mitochondriaux Download PDF

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WO2023171806A1
WO2023171806A1 PCT/JP2023/009408 JP2023009408W WO2023171806A1 WO 2023171806 A1 WO2023171806 A1 WO 2023171806A1 JP 2023009408 W JP2023009408 W JP 2023009408W WO 2023171806 A1 WO2023171806 A1 WO 2023171806A1
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deficiency
syndrome
mitochondrial
disease
perk
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Japanese (ja)
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耕史 木下
遥 佐藤
良和 長垣
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株式会社幹細胞＆デバイス研究所
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a therapeutic or preventive agent for diseases accompanied by mitochondrial dysfunction.
  • Patent Document 1 a cell line in which mitochondrial damage was caused by an electron transport chain inhibitor is used to analyze the pathology of a disease accompanied by mitochondrial dysfunction.
  • Patent Document 1 the study was conducted using an artificial mitochondrial disorder model, and no study was conducted using patient-derived model cells. Thus, methods for treating or preventing diseases involving mitochondrial dysfunction have not yet been established.
  • the present invention aims to provide a novel therapeutic or preventive agent that can treat or prevent diseases accompanied by mitochondrial dysfunction.
  • GCN2 general control nonderepressible 2
  • PERK PSR-like endoplasmic reticulum kinase
  • a therapeutic or preventive agent for a disease accompanied by mitochondrial dysfunction comprising at least one of a GCN2 (general control nonderepressible 2) inhibitor and a PERK (PKR-like endoplasmic reticulum kinase) inhibitor.
  • GCN2 general control nonderepressible 2
  • PERK PSR-like endoplasmic reticulum kinase
  • the therapeutic or preventive agent according to [1] which comprises a GCN2 and PERK dual inhibitor.
  • the therapeutic or preventive agent according to [1] or [2] which contains at least one selected from the group consisting of GCN2iB, GSK2656157, and AMG PERK 44.
  • the therapeutic or preventive agent according to any one of [1] to [3], wherein the disease is a disease accompanied by peripheral nerve-specific axonopathy.
  • the above diseases include Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), Leigh syndrome (LS), MEGDEL syndrome, mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathies, lactic acidosis, and stroke-like episodes ( MELAS), Ragged Red Fiber Myoclonic Epilepsy Syndrome (MERRF), Mitochondrial Neurogenic Gastrointestinal Encephalomyopathy (MNGIE), Neurogenic Ataxia Retinitis Pigmentosa (NARP), OPA1 mutation, Pearson syndrome, progressive extraocular Muscular paralysis (PEO), mitochondrial complex I deficiency, mitochondrial complex II deficiency, mitochondrial complex III deficiency, mitochondrial complex IV deficiency, mitochondrial complex V (ATP synthase) deficiency,
  • EAOH Early-onset ataxia
  • Charcot-Marie-Tooth disease type 2A Charcot-Marie-Tooth disease type 2A
  • sudden infant death syndrome MERRF/MELAS overlap syndrome
  • leukoencephalopathy with brain stem and spinal cord damage and elevated lactate LBSL
  • Mitochondrial disease optic atrophy type 1, ethylmalonic acid encephalopathy, carnitine acylcarnitine translocase deficiency, primary systemic carnitine deficiency, creatine deficiency syndrome, cerebral creatine deficiency syndrome-1, cerebral creatine deficiency syndrome-2, cerebral Creatine deficiency syndrome-3, carnitine palmitoyltransferase 1 (CPTI) deficiency, carnitine palmitoyltransferase 2 (CPTII) deficiency, short chain acyl CoA dehydrogenase deficiency, very long chain acyl CoA dehydrogenase deficiency, long chain 3-
  • FIG. 2 is a diagram showing an overview of the integrated stress response pathway. It is an observation image of a motor nerve spheroid used in an example.
  • FIG. 3 is a diagram showing the frequency distribution of mitochondrial aspect ratios before and after the addition of GCN2iB to a healthy human strain.
