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DISEASE MODEL ANIMAL AND DISEASE THERAPEUTIC AGENT commons

Foreign code F180009394
File No. (NU-665)
Posted date Apr 20, 2018
Country WIPO
International application number 2017JP025273
International publication number WO 2018012497
Date of international filing Jul 11, 2017
Date of international publication Jan 18, 2018
Priority data
  • P2016-139308 (Jul 14, 2016) JP
Title DISEASE MODEL ANIMAL AND DISEASE THERAPEUTIC AGENT commons
Abstract The present invention mainly addresses the problem of providing a novel and specific knockout model animal that presents a symptom of a disease accompanied by a synapse abnormality in the brain, a method for producing same, and a therapeutic agent for said disease. