WO2021107005A1 - Agent prophylactique ou thérapeutique pour des maladies associées au cytomégalovirus - Google Patents

Agent prophylactique ou thérapeutique pour des maladies associées au cytomégalovirus Download PDF

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WO2021107005A1
WO2021107005A1 PCT/JP2020/044004 JP2020044004W WO2021107005A1 WO 2021107005 A1 WO2021107005 A1 WO 2021107005A1 JP 2020044004 W JP2020044004 W JP 2020044004W WO 2021107005 A1 WO2021107005 A1 WO 2021107005A1
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protein
homolog
cytomegalovirus
family
factor
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中村　浩幸
拓実 渡邉
成悦 藤原
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国立研究開発法人国立成育医療研究センター
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention relates to an agent for preventing or treating cytomegalovirus-related diseases.
  • Cytomegalovirus is a general term for viruses belonging to the genus Cytomegalovirus of the herpesvirus family, and human cytomegalovirus (HCMV) that infects humans is known.
  • HCMV human cytomegalovirus
  • HCMV infection occurs frequently, but in most healthy individuals, the symptoms do not manifest themselves. On the other hand, in the fetal and those with weakened immune function, infection with HCMV often causes serious symptoms.
  • HCMV infects the foetation through the placenta of a pregnant woman (so-called congenital infection). As a result, it can cause a delay in fetal intrauterine development.
  • congenital HCMV presenting with various organ disorders such as microcephaly; mental retardation; and neurological / sensory disorders such as sensory hearing loss; after the fetal period (ie, fetal and postnatal).
  • HCMV causes opportunistic infections such as pneumonia, enteritis, and retinitis in patients with iatrogenic immunodeficiency associated with transplantation medicine and patients with AIDS.
  • antiviral drug targets DNA polymerase encoded by HCMV
  • drug-resistant HCMV strains appear.
  • the above-mentioned antiviral drugs may cause serious side effects, so that the indications are limited.
  • some antiviral drugs are contraindicated for maternal administration because they can cause very serious side effects on the foetation.
  • fomivirsen is an antisense RNA against IE2 encoded by HCMV, and it has been pointed out that there is a risk of drug-resistant HCMV strains appearing.
  • the present invention has been made in view of the above problems, and an object of the present invention is to provide a novel agent that can be used for the prevention or treatment of cytomegalovirus-related diseases, which has a different mechanism of action from conventional agents for HCMV infection. To provide.
  • cytomegalovirus-related diseases by suppressing the expression or function of a specific gene in humans infected with HCMV.
  • the present invention has been completed. That is, one aspect of the present invention is as follows. ⁇ 80.
  • An agent for preventing or treating a cytomegalovirus-related disease which comprises a component that suppresses the expression or function of at least one gene selected from the group consisting of the genes of. 1.
  • AHNAK2 AHNAK nucleoprotein 2
  • AIDA axin interactor, dorsalization associated
  • AKAP5 A kinase (PRKA) anchor protein 5
  • AP1S2 adaptive protein complex 1, sigma 2 subunit
  • APC adenomatous polyposis coli
  • C3orf74 chromosome 3 open reading frame 74
  • C9orf9 chromosome 9 open reading frame 9)
  • C11orf67 chromosome 11 open reading frame 67
  • C19orf33 chromosome 19 open reading frame 33
  • CHTF18 CTF18, chromosome transmission fidelity factor 18 homolog (S. cerevisiae)
  • CREB1 cAMP responsive element binding protein 1
  • CYTH1 cytohesin 1
  • EML1 echinoderm microtubule associated protein like 1
  • EMP2 epidermal membrane protein 2 15.
  • EPHB6 EPH receptor B6
  • FAM160A1 family with sequence similarity 160, member A1
  • FAM176A family with sequence similarity 176, member A
  • FXR2 fragment X mental retardation, autosomal homolog 2
  • GPR126 G protein-coupled receptor 126)
  • HDHD1A haloacid dehalogenase-like hydrolase domain containing 1A
  • HNRNPH3 heterogeneous nuclear ribonucleoprotein H3 (2H9)
  • TESPA1 Thymocyte Expressed, Positive Selection Associated 1
  • PALD1 Phosphatase Domain Containing Paladin 1
  • KRTAP12-1 Keratin associated protein 12-1) 25.
  • MBD1 methyl-CpG binding domain protein 1 26.