  • FIG. 2 is a diagram showing the frequency distribution of mitochondrial aspect ratios before and after addition of GCN2iB to CMT2A strain.
  • FIG. 3 is a diagram comparing the percentage of abnormal mitochondria in motor nerve spheroids derived from the CMT2A strain before and after addition of each drug.
  • FIG. 3 is a diagram comparing the percentage of normal mitochondria in motor nerve spheroids derived from the CMT2A strain before and after addition of each drug.
  • FIG. 3 is a diagram showing an overview of the integrated stress response pathway. It is an observation image of a motor nerve spheroid used in an example.
  • FIG. 3 is a diagram showing the frequency distribution of mitochondrial aspect ratios before and after the
  • FIG. 2 is a diagram of bands in which ATF4 and ⁇ -actin proteins were detected in motor neurons derived from healthy individuals and from CMT2A patients.
  • FIG. 2 is a graph quantifying the protein amount of ATF4 in motor neurons derived from healthy individuals and CMT2A patients after correction with ⁇ -actin.
  • FIG. It is a graph in which the gene expression levels of ATF4, ASNS, and CHOP in motor neurons derived from healthy individuals and CMT2A patients were quantified after being corrected with GAPDH.
  • the present embodiment a mode for carrying out the present invention (hereinafter referred to as "the present embodiment") will be described in detail, but the present invention is not limited thereto, and various modifications may be made without departing from the gist thereof. is possible.
  • the therapeutic or preventive agent for diseases accompanied by mitochondrial dysfunction includes a GCN2 (general control nonderepressible 2) inhibitor and a PERK (PKR-like endoplasmic reticulum kinase) inhibitor (hereinafter also simply referred to as "inhibitor").
  • GCN2 general control nonderepressible 2
  • PERK PSR-like endoplasmic reticulum kinase
  • GCN2 and PERK are protein kinases known as regulators of the integrated stress response (ISR) pathway.
  • ISR pathway is a pathway that is activated within eukaryotic cells when they receive stress such as viral infection, nutrient (amino acid, sugar, serum) deficiency, ischemia, heat shock, and oxidative stress. This pathway plays an important role in adaptation to stress and environmental changes.
  • eIF2 ⁇ is a subunit that constitutes eukaryotic protein translation initiation factor 2 (eIF2).
  • eIF2 is a heterotrimer containing eIF2 ⁇ and eIF2 ⁇ in addition to eIF2 ⁇ , and has the function of incorporating initiator tRNA into ribosomes.
  • eIF2 ⁇ is phosphorylated, the function of eIF2 is suppressed and protein synthesis is suppressed. be done.
  • ATF4 activating transcription factor 4
  • ISR regulators include, for example, HRI (heme-regulated inhibitor) and PKR (double-stranded RNA dependent protein kinase).
  • GCN2 is an eIF2 ⁇ kinase that is activated by amino acid deficiency, etc., and PERK is activated by endoplasmic reticulum stress (ER stress (stress due to accumulation of unfolded protein; UP)). It is a kinase of eIF2 ⁇ .
  • the ISR pathway involving GCN2 or PERK means a pathway in which GCN2 and/or PERK is activated and eIF2 ⁇ is phosphorylated in response to stress such as amino acid deficiency or endoplasmic reticulum stress. Activation of this pathway suppresses protein synthesis and induces the synthesis of stress-induced proteins such as ATF4.
  • the inhibitor contained in the therapeutic or preventive agent according to this embodiment is not particularly limited as long as it is at least one of a GCN2 inhibitor and a PERK inhibitor.
  • GCN2 inhibitor or PERK inhibitor refers to (1) a substance that inhibits the kinase activity of GCN2 or PERK, (2) a substance that inhibits the binding of GCN2 or PERK to eIF2 ⁇ , (3) GCN2 or Includes substances that inhibit gene expression of PERK, and (4) substances that degrade GCN2 or PERK.
  • “inhibition of activity” also includes reducing or eliminating a function or activity that exists in the absence of an inhibitor.
