WO2009136444A1 - Procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type i - Google Patents

Procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type i Download PDF

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WO2009136444A1
WO2009136444A1 PCT/JP2008/058665 JP2008058665W WO2009136444A1 WO 2009136444 A1 WO2009136444 A1 WO 2009136444A1 JP 2008058665 W JP2008058665 W JP 2008058665W WO 2009136444 A1 WO2009136444 A1 WO 2009136444A1
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mice
mouse
type
test
dgkβ
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PCT/JP2008/058665
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Japanese (ja)
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英彰 原
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カルナバイオサイエンス株式会社
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0276—Knock-out vertebrates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0356—Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy

Definitions

  • the present invention relates to a method for screening a preventive or therapeutic agent for bipolar disorder type I.
  • Bipolar disorder is a type of mental illness also called bipolar mood disorder or bipolar manic depression. Mood disorders are divided into unipolar, where only one symptom of manic depression appears, and bipolar, where both symptoms appear, and in theory there are unipolar mania and unipolar depression. However, since many patients with unipolar mania later develop depressive symptoms, unipolar mania is now classified as part of bipolar disorder (DSM (Diagnostic and Statistical Manual of Mental Disorders)- IV-TR Classification and Diagnosis Guide for Psychiatric Disorders (New Revised Edition) Medical School March 1, 2005 New Edition 4th edition, text psychiatry Revised 3rd edition Nanzan-do April 10, 2007 3rd edition 1st edition etc. reference). Therefore, mood disorders are now classified into bipolar disorder and unipolar depression. Bipolar disorder is broadly divided into type I, which is severe in depression, and type II, which is severe in depression.
  • type I includes those with a long manic state and very mild depression, and those that have traditionally been unipolar (unipolar) manic, and that manic state affects social life. It has the feature that it is often intense enough to affect
  • Type II is not as violent as the type I addictive state, but has a longer depressive state compared to the addictive state, and the depressed state drives itself and sometimes attempts to commit suicide. It shows the feature that it is intense as there are cases.
  • bipolar disorder the current treatment methods for bipolar disorder are that type I may be used in combination with antipsychotic drugs and type II may be used in combination with antidepressants.
  • type I may be used in combination with antipsychotic drugs
  • type II may be used in combination with antidepressants.
  • the current situation is that there is only a common and symptomatic drug called “mood stabilizer” or “emotion modifier”, and there are almost no drugs exclusively for type I and type II.
  • Patent Document 1 suggests that human-derived DGK ⁇ (diacylglycerol kinase ⁇ ) may be related to bipolar disorder, and the authors of this document later published Patent Document 1 also describes the possibility.
  • DGK ⁇ diacylglycerol kinase ⁇
  • mice lacking the function of DGK ⁇ are commercially available (Taconic, TF0164 (catalog No.), etc.), but the relationship between the mice and bipolar disorder is not known.
  • mice deficient in the function of DGK ⁇ are not type II but clearly have type I symptoms of bipolar disorder.
  • the present invention has been completed and the object of the present invention is to provide a drug screening method using a disease model specialized in bipolar disorder type I. .
  • a prophylactic or therapeutic agent for bipolar disorder type I according to the first invention characterized in that a non-human animal in which a deficiency in DGK ⁇ function occurs in at least part of the forebrain to midbrain region is used. Screening method.