  • MESDC2 mesoderm development candidate 2 27.
  • MUC5AC mucin 5AC, oligomeric mucus / gel-forming
  • NOL12 nucleolar protein 12
  • NRP1 neutral protein 1 30.
  • NUP153 nucleoporin 153kDa
  • PATL2 protein associated with topoisomerase II homolog 2 (yeast)
  • PCBD1 pterin-4 alpha-carbinolamine dehydratase / dimerization cofactor of hepatocyte nuclear factor 1 alpha 33.
  • PPKRIR protein-kinase, interferon-inducible double stranded RNA dependent inhibitor, repressor of (P58 repressor) 34.
  • RBM26 RNA binding motif protein 26
  • RSBN1 round spermatid basic protein 1
  • SCXA seroton homolog A (mouse)
  • SPINT3 serpin peptidase inhibitor, Kunitz type, 3)
  • TATDN3 TatD DNase domain containing 3
  • TBC1D3G TBC1 domain family, member 3G
  • TSC22D1 TSC22 domain family, member 1
  • UNC119B unc-119 homolog B (C. elegans) 42.
  • WBP4 WW domain binding protein 4 (formin binding protein 21)) 43.
  • ZNF354A zinc finger protein 354A 44.
  • ATF1 Activating Transcription Factor 1
  • PGAM5 PGAM Family Member 5, Mitochondrial Serine / Threonine Protein Phosphatase
  • IPO8 Importin 8 47.
  • OGA O-GlcNA case
  • PROX1 Prospero Homeobox 1
  • CIDEC Cell Death Inducing DFFA Like Effector C
  • JPH2 Junctophilin 2
  • RNF208 Ring Finger Protein 208)
  • STEAP1B STEAP Family Member 1B 53.
  • TENM4 Teeurin Transmembrane Protein 4
  • GCDH Glutaryl-CoA Dehydrogenase
  • INTS6L Integrator Complex Subunit 6 Like
  • MAN1A2 Mannosidase Alpha Class 1A Member 2
  • RBM5 RNA Binding Motif Protein 5
  • PIGW Phosphatidylinositol Glycan Anchor Biosynthesis Class W
  • SMARCA2 SWI / SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
  • MYCBP2 MYC Binding Protein 2
  • SEC24B SEC24 Homolog B, COPII Coat Complex Component
  • RNF13 Ring Finger Protein 13
  • DUSP22 Dual Specificity Phosphatase 22
  • SMNDC1 Sudvival Motor Neuron Domain Containing 1
  • SYF2 SYF2 Pre-MRNA Splicing Factor
  • SDHB Succinate Dehydrogenase Complex Iron Sulfur Subunit B
  • RASA1 RASA1 (RAS P21 Protein Activator 1)
  • ALKBH1 AlkB Homolog 1, Histone H2A Dioxygenase
  • CEP85 Cerrosomal Protein 85
  • PXN Paxillin
  • PEX12 Peroxisomal Biogenesis Factor 12
  • COMMD8 COMM Domain Containing 8
  • RHOQ Ras Homolog Family Member Q
  • SIL1 SIL1 Nucleotide Exchange Factor
  • F8 Coagulation Factor VIII
  • TCHP Trichoplein Keratin Filament Binding
  • NUP210 Nucleoporin 210)
  • MIR7-3HG MIR7-3 Host Gene
  • MFAP5 Microfibril Associated Protein 5 80.
  • TUG1 (Taurine Up-Regulated 1)
  • ⁇ 80 This is a method for screening candidate substances for the prevention or treatment of cytomegalovirus-related diseases, wherein one index is whether to suppress the expression or function of at least one gene selected from the group consisting of the genes of.
  • Cytomegalovirus-related diseases [1. Drugs for the prevention or treatment of cytomegalovirus-related diseases] (Cytomegalovirus-related diseases)
  • cytomegalovirus (CMV) is a general term for viruses belonging to the genus Cytomegalovirus of the herpesvirus family in terms of taxonomy.
  • HCMV human cytomegalovirus
  • cytomegalovirus-related disease is a general term for diseases caused by infecting humans with cytomegalovirus.
  • Cytomegalovirus-related diseases are also referred to as “cytomegalovirus infections”.
  • the category of "cytomegalovirus-related diseases” includes, for example, 1) delayed fetal intrauterine development, miscarriage, stillbirth, etc., 2) microcephaly, 3) mental retardation, 4) caused by CMV infection.
  • Neuro-sensory disorders such as sensory deafness, 5) Hepatic splenoma, 6) Pneumonia, enteritis, esophagitis, retinitis, and 7) Degeneration of tumor cells (oncomodulation).
  • infected with CMV means a state in which the cells of an individual are infected with CMV, whether temporarily or persistently.
  • Periodically infected with CMV means a state of persistent CMV infection in an individual's cells.
  • the persistently infected individual exhibits or does not exhibit the symptoms associated with CMV infection (the latter individual is also referred to as a carrier).
  • prevention or treatment of cytomegalovirus-related diseases is intended to reduce the risk of CMV infection in humans as compared to the case where the agent according to one embodiment of the present invention is not administered. Particularly preferably, it means that the infection of CMV in humans is substantially completely prevented as compared with the case where the agent according to one embodiment of the present invention is not administered.
  • the agent according to one embodiment of the present invention can also be regarded as an agent that suppresses CMV infection in humans.
  • the target for prevention of cytomegalovirus-related diseases is not particularly limited, but in one example, it may be a foetation in the mother's body. That is, in one aspect of the present invention, infection of the foetation through the placenta of a pregnant woman (so-called congenital infection) is targeted for prevention.
  • the mother to whom the agent according to one embodiment of the present invention is administered may or may not be infected with CMV, but in a typical example, the mother is a carrier of CMV.
  • the human being targeted for prevention of cytomegalovirus-related disease may be a human with reduced immune function.
  • the human with reduced immune function is, for example, a patient with iatrogenic immunodeficiency associated with transplantation medicine, a patient with AIDS, and the like.
  • the term "treatment of a cytomegalovirus-related disease” means that the progression of symptoms of a cytomegalovirus-related disease is at least delayed as compared with the case where the agent according to one embodiment of the present invention is not administered. Preferably, at least one symptom is intended to be ameliorated.
  • the human beings to be treated for cytomegalovirus-related diseases are not particularly limited as long as they are infected with CMV.
  • the effect of the agent of the present invention can be evaluated by an existing method such as real-time PCR of the CMV genome.
  • Agents for the prevention or treatment of cytomegalovirus-related diseases according to one embodiment of the present invention are described in the column of (Means for Solving Problems). ⁇ 80. It contains a component (hereinafter, "active ingredient") that suppresses the expression or function of at least one gene selected from the group consisting of the genes of. All of these genes are targets present in human cells. Therefore, it is expected that the agent according to the present embodiment is less likely to develop drug-resistant CMV as compared with conventional antiviral agents and the like.
  • the agent according to the present embodiment exhibits an anti-CMV effect by a mechanism of action mediated by a cell factor, which is different from conventional antiviral drugs and the like. Therefore, the agent according to the present embodiment is also expected to be an alternative drug that exerts a complementary therapeutic effect on drug-resistant CMV.
  • the agent according to the present embodiment has the above-mentioned 1. ⁇ 80.
  • genes of it may be preferable to contain a component that suppresses the expression or function of at least one gene selected from the group consisting of the following 14 genes. 5.
  • APC adenomatous polyposis coli
  • C3orf74 chromosome 3 open reading frame 74
  • CREB1 cAMP responsive element binding protein 1
  • FAM160A1 family with sequence similarity 160, member A1
  • GPR126 G protein-coupled receptor 126) 27.
  • MUC5AC mofetin 5AC, oligomeric mucus / gel-forming 29.
  • NRP1 neuroropilin 1 36.
  • SCXA salivary homolog A (mouse) 37.
  • SPINT3 serotonin inhibitor, Kunitz type, 3 42.
  • WBP4 WW domain binding protein 4 (formin binding protein 21)).
  • ATF1 Activating Transcription Factor 1 45.
  • PGAM5 PGAM Family Member 5, Mitochondrial Serine / Threonine Protein Phosphatase 46.
  • IPO8 Importin 8) 47.
  • OGA O-GlcNA case
  • the agent according to this embodiment is 1. ⁇ 80.
  • An active ingredient (one type) that suppresses the expression or function of 10 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 gene selected from the group consisting of the genes of Also, there may be multiple species depending on the number of genes). Typically, one active ingredient suppresses the expression or function of one corresponding gene, but one active ingredient may suppress the expression or function of multiple genes.