  • Embodiments of the inhibitor include, for example, (1) a substance that inhibits the activation of GCN2 and/or PERK; a substance that inhibits activated GCN2 and/or PERK from phosphorylating eIF2 ⁇ ; (2) a substance that inhibits GCN2 and/or PERK from phosphorylating eIF2 ⁇ ; / or a substance that binds to PERK and inhibits the binding to eIF2 ⁇ ; a substance that binds to eIF2 ⁇ and inhibits the binding to GCN2 and/or PERK; (3) a substance that suppresses gene expression of GCN2 and/or PERK; (4) Examples include substances that decompose GCN2 and/or PERK.
  • the inhibitor is preferably a substance that (1) inhibits the kinase activity of GCN2 and/or PERK.
  • the therapeutic or preventive agent according to this embodiment contains a GCN2 and PERK dual inhibitor as an inhibitor.
  • GCN2 and PERK dual inhibitors are (1) substances that inhibit the kinase activities of GCN2 and PERK, (2) substances that inhibit the binding between GCN2 and eIF2 ⁇ , and the binding between PERK and eIF2 ⁇ , (3) GCN2 and Includes substances that inhibit gene expression of PERK, and (4) substances that degrade GCN2 and PERK.
  • the inhibitor is not particularly limited as long as it functions as at least one of a GCN2 inhibitor and a PERK inhibitor, and includes, for example, proteins such as antibodies, peptides, peptidomimetics, nucleic acids, carbohydrates, lipids, or low molecular weight compounds. It may be.
  • the term "low molecular compound” refers to compounds other than proteins, peptides, peptidomimetics, nucleic acids, carbohydrates, and lipids, such as those with a molecular weight of 1000 or less, 900 or less, 800 or less, 700 or less, or 600 or less.
  • Substances that inhibit the kinase activity of GCN2 include, for example, GCN2iB, GZD824, GCN2-IN-6, and the compounds described in WO 2013/110309 (for example, compounds represented by formula I, among which preferably those described in Examples) compounds described in WO 2013/124026 (e.g. compounds represented by formula I, preferably compounds described in Examples), compounds described in WO 2013/131609 (e.g. compounds represented by formula I) Compounds represented by formula I, particularly preferably the compounds described in Examples), compounds described in WO 2014/135244 (e.g. compounds represented by formula I, particularly preferably compounds described in Examples), Compounds described in WO 2014/135245 (e.g.
  • GCN2iB, GZD824, and GCN2-IN-6 are compounds having structures shown in the table below.
  • Examples of substances that inhibit the kinase activity of PERK include compounds described in GSK2656157, AMG PERK 44, and International Publication No. 2012/013557 (for example, compounds represented by formula I, preferably compounds described in Examples), Compounds described in WO 2014/161808 (for example, compounds represented by formula (I), preferably compounds described in Examples), compounds described in WO 2015/056180 (for example, compounds represented by formula (I) ), preferably the compounds described in Examples), the compounds described in International Publication No. 2015/136463 (for example, the compounds represented by formula (X), especially the compounds described in Examples) ), compounds described in WO 2017/046737 (e.g.
  • 2018/015879 such as a compound represented by formula (I), preferably a compound described in Examples
  • the compounds described in International Publication No. 2018/194885 e.g. compounds represented by formula (I), preferably the compounds described in Examples
  • the compounds described in International Publication No. 2019/021208 Compounds (e.g. compounds represented by formula (I), particularly preferably the compounds described in the Examples), compounds described in International Publication No. 2021/041970 (e.g. compounds represented by formula (I), among them preferably Compounds described in WO 2021/041975 (e.g. compounds represented by formula (I), preferably compounds described in Examples), WO 2021/041976 Compounds described in WO 2021/231782 (e.g.
  • GSK2656157 and AMG PERK 44 are compounds having structures shown in the table below.
  • substances that inhibit the kinase activities of GCN2 and PERK include substances known as GCN2 and PERK dual inhibitors among the above-mentioned substances, such as GCN2iB and AMG PERK 44.
  • the substance that suppresses the gene expression of GCN2 and/or PERK is not particularly limited as long as it is a substance that is involved in the expression of the GCN2 and/or PERK gene and suppresses the expression of GCN2 and/or PERK.
  • the expression suppressor of the gene may be siRNA (short interfering RNA), shRNA (short hairpin RNA), miRNA (micro RNA), ribozyme, and antisense oligonucleotide corresponding to the GCN2 and/or PERK gene; It may be siRNA, shRNA, miRNA, ribozyme, and antisense oligonucleotide corresponding to the gene involved in the expression of the gene.
  • siRNA, shRNA, miRNA, and ribozyme may be artificially chemically synthesized. For example, it may be synthesized in vitro from template DNA using T7 RNA polymerase and a T7 promoter.
  • the antisense oligonucleotide may be any nucleotide that is complementary to or hybridizes to a base sequence of less than about 30 consecutive bases in the DNA sequence of the above-mentioned gene, and may be either DNA or RNA. . Further, it may be modified as long as it does not impede the function. Antisense oligonucleotides can be synthesized by conventional methods, for example, easily using a commercially available DNA synthesizer.
  • the gene expression suppressor may suppress gene expression by inhibiting transcription, translation, or both of the GCN2 and/or PERK genes.
  • Examples of substances that decompose GCN2 and/or PERK include degron and PROTAC.
  • the inhibitor has cell permeability. Therefore, among the above-mentioned examples, the inhibitor is preferably a low molecular compound. Alternatively, it is also preferable to use the antibodies exemplified above that are made cell-permeable.
  • the inhibitor is at least one selected from the group consisting of GZD824, GCN2-IN-6, GCN2iB, GSK2656157, and AMG PERK 44, more preferably GCN2iB, GSK2656157, and At least one type selected from the group consisting of AMG PERK 44.
  • the therapeutic or preventive agent according to the present embodiment may contain one type of the above-mentioned inhibitors alone, or may contain two or more types in combination.
  • the low-molecular compound may be produced by a known method, or may be obtained by purchasing a commercially available product.
  • the inhibitor is an antibody, it can be produced by a known method using GCN2 and/or PERK or a fragment thereof as an immunogen.
  • the therapeutic or prophylactic agent according to this embodiment is not particularly limited as long as it contains at least one of the above inhibitors, but may further contain a pharmaceutically acceptable carrier and/or additive, and may further contain a pharmaceutically acceptable carrier and/or additive.
  • may be Forms of formulation include, for example, oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, and emulsions; injections, infusions, suppositories, ointments, and parenteral preparations such as patches.
  • the content of the carrier or additive may be appropriately set based on the range normally adopted in the pharmaceutical field.
  • Examples of the carrier include, but are not particularly limited to, water, physiological saline, other aqueous solvents, and aqueous or oily bases.
  • the above-mentioned additives include, but are not particularly limited to, excipients, binders, pH adjusters, disintegrants, absorption enhancers, lubricants, colorants, flavoring agents, fragrances, and the like.
  • the above carriers and/or additives may be used alone or in combination of two or more.
  • the low-molecular compound can be used as an oral preparation (e.g., tablet, coated tablet, pill, powder, granule, capsule) formulated with a pharmaceutically acceptable carrier. , solutions, suspensions, or emulsions) by the oral route of administration.
  • the antibody can be administered by parenteral routes (e.g., intravenous, intramuscular, intradermal, intraperitoneal) as an injection or infusion formulated with a pharmaceutically acceptable carrier. , subcutaneously or topically).
  • parenteral routes e.g., intravenous, intramuscular, intradermal, intraperitoneal
  • injections or infusions containing antibodies may be used as solutions, suspensions, or emulsions.
  • solvents used include distilled water for injection, physiological saline, glucose solutions, and isotonic solutions (e.g., solutions of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, propylene glycol, etc.) etc. These solvents may be used alone or in combination of two or more.