  • the disease model used in the method for screening a preventive or therapeutic agent for bipolar disorder type I of the present invention is characterized by comprising a non-human animal deficient in the function of DGK ⁇ .
  • Examples of the method for deleting the function of DGK ⁇ in a non-human animal include a method for deleting or mutating the DGK ⁇ gene by a known genetic engineering technique and inhibiting its expression or function.
  • a method using RNAi a method using antisense RNA, a method using a targeting gene with a modified target gene, a method for producing a mutant mouse using a transposon (International Publication No. WO 02/13602, Molecular and Cellular Biology (see vol.23, No.24, pp.9189-9207, 2003, etc.), etc., but among them, targeting genes with modified target genes can be more reliably suppressed in terms of expression.
  • the method used is preferred.
  • Such a mouse deficient in the function of DGK ⁇ can also be obtained as TF0164 (catalog No.) or the like from Taconic.
  • the non-human animal used as the disease model used in the screening method of the present invention may be any animal other than humans, and examples include rodents, dogs, cats, monkeys, horses, pigs, etc. Rodent animals are preferred. Examples of rodent animals include mice, rats, rabbits, hamsters, and guinea pigs. Among these, mice and rats are preferable, and mice are particularly preferable. For example, C57BL / 6N mice such as C57BL / 6N Cr / Cr / j (also referred to as B6 mice), Balb / c mice and the like are preferably used, and among these, B6 mice are preferable.
  • C57BL / 6N mice such as C57BL / 6N Cr / Cr / j (also referred to as B6 mice), Balb / c mice and the like are preferably used, and among these, B6 mice are preferable.
  • DSM-IV-TR classification and diagnosis of mental illness
  • diagnosis of mental illness Medical Shoin March 1, 2005
  • fourth edition of the new edition As described above, this includes not only those with a long manic state and very mild depression, but also those that have been conventionally regarded as unipolar (unipolar) mania.
  • screening in addition to so-called primary screening for selecting a desired preventive or therapeutic agent from a plurality of candidates, secondary screening for confirming the prophylactic or therapeutic effect of a test substance is possible. Screening (re-evaluation or confirmation test) is also included.
  • Tp is a method for obtaining various transgenic mice (hereinafter referred to as Tg mice) by utilizing transposition to various positions within the gene.
  • a mouse (DGK ⁇ -KO mouse) lacking the function of DGK ⁇ was selected from various Tg mice obtained by this method.
  • Tg mice having a Tp sequence and a Tg mouse (SB) having an enzyme (transposase) that causes translocation of this Tp sequence are crossed to create a variety of Tg mice.
  • SB Tg mouse
  • transposase enzyme that causes translocation of this Tp sequence
  • the transposase recognizes the repetitive sequence in the reverse direction present in the Tp sequence, excises the Tp sequence from the genomic DNA, and the excised Tp sequence is inserted again at an arbitrary position by the action of the transposase. This is because.
  • FIG. 12 (A) is a schematic diagram showing a donor site in which a plurality of Tp vector units are incorporated, and its cleavage site by Bgl II and Nco I in a Tg mouse having a Tp sequence.
  • sequence is Tp arrangement
  • this Tp gene incorporates a promoter sequence and LacZ and GFP sequences as markers.
  • DGK ⁇ -KO mice mice in which the Tp sequence was translocated between DGK ⁇ sequences
  • mice mice in which mutations occurred in the gene sequence.
  • the DGK ⁇ -KO mouse is selected by collecting Tg mouse genomic DNA, determining the genomic sequence of the Tp sequence insertion site by PCR, etc., and collating it with the mouse genome database, thereby translocating the Tp sequence into the DGK ⁇ gene. The method of identifying the mouse was performed.
  • FIG. 12 (B) is a schematic diagram showing a state in which the Tp sequence is incorporated into the DGK ⁇ sequence by Tp rearrangement and its cleavage site by BglII and NcoI.
  • the donor site does not exist in the selected mouse gene, the presence or absence of a neoplasm derived from a plasmid vector that exists only at the donor site was confirmed.