  • suppressing gene expression or function means 1) synthesis of protein from gene (transcription and translation process), 2) action of transcribed gene (mRNA), and 3) from gene. It refers to directly or indirectly suppressing any of the actions of synthesized proteins.
  • the active ingredient described above suppresses its expression or function in a gene-specific manner as a target.
  • Examples of such an active ingredient include, but are not limited to, low molecular weight compounds, nucleic acid polymers such as oligonucleotides, high molecular weight compounds, and combinations thereof.
  • Examples of low molecular weight compounds include inhibitors of proteins encoded by the above genes.
  • Nucleic acid polymers such as oligonucleotides include 1) antisense oligonucleotides of the target gene, 2) nucleic acid polymers for RNAi (oligonucleotides), 3) hetero double-stranded nucleic acids (DNA / RNA), 4). Examples thereof include miRNA target nucleic acids and 5) nucleic acid aptamers for proteins encoded by the above genes.
  • a molecule having a size capable of crossing the blood-brain barrier and a substance delivery means may be required.
  • Nucleic acid polymers for RNAi are typically RNA molecules with complementary double-stranded moieties.
  • the complementary double-stranded portion may be, for example, 16 bp or more, preferably 17 bp or more, and more preferably 20 bp or more.
  • the complementary double-stranded portion may be, for example, 30 pb or less, preferably 27 or 26 bp or less, and more preferably 25 bp or less.
  • the structure of the nucleic acid polymer for RNAi is not particularly limited as long as it causes RNA interference with the target mRNA.
  • the nucleic acid polymer for RNAi can be, for example, shRNA, dumbbell type, siRNA, miRNA, or the like, and in one example, shRNA.
  • the base sequence of the loop portion in the shRNA is not particularly limited and can be appropriately designed.
  • the loop portion can be "CTCGAG" (from 5'end to 3'end, indicated by the sequence of the template DNA).
  • the active ingredient in this embodiment may be a vector expressing the above-mentioned nucleic acid polymer.
  • a vector can be prepared using a commercially available kit.
  • a vector expressing shRNA can be prepared by inserting a DNA that produces shRNA by transcription into a commercially available vector (for example, an adenovirus vector).
  • the base sequences of the promoter and terminator to be included in the DNA to be inserted are not particularly limited and can be appropriately designed.
  • the promoter portion can be "CCGG" and the terminator portion can be "TTTTTG" (both from the 5'end to the 3'end).
  • the agent according to this embodiment may contain other ingredients in addition to the above-mentioned active ingredients.
  • RNA Ribonucleic acid
  • the DNA sequences of # 1 to # 80 are all ordered from the 5'side (from the left side in the table), (1) the promoter portion "CCGG”, and (2) the first strand forming a complementary double-stranded portion. Consists of (sense side), (3) loop portion "CTCGAG”, (4) second strand (antisense side) forming a complementary double-stranded portion, and (5) terminator portion "TTTTTG”.
  • RNA RNA corresponding to the first strand of (2) above (using the first strand as a template) and the RNA corresponding to the second strand of (4) above are complementary. Form a chain portion.
  • RNA The expression products (RNA) of the DNA sequences # 1 to # 80 shown in Table 1 are described in 1. above. ⁇ 80. It is possible to suppress the expression or function of the gene having the corresponding number among the genes of.
  • RNA molecule having a complementary double-stranded portion equivalent to the expression product (RNA) of the DNA sequence shown in Table 1 functions as an oligonucleotide for RNAi.
  • SEQ ID NOs: 1 to 80 in the sequence listing indicate the first strand (sense side) forming the complementary double-stranded portion of (2) above in the DNA sequences # 1 to # 80 shown in Table 1.
  • RNA molecules that functions as a nucleic acid polymer for RNAi include a) RNA using DNA containing 16 or more consecutive bases in any of the base sequences shown in SEQ ID NOs: 1 to 80 as a template, and b). It contains at least one of RNA, which uses a DNA complementary to the DNA as a template.
  • the RNA molecule is preferably a nucleic acid polymer in which the RNAs of a) and b) above form a double-stranded structure. This RNA molecule can be administered in the form of DNA (vector, etc.).
  • the number of consecutive bases described above is preferably 17 or more, more preferably 18 or more or 19 or more, and even more preferably 20 or more.
  • the nucleic acid polymer as an active ingredient may be a natural nucleic acid polymer or a non-natural nucleic acid polymer.