  • the injection or infusion may contain additives such as stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, preservatives, and pH adjusters.
  • additives such as stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, preservatives, and pH adjusters.
  • stabilizer include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, ascorbic acid, sodium bisulfite, sodium thiosulfate, sodium EDTA, sodium citrate, and dibutylhydroxytoluene. It will be done.
  • solubilizing agents include alcohols (e.g., ethanol, etc.), polyalcohols (e.g., propylene glycol, polyethylene glycol, etc.), and nonionic surfactants (e.g., polysorbate 80 (registered trademark), HCO-50, etc.). ) etc.
  • the suspending agent include glyceryl monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and sodium lauryl sulfate.
  • emulsifiers include gum arabic, sodium alginate, and tragacanth.
  • soothing agents include benzyl alcohol, chlorobutanol, and sorbitol.
  • Examples of the buffer include phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, and Tris buffer.
  • Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and Examples include borax.
  • Examples of the preservative include benzalkonium chloride, paraoxybenzoic acid, and chlorobutanol.
  • Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid.
  • the disease targeted by the therapeutic or preventive agent according to this embodiment is not particularly limited as long as it is a disease accompanied by mitochondrial dysfunction.
  • By administering the therapeutic or preventive agent according to the present embodiment to a subject having such a disease it is possible to suppress overactivation of the ISR pathway that is presumed to be caused by mitochondrial dysfunction, and to prevent mitochondrial dysfunction and the relevant disease.
  • the pathology of the disease can be improved or prevented.
  • Such diseases include, for example, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON), Leigh syndrome (LS), MEGDEL syndrome, mitochondrial DNA depletion syndrome (MDS), mitochondrial encephalomyopathy, lactic acidosis, Stroke-like episodes (MELAS), Ragged Red Fiber Myoclonic Epilepsy Syndrome (MERRF), Mitochondrial Neurogenic Gastrointestinal Encephalomyopathy (MNGIE), Neurogenic Ataxia Retinitis Pigmentosa (NARP), OPA1 mutation, Pearson syndrome, progressive external ophthalmoplegia (PEO), mitochondrial complex I deficiency, mitochondrial complex II deficiency, mitochondrial complex III deficiency, mitochondrial complex IV deficiency, mitochondrial complex V (ATP synthase) deficiency, Primary coenzyme Q10 deficiency (COQIOD), CODAS syndrome, PolG-associated mitochondrial disease, chronic progressive extraocular myalg
  • the disease targeted by the therapeutic or preventive agent according to the present embodiment is preferably Charcot-Marie-Tooth disease type 2A (hereinafter referred to as "CMT2A").
  • Charcot-Marie-Tooth disease is a general term for genetic diseases accompanied by peripheral neuropathy.
  • CMT is classified into demyelinating type, axonal type, etc. depending on the pathological condition, and is further classified into subclasses such as CMT types 1 to 4.
  • CMT type 2 is a disease classified as an axonal type that causes degeneration of axons, and is further subdivided into CMT2A type, CMT2D type, etc., depending on the causative gene and phenotype.
  • CMT2A type and CMT2D type have different gene expression profiles.
  • CMT2A type is a disease that causes axonal and mitochondrial disorders due to mutations in the mitofusin 2 (MFN2) gene, so MFN2 agonists are known to improve the pathology of CMT2A type (A. Rocha et al. , Science 360, 336-341 (2016)).
  • the disease targeted by the therapeutic or preventive agent according to the present embodiment may be a disease in which the causative factor of the disease is not in the ISR pathway among diseases accompanied by mitochondrial dysfunction, and the disease can be treated with a GCN2 inhibitor and a PERK inhibitor. It may be a disease for which no therapeutic or preventive effect has been found.
  • the disease targeted by the therapeutic or preventive agent according to the present embodiment may be a disease that causes peripheral nerve-specific mitochondrial dysfunction, or may be a disease that is accompanied by peripheral nerve-specific axonal damage.