  • Southern blot analysis was performed by cutting the genomic genes of hetero (Tp / +) and wild type (WT (+ / +)) mice with SpeI and using the neo sequence as a probe. It was.
  • FIG. 14 is a schematic diagram showing a SpeI cleavage site in a donor site incorporating a plurality of Tp vectors.
  • Control indicates the analysis result of genomic DNA having one neo gene. From this genomic DNA, it is expected that a 4.2 kb band will be obtained by cleavage with SpeI, but a band of the expected size is detected. This confirmed that the probe complementary to the neo sequence used was indeed functioning.
  • KO DGK ⁇ -KO mouse
  • WT syngeneic wild-type mice
  • ⁇ no movement '' means that the mouse floats in the water without resistance and stays in the minimum movement necessary to bring the face out of the water surface (the movement of the forelimbs stops and one of the hind limbs is in posture). To maintain a slight movement).
  • KO mice had a significant decrease in immobility time compared to WT mice (**; p ⁇ 0.01 vs. WT).
  • This Pre test induces a kind of depression before starting the Post test, but as described above, it was found that depression was difficult to be induced in KO mice.
  • Test Example 2 Novel substance search test
  • a plastic open field (length 30 mm ⁇ width 30 mm ⁇ height 14 cm) was used for the test. The mice were habituated for 10 minutes each in an open fold for 3 days before the test.
  • mice The search time for each substance in mice for 10 minutes in acquisition and retention trials was measured using an EthoVision XT (Noldus, Wageningen, The Netherlands).
  • the mouse's search preference for novel substances in retention trials was calculated as a percentage of the total search time. The results are shown as an average of 8-10 mice in each group.
  • Test Example 3 Spontaneous exercise test
  • mice Using a group of mice different from those used in Test Examples 1 and 2, spontaneous movement in a novel environment was measured using a plastic open field (length 30 ⁇ width 30 ⁇ height 14 cm). Mice were placed in an open field and allowed to explore freely for 120 minutes.
  • mice The results are shown as an average of 4 mice in each group.
  • DGK ⁇ -KO mice showed an increase in locomotor activity at 120 minutes compared to WT mice.
  • Total movement distance (Fig. 4), time-dependent change of movement distance (Fig. 5), and movement speed (Fig. 6) are increased in KO mice compared to WT mice, respectively, Significant differences were seen.
  • FIG. 4 (*; p ⁇ 0.05 vs. WT)
  • FIG. 5 (*; p ⁇ 0.05 vs. WT) (**; p ⁇ 0.01 vs. WT)
  • Test Example 4 Open field test
  • the mouse used in Test Example 3 was placed in a plastic open field (length 30 ⁇ width 30 ⁇ height 14 cm) and allowed to search freely for 120 minutes.
  • the total movement distance of the mouse and the time spent in the center (15 ⁇ 15 cm) were automatically measured using a behavior tracking / analysis video tracking system (EthoVision XT TM, manufactured by NOLDUS).
  • the number of standing up and abdominal scratching actions during the first 10 minutes was measured manually.
  • DGK ⁇ -KO mice In DGK ⁇ -KO mice, an increase in exploratory behavior was observed in the open field test. DGK ⁇ -KO mice had increased time spent in the center of the open field and the number of intrusions into the center compared to WT mice (FIGS. 7 and 8).
  • KO mice were in an overactive state, that is, a kind of “snoring state” at the time of performing Test Example 4.
  • a large number of intrusions into the center indicates a low level of anxiety, that is, hyperactivity
  • a large number of standing up actions indicate overactivity
  • a large number of scratching actions indicate administration of excitatory drugs. It shows normal behaviors like psychiatric disorders similar to models.
  • Test Example 5 LacZ staining
  • a group of mice different from those used in Test Examples 1 to 4 was used, and LacZ staining was performed in order to confirm the “defect site of the DGK ⁇ gene in the mouse body”.
  • a 15-week-old male mouse from each of WT and KO mice was anesthetized with pentobarbital, and 0.1% M phosphate buffer (PB; pH 7.4) containing 4% paraformaldehyde was injected into the left ventricle to perform perfusion fixation (perfusion pressure 130 cm H2O). After 20 minutes, the brain was removed and left overnight in the same solution. Subsequently, it was allowed to stand in a 0.1% M PB (pH 7.4) solution containing 25% sucrose for 24 hours. Thereafter, it was quickly frozen with powdered dry ice and stored at ⁇ 80 ° C. until sliced.
  • PB 0.1% M phosphate buffer
  • LacZ staining was performed using ⁇ -garactosidase staining kit (Actove motif, Carlsbad, CA). After infiltrating the slices with 0.2% glutaraldehyde and 1% formalin, the reaction solution containing 5-bromo-4-chloro-3-indoly- ⁇ -galactoside (X-Gal), a substrate of ⁇ -galactosidase, was kept for 2 hours. Colored by soaking.
  • X-Gal 5-bromo-4-chloro-3-indoly- ⁇ -galactoside
  • Tp translocation occurred in the forebrain-mesencephalon region of the mouse. That is, as a result of the translocation of the LacZ sequence promoter inserted as a marker in the Tp gene, LacZ is translated to express ⁇ -galactosidase, and the substrate X-gal (5-Bromo-4 -Chloro-3-Indolyl- ⁇ -D-Galactoside) was decomposed to produce an insoluble blue coloring substance. In other words, it can be seen that Tp translocation (DGK ⁇ deficiency) occurs in tissues exhibiting blue color development.
  • DGK ⁇ deficiency in the forebrain to midbrain region is one of the causes of bipolar disorder type I symptoms (such as hyperactivity and memory impairment).
  • Example 1 Screening method for preventing or treating bipolar disorder type I
  • a test substance is administered to the model of Reference Example 1, and a preventive or therapeutic drug for bipolar disorder type I is screened by comparing the results of Test Examples 1 to 4 before and after the administration.
  • the screening method of the present invention can be expected to develop an innovative preventive / therapeutic agent specialized in bipolar disorder type I.
  • * indicates that the standard deviation of the test result of the disease model mouse against wild type is p ⁇ 0.05
  • # indicates that the standard deviation of the second day relative to the first day is p ⁇ 0.05.
  • FIG. 1 It is a figure showing the result (time-dependent change of spontaneous exercise amount) which used the disease model mouse (KO) of the reference example 1, and the wild type mouse (WT) for the spontaneous exercise test of the test example 3.
  • FIG. It is a figure showing the result (movement speed (cm / sec)) which used the disease model mouse (KO) of the reference example 1, and the wild type mouse (WT) for the spontaneous movement test of the test example 3.
  • FIG. It is a figure showing the result (time (second) spent in the center of an open field) which used the disease model mouse (KO) of the reference example 1, and the wild type mouse (WT) for the open field test of the test example 4.
  • FIG. A, C, E, G, and I represent staining results of olfactory bulb, striatum, hippocampus, substantia nigra, and cerebellum in KO mice.
  • B, D, F, H, and J represent staining results of the olfactory bulb, striatum, hippocampus, substantia nigra, and cerebellum in WT mice.
  • FIG. (A) is a schematic diagram showing a donor site into which a Tp sequence has been inserted, and its cleavage site by Bgl II and Nco I, used when preparing the disease model mouse (KO) of Reference Example 1.
  • FIG. (B) is a schematic diagram showing a DGK ⁇ sequence in which a Tp sequence is incorporated, and its cleavage site by BglII and NcoI.
  • B and N represent cleavage sites by Bgl II and Nco I, respectively.
  • the results of Southern blot analysis using the LacZ sequence as a probe for the genomic genes of wild type (WT (+ / +)), heterozygous (Tp / +), and homozygous (Tp / Tp) mice are shown.
  • FIG. 1 It is a schematic diagram which shows the donor site which inserted the Tp arrangement
  • S represents a site cleaved by SpeI.
  • the results of Southern blot analysis using a polynucleotide complementary to the neo sequence as a probe for each genomic gene of heterozygous (Tp / +) and wild type (WT (+ / +)) mice are shown.