  • Nucleic acid polymers may be modified, eg, peptide nucleic acids (PNA), locked nucleic acids (LNA), phosphorothioate oligonucleotides, 2'O-Me modified oligonucleotides, 2'. Examples include, but are not limited to, -O, 4'-C-ethylene cross-linked nucleic acid species (ENA). Such modification can enhance the stability of the nucleic acid polymer in vivo.
  • PNA peptide nucleic acids
  • LNA locked nucleic acids
  • EDA phosphorothioate oligonucleotides
  • EDA 4'-C-ethylene cross-linked nucleic acid species
  • Ingredients other than the active ingredient constituting the agent according to the present embodiment are not particularly limited, and for example, pharmaceutically acceptable carriers, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmoregulation, etc. , Buffers, colorants, flavors, sweeteners, antioxidants, viscosity modifiers and the like.
  • the pharmaceutically acceptable carrier is not particularly limited, but is a carrier that does not inhibit the efficacy of the active ingredient when co-administered with the active ingredient, and is substantially the same for a human to be administered. It is preferable to have the property of not having an adverse effect.
  • a carrier those conventionally known in this field can be widely used, and specifically, for example, water, various salt solutions, alcohol, vegetable oil, polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, and talc. , Silica, paraffin, fatty acid monoglyceride, fatty acid diglyceride, hydroxymethyl cellulose, polyvinylpyrrolidone and the like, but are not particularly limited thereto.
  • the type of carrier may be appropriately selected according to the dosage form, administration method, etc. of the agent according to the present embodiment.
  • the agent according to this embodiment can also be used in combination with an existing anti-cytomegalovirus agent.
  • One form of the combination is a so-called combination drug in which the agent according to the present embodiment is formulated containing an existing anti-cytomegalovirus agent.
  • the agent according to the present embodiment and the anti-cytomegalovirus agent are separately formulated, and these agents are used in combination (separate agents are administered simultaneously or sequentially). It is a form.
  • Existing anti-cytomegalovirus agents include, for example, ganciclovir and its salts, foscarnet and its salts (such as foscarnet sodium hydrate), sodium phosphenitoin and its salts (such as hydrate), valganciclovir and Examples include the group consisting of its salts (such as valganciclovir hydrochloride), letermovir, cidofovir and its salts, and fomivirsen.
  • the agent according to the present embodiment can be administered to an individual human for the purpose of preventing or treating a cytomegalovirus-related disease.
  • an amount of the active ingredient effective for the prevention or treatment of cytomegalovirus-related diseases is administered to the human.
  • the active ingredient may be administered alone or as a component of an agent suitable for the purpose of administration.
  • the dose of the active ingredient contained in the agent according to the present embodiment is not particularly limited, and depends on the disease state, body weight, response to treatment, administration form of the agent, stage of disease course, or administration interval. Can be adjusted as appropriate.
  • the administration may be divided into one to several times, for example, one to several times per day.
  • the administration route of the agent according to this embodiment is not particularly limited, and may be systemically administered by a method such as oral administration, intravenous or intraarterial administration, and intestinal administration.
  • the agent according to the present embodiment may be locally administered by a method such as injection (using a syringe or an infusion pump), transdermal administration, sublingual administration, and organ surface administration.
  • the dosage and administration method may be appropriately selected by those skilled in the art according to the purpose of treatment, the weight, age, symptoms and the like of the patient.
  • the dosage form of the agent according to the present embodiment is not particularly limited, and for example, tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, patches, ointments, injections and the like. Can be mentioned.
  • the agent according to this embodiment can be a gene therapy agent.
  • the gene therapy agent may be in the form of directly administering the active ingredient to humans by injection, or in the form of directly administering the vector incorporating the nucleic acid polymer to humans by injection. There may be.
  • the vector is not particularly limited, and examples thereof include vectors applicable to gene therapy, such as an adenovirus vector, an adeno-related virus vector, an adeno-associated virus vector, a herpesvirus vector, a vaccinia virus vector, and a retrovirus vector.
  • the gene therapy agent may be a liposome preparation.
  • the vector constituting the gene therapy agent incorporates an expression regulatory sequence that specifically expresses the active ingredient at the target site.
  • the expression regulatory sequence is, for example, a promoter or an enhancer.