  • the disease targeted by the therapeutic or preventive agent according to this embodiment may be a disease caused by mitochondrial dysfunction or a disease related to mitochondrial dysfunction.
  • a preferred aspect of the present embodiment is a CMT2A type therapeutic or preventive agent containing at least one of a GCN2 inhibitor and a PERK inhibitor (more preferably a GCN2 and PERK dual inhibitor).
  • the therapeutic or preventive agent may contain as an inhibitor at least one selected from the group consisting of GZD824, GCN2-IN-6, GCN2iB, GSK2656157, and AMG PERK 44; and AMG PERK 44.
  • the therapeutic or preventive agent according to this embodiment can improve or prevent mitochondrial dysfunction.
  • the mitochondrial dysfunction may be mitochondrial dysfunction in a motor neuron.
  • the therapeutic or preventive agent according to this embodiment can increase the proportion of normal mitochondria and decrease the proportion of abnormal mitochondria in a subject with a disease accompanied by mitochondrial dysfunction.
  • the normal mitochondria may be mitochondria with an aspect ratio of 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more
  • the abnormal mitochondria may have an aspect ratio of 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more.
  • the therapeutic or preventive agent according to the present embodiment can increase the amount of ATP produced per mitochondrial cell in motor neurons of a subject having a disease accompanied by mitochondrial dysfunction.
  • the therapeutic or preventive agent according to this embodiment can improve or prevent the pathology of a disease.
  • peripheral nerve-specific axonopathy may be improved or prevented.
  • peripheral nerve-specific axonal degeneration may be improved or prevented.
  • the pharmaceutical formulation of this embodiment includes the therapeutic or preventive agent according to this embodiment.
  • the pharmaceutical formulation comprises any of the substances mentioned above that inhibit the activity of the integrated stress response pathway (substances mentioned above as examples of GCN2 inhibitors or PERK inhibitors).
  • the pharmaceutical formulation comprises any of the substances mentioned above that inhibit the activity of the integrated stress response pathway (substances mentioned above as examples of GCN2 inhibitors or PERK inhibitors).
  • One aspect of this embodiment is to administer any of the above substances that are at least one of a GCN2 inhibitor and a PERK inhibitor to a patient with a disease accompanied by mitochondrial dysfunction.
  • a method for treating or preventing a disease accompanied by mitochondrial dysfunction comprising administering a substance (substance) in a pharmacologically effective amount.
  • the subject to which the method for treating or preventing diseases involving mitochondrial dysfunction is applied may be humans, and non-human mammals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) It may be.
  • the dosage of any of the above substances (inhibitors), which is at least one of a GCN2 inhibitor and a PERK inhibitor, depends on the purpose, severity of the disease, age, weight, sex, medical history of the patient, and type of active ingredient. etc., and may be set as appropriate.
  • GCN2 inhibitors or PERK inhibitors for use in the treatment or prevention of diseases involving mitochondrial dysfunction
  • a pharmaceutical composition comprising at least one of a GCN2 inhibitor and a PERK inhibitor for use in the treatment or prevention of a disease associated with mitochondrial dysfunction; Use of at least one of a GCN2 inhibitor and a PERK inhibitor to treat or prevent a disease associated with mitochondrial dysfunction; Use of at least one of a GCN2 inhibitor and a PERK inhibitor in the manufacture of a medicament for the treatment or prevention of a disease accompanied by mitochondrial dysfunction; or Use in the manufacture of a medicament for the treatment or prevention of a disease accompanied by mitochondrial dysfunction.
  • a GCN2 inhibitor or a PERK inhibitor a GCN2 inhibitor or a PERK inhibitor.
  • the GCN2 inhibitor and the PERK inhibitor may be any of the substances mentioned above as examples of the GCN2 inhibitor or the PERK inhibitor.
  • the disease may be any of the diseases described above.
  • the culture medium used Neurobasal TM Medium (manufactured by Thermo Fisher Scientific, product number "21103049”) as the basal medium, and 2% B-27 TM Supplement, minus vitamin A (manufactured by Thermo Fisher Scientific, product number "12587010”), 0.5%.