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Abstract

La présente invention vise à fournir un procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type I mettant en œuvre un modèle de maladie spécialisé pour le trouble bipolaire de type I. L’invention concerne donc un procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type I caractérisé en ce qu’il utilise un modèle de maladie de trouble bipolaire de type I, comportant un animal non humain déficitaire en fonction DGKβ.
PCT/JP2008/058665 2008-05-09 2008-05-09 Procédé de criblage d’agent de prévention ou de traitement de trouble bipolaire de type i WO2009136444A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001512007A (ja) * 1997-08-01 2001-08-21 ゼネカ・リミテッド Ｚｇｇｂｐ１、１型双極性感情障害に関与する新規ペプチド、配列及びその使用
JP2002540765A (ja) * 1999-02-15 2002-12-03 グラクソ グループ リミテッド 新規タンパク質

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001512007A (ja) * 1997-08-01 2001-08-21 ゼネカ・リミテッド Ｚｇｇｂｐ１、１型双極性感情障害に関与する新規ペプチド、配列及びその使用
JP2002540765A (ja) * 1999-02-15 2002-12-03 グラクソ グループ リミテッド 新規タンパク質

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* Cited by examiner, † Cited by third party
Title
CARICASOLE A ET AL.: "Molecular Cloning and Characterization of the Human Diacylglycerol Kinase beta (DGKbeta) Gene. Alternative Splicing Generates DGKbeta Isotypes with Different Properties", J BIOL CHEM, vol. 277, no. 7, 2002, pages 4790 - 4796 *
KAORU GOTO ET AL.: "Nonai ni Okeru Shishitsusei Niji Messenger Taisha Koso Diacylglycerol Kinase no Bunshi.Hatsugen Kyokuzai no Tayosei to Kinoteki Yakuwari", ELECTRON-MICROSCOPY, vol. 37, no. 3, 2002, pages 183 - 187 *
KAZUKI KASAHARA ET AL.: "Sokyokusei Shogai Model Mouse ni Okeru Jikan Seibutsugakuteki Kento", JOURNAL OF CHRONOBIOLOGY, vol. 12, no. 2, 2006, pages 59 - S2-5 *
MIE KUBOTA ET AL.: "Sokyokusei Shogai Model Dobutsu ni Okeru Saibonai Ca2 + Signaling Ijo no Kento", BULLETIN OF THE JAPANESE SOCIETY FOR NEUROCHEMISTRY, vol. 45, no. 2/3, 2006, pages 492 - P3-B-055 *
MIKAKO UENO ET AL.: "Seishinka Ryoiki no Yogo Kaisetsu Retroposon", JAPANESE JOURNAL OF MOLECULAR PSYCHIATRY, vol. 6, no. 2, 2006, pages 177 - 179 *
SOICHIRO NOMURA ET AL.: "Dobutsu Model kara Mita Utsubyo no Byotai to Chiryo Senryaku", PSYCHIATRIA ET NEUROLOGIA JAPONICA, vol. 91, no. 9, 1989, pages 634 - 638 *
TADAFUMI KATO ET AL.: "Kanjo Shogai no Hassho Zeijakusei Soin ni Kansuru Shinkei Hattatsu. Shinkei Shinseiteki Sokumen kara no Kento Narabini Sono Shufuku Kijo ni Kansuru Bunshi Seibutsugakuteki Kenkyu", DOBUTSU MODEL O MOCHIITA SOUTSUBYO NO SAIHATSU ZEIJAKUSEI NI KANSURU KENKYU, KANJO SHOGAI NO HASSHO ZEIJAKUSEI SOIN NI KANSURU SHINKEI HATTATSU. SHINKEI SHINSEITEKI SOKUMEN KARA NO KENTO NARABINI SONO SHUFUKU KIJO NI KANSURU BUNSHI SEIBUTSUGAKUTEKI K, 2005, pages 43 - 45 *
TORU TSUJIMURA ET AL.: "No · Shinkeikei Jikken Model Technic.Hohoron Kibun Shogai.Dobutsu Model no Kodo Hyokaho", JAPANESE JOURNAL OF MOLECULAR PSYCHIATRY, vol. 2, no. L, 2002, pages 62 - 67 *

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