  • the screening method of the present embodiment is a screening method for a candidate substance for prevention or treatment of cytomegalovirus-related diseases, and 1. ⁇ 80.
  • This is a screening method in which one index is whether to suppress the expression or function of at least one gene selected from the group consisting of the above genes.
  • One aspect of the screening method of the present invention is a step of contacting a cell sample with a test substance (contact step), 1. ⁇ 80.
  • the cell sample used in the above contact step is, for example, a sample containing cells to be infected with CMV.
  • the cell sample include non-human organisms, cultured cells of various cell lines, and biological samples isolated from the organism.
  • the cultured cells are, for example, living cells of human and non-human organisms, ES cells, iPS cells and the like, and more specifically, a human nervous system cell line (U373MG cell line), a human fibroblast cell line and the like can be mentioned. ..
  • test substance examples include, but are not limited to, low molecular weight compounds, nucleic acid polymers such as oligonucleotides, peptides, proteins, high molecular weight compounds, and combinations thereof.
  • the test substance may be naturally occurring or chemically synthesized.
  • the candidate substance can preferably be a substance that is harmless in vivo.
  • An example of a test substance is shRNA.
  • the specific method of contacting the cell sample with the test substance is not particularly limited.
  • the candidate substance when the cell sample is a cultured cell, the candidate substance can be directly administered to the culture medium in which the cell is cultured.
  • the test substance when the test substance is an oligonucleotide, the test substance can be more reliably introduced into the cell by using a lipofection method, an electroporation method, or the like.
  • the test substance when the test substance is a polypeptide or a polymer compound, the test substance can be more reliably introduced into the cell by using an injection method, a liposome method, or the like.
  • the concentration of the test substance added can be appropriately selected according to the type of the substance as long as it does not adversely affect the growth of cells.
  • the contact period, the temperature during the contact period, and the like can also be appropriately selected.
  • the evaluation of gene expression or function in the evaluation step can be evaluated by, for example, real-time PCR, quantitative PCR such as digital PCR, or analysis such as microarray analysis.
  • the protein transcribed from the gene may be targeted and evaluated using ELISA or Western blotting method, Southern blotting method, immunofluorescent staining, etc., or evaluated based on whether cell death is observed. May be good. These operations can be performed according to a conventional method.
  • the genes used as indicators are 1. ⁇ 80. It is at least one gene selected from the group consisting of genes of, preferably two or more, more preferably three or more, even more preferably four or more, particularly preferably five or more, most preferably ten. The above is preferable.
  • the degree of gene expression or functional activity is compared with a control (for example, the degree of gene expression or functional activity in a cell sample to which the test substance was not administered).
  • the comparison is preferably made in consideration of the presence or absence of a significant difference.
  • the test substance is selected as a candidate substance for prevention or treatment of CMV-related diseases.
  • the screening method as described above is very useful as a method for efficiently obtaining a candidate substance for prevention or treatment of CMV-related diseases.
  • the present invention is not limited to the above-described embodiments, and various modifications can be made within the scope of the claims, and the technical means disclosed in the different embodiments can be used. Embodiments obtained by appropriately combining them are also included in the technical scope of the present invention.
  • the present invention includes, for example, the following aspects.
  • ⁇ 80 An agent for the prevention or treatment of cytomegalovirus-related diseases, which comprises a component that suppresses the expression or function of at least one gene selected from the group consisting of the genes of.
  • the nucleic acid polymer 1) uses RNA as a template for DNA containing 16 or more consecutive bases in any of the base sequences shown in SEQ ID NOs: 1 to 80, and DNA complementary to the DNA as a template.
  • the anti-cytomegalovirus agent is ganciclovir and its salt, foscarnet and its salt (foscarnet sodium hydrate, etc.), phosphenitoin sodium and its salt (hydrate, etc.), valganciclovir and its salt.
  • the agent of (F) which is at least one selected from the group consisting of salts (such as valganciclovir hydrochloride), letermovir, cidofovir and salts thereof, and homivirsen.
  • ⁇ 80 A method for screening candidate substances for the prevention or treatment of cytomegalovirus-related diseases, wherein one index is whether to suppress the expression or function of at least one gene selected from the group consisting of the genes of.
  • U373MG cell line Human nervous system cells (U373MG cell line) were used as target cells.