  • Penicillin-streptomycin (5,000 U/mL) (manufactured by Thermo Fisher Scientific, product number "15070063”), 10 ng/mL BDNF (manufactured by Peprotec, product number "450-02”), 10 ng/mL GDNF (manufactured by Peprotec, product number "450-02”) A sample containing 10 ng/mL NT-3 (manufactured by Peprotec, product number 450-03) was used.
  • the cells were transferred to a 35 mm glass bottom dish (manufactured by IWAKI Co., Ltd., product number "3971-035-SK” or “3960-035”) coated with 35 mm, and cultured in the same medium as above.
  • Figure 2 shows motor nerve spheroids observed on a glass bottom dish.
  • mitochondria in the axons were observed for fluorescence using a fluorescence microscope (manufactured by Keyence Corporation, model number "BZ-710") equipped with a 60x objective lens.
  • GCN2iB or AMG PERK 44 (GCN2 and PERK dual inhibitor), or GSK2656157 (PERK inhibitor) was added at a final concentration of 1 ⁇ M.
  • Each compound was dissolved in DMSO, and the DMSO concentration in the medium, including the control group, was 0.01% (10,000-fold dilution).
  • FIG. 3 and FIG. 4 are diagrams showing the frequency distribution of mitochondrial aspect ratios before and after the addition of GCN2iB in the healthy human strain and the CMT2A strain, respectively.
  • Figures 5 and 6 are diagrams comparing the proportions of abnormal mitochondria and normal mitochondria in the CMT2A strain before and after addition of each drug.
  • GCN2iB was added at a final concentration of 1 ⁇ M or 10 ⁇ M on the 6th day of culture.
  • the DMSO concentration contained in the culture medium was 0.1% (1,000-fold dilution) including the control group.
  • the prepared sample was applied to a polyacrylamide gel and electrophoresed, and then the proteins were transferred from the polyacrylamide gel to a PDVF membrane. After blocking was performed using EveryBlot blocking buffer (Bio-Rad Laboratories, Inc., model: 12010020), a primary antibody reaction was performed overnight at 4°C. As primary antibodies, anti-ATF4 antibody (Cell Signaling, 97038) and anti- ⁇ -actin antibody (SANTA CRUZ, sc-47778) were used. After washing the membrane with TBS-T (0.05% Tween20) buffer, a secondary antibody reaction was performed at room temperature for 1 hour. As the secondary antibody, Goat Anti-Mouse IgG (H+L)-HRP Conjugate (Bio-Rad, 1706515) was used. After washing the membrane with TBS-T buffer, signals were detected using ECL substrate.
  • EveryBlot blocking buffer Bio-Rad Laboratories, Inc., model: 12010020
  • primary antibodies anti-ATF4 antibody (Cell Signal
  • FIG. 7 is a diagram of bands in which ATF4 and ⁇ -actin proteins were detected.
  • FIG. 8 is a graph in which the amount of ATF4 protein is quantified after being corrected by the amount of ⁇ -actin protein.
  • GCN2iB was added at a final concentration of 1 ⁇ M or 10 ⁇ M on the 6th day of culture.
  • the DMSO concentration contained in the culture medium was 0.1% (1,000-fold dilution) including the control group.
  • RNA concentration was calculated from the absorbance at 260 nm and 280 nm.
  • the extract was fractionated to a certain amount of RNA, and cDNA was synthesized using ReverTra Ace (registered trademark) qPCR RT Master Mix with gDNA Remover (TOYOBO, FSQ-301).
  • ATF4 TTCTCCAGCGACAAGGCTAAGG and CTCCAACATCCAATCTGTCCCG
  • ASNS CTGTGAAGAACAACCTCAGGATC and AACAGAGTGGCAGCAACCAAGC
  • CHOP GGTATGAGGACCTGCAAGAGGT and CTTGTGACCTCTGCTGGTTCTG (SEQ ID NO: 1 to 6, respectively).
  • a commercially available product (Primer set ID: HA067812, Takara Bio) was used as the primer set for the GAPDH gene.
  • FIG. 9 is a graph in which the gene expression levels of ATF4, ASNS, and CHOP are quantified after being corrected by the gene expression level of GAPDH.

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Abstract

La présente invention concerne un nouvel agent thérapeutique ou prophylactique qui peut traiter ou prévenir des maladies associées à des dysfonctionnements mitochondriaux. La présente invention concerne un agent thérapeutique ou prophylactique pour des maladies associées à des dysfonctionnements mitochondriaux, l'agent thérapeutique ou prophylactique comprenant au moins un composant choisi parmi un inhibiteur 2 non dépressible de régulation générale (GCN2) et un inhibiteur de kinase de réticulum endoplasmique de type PKR (PERK).
PCT/JP2023/009408 2022-03-11 2023-03-10 Agent thérapeutique ou prophylactique pour des maladies associées à des dysfonctionnements mitochondriaux WO2023171806A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
JP2019052125A (ja) * 2017-09-19 2019-04-04 国立大学法人大阪大学 パーキンソン病の処置用医薬、およびパーキンソン病の処置用医薬のスクリーニング方法
WO2021211742A1 (fr) * 2020-04-14 2021-10-21 The General Hospital Corporation Utilisation d'inhibiteurs de gcn2 dans le traitement de myopathies mitochondriales et de maladies associées à un dysfonctionnement mitochondrial
US20210393591A1 (en) * 2018-10-26 2021-12-23 The Jackson Laboratory Treatments for charcot-marie-tooth disease
WO2022192944A1 (fr) * 2021-03-15 2022-09-22 Genieus Genomics Pty Ltd Polythérapie pour le traitement de la sla

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Publication number Priority date Publication date Assignee Title
JP2019052125A (ja) * 2017-09-19 2019-04-04 国立大学法人大阪大学 パーキンソン病の処置用医薬、およびパーキンソン病の処置用医薬のスクリーニング方法
US20210393591A1 (en) * 2018-10-26 2021-12-23 The Jackson Laboratory Treatments for charcot-marie-tooth disease
WO2021211742A1 (fr) * 2020-04-14 2021-10-21 The General Hospital Corporation Utilisation d'inhibiteurs de gcn2 dans le traitement de myopathies mitochondriales et de maladies associées à un dysfonctionnement mitochondrial
WO2022192944A1 (fr) * 2021-03-15 2022-09-22 Genieus Genomics Pty Ltd Polythérapie pour le traitement de la sla

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LARREA DELFINA, PERA MARTA, GONNELLI ADRIANO, QUINTANA–CABRERA RUBÉN, AKMAN H ORHAN, GUARDIA-LAGUARTA CRISTINA, VELASCO KEVIN R, A: "MFN2 mutations in Charcot–Marie–Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics", HUMAN MOLECULAR GENETICS, OXFORD UNIVERSITY PRESS, GB, vol. 28, no. 11, 1 June 2019 (2019-06-01), GB , pages 1782 - 1800, XP093090257, ISSN: 0964-6906, DOI: 10.1093/hmg/ddz008 *
MUÑOZ JUAN PABLO, IVANOVA SAŠKA, SÁNCHEZ-WANDELMER JANA, MARTÍNEZ-CRISTÓBAL PAULA, NOGUERA EDUARD, SANCHO ANA, DÍAZ-RAMOS ANGELS, : "Mfn2 modulates the UPR and mitochondrial function via repression of PERK", THE EMBO JOURNAL / EUROPEAN MOLECULAR BIOLOGY ORGANIZATION, IRL PRESS, OXFORD, vol. 32, no. 17, 6 August 2013 (2013-08-06), Oxford , pages 2348 - 2361, XP093090258, ISSN: 0261-4189, DOI: 10.1038/emboj.2013.168 *

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