  • U373MG cells contain 10% fetal bovine serum (BioWest) and an antibiotic-antifungal mixed solution (penicillin 100 u / mL, streptomycin 100 ⁇ g / mL and amphotericin B 250 ng / mL) as a medium. ) was used, and the cells were cultured in an incubator at 37 ° C. and 5% CO 2.
  • a library of lentivirus-incorporated shRNAs included in a commercially available kit was introduced into U373MG cells.
  • U373MG cells into which shRNA was introduced were cultured in a 10 ⁇ g / mL Puromycin (Invivogen) medium at 37 ° C. in a 5% CO 2 incubator for 14 days, and a cell population showing Puromycin resistance was selected.
  • a U373MG cell population into which shRNAs that do not interfere with the survival and proliferation of U373MG cells were introduced (hereinafter referred to as shRNA-introduced U373MG cell population) was acquired.
  • the shRNA-introduced U373MG cell population was infected with the human cytomegalovirus Towne strain (ATCC, product number VR-977), and the culture was continued to observe resistance to cell death.
  • U373MG cells into which the shRNA library had not been introduced were similarly infected with the human cytomegalovirus Towne strain.
  • FIG. 1 cell population A shows a strength-tolerant clone and cell population B shows a moderately resistant clone.
  • the cell populations that survive after about 3 weeks are the cell populations that are resistant to the human cytomegalovirus Towne strain (hereinafter referred to as human CMV resistance). Cell population). Most of the U373MG cells used in the control experiment died about 3 weeks after infection.
  • Single-cell cloning was performed on a human CMV-resistant cell population using the limiting dilution method using a 96-well plate. Subsequently, genomic DNA was extracted from each single cell clone according to a conventional method. The shRNA region of the extracted genomic DNA was amplified by the Polymerase Chain Reaction (PCR) method. Subsequently, each PCR product was introduced into a plasmid, and the nucleotide sequence of shRNA was determined by the dideoxy method. Furthermore, based on the information in the shRNA library provided by the seller of the kit, the cell gene targeted by each shRNA was identified from the determined nucleotide sequence of shRNA. The nucleotide sequences of shRNA and the cell genes targeted by each shRNA are shown in Tables 1 and 2 below.
  • Samples A to F Six clones (referred to as Samples A to F) of the single cell clones obtained by single cell cloning from the above-mentioned human CMV resistant cell population and U373MG cells (control) into which negative control shRNA was introduced were used. The expression of the HCMV gene in each cell was compared. More specifically, the expression level of the HCMV gene was compared using the expression level of the IE2 protein transcribed from the HCMV gene as an index. Western blotting and immunofluorescence staining were used to detect the IE2 protein. In the western blotting method, 3 out of 6 clones were used, and ⁇ -actin was used as a loading control.
  • the remaining 3 clones were used for immunofluorescence staining.
  • the cell nuclei were stained with DAPI.
  • suppression of IE2 protein expression was observed in U373MG cells resistant to human cytomegalovirus into which a specific shRNA was introduced, suggesting suppression of HCMV gene expression (results not shown). ).
  • RT-PCR Reverse Transcription-PCR
  • U373MG cells were newly prepared and cultured under the above conditions (Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and an antibiotic-antifungal mixed solution, 37 ° C., 5% CO 2 incubator).
  • U373MG cells newly introduced with # 5 and # 11 shRNA and U373MG cells (control) introduced with negative control shRNA were used in a 10 ⁇ g / mL Puromycin medium at 37 ° C. in a 5% CO 2 incubator for 14 days. After culturing, a cell population showing Puromycin resistance was selected. Selected cell populations were infected with the human cytomegalovirus Towne strain and their resistance to cell death was compared. As shown in FIG. 2, it was confirmed that U373MG cells into which a specific shRNA was introduced showed resistance to cell death associated with CMV infection.

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Abstract

La présente invention concerne un nouvel agent qui peut être utilisé pour la prévention ou le traitement de maladies associées au cytomégalovirus, et a un mécanisme d'action différent de celui des médicaments existants pour les maladies infectieuses du CMVH. L'invention concerne également un agent prophylactique ou thérapeutique pour des maladies associées au cytomégalovirus, ledit agent comprenant un composant qui supprime l'expression ou la fonction d'au moins un gène choisi dans un groupe constitué de 80 gènes.
PCT/JP2020/044004 2019-11-27 2020-11-26 Agent prophylactique ou thérapeutique pour des maladies associées au cytomégalovirus WO2021107005A1 (fr)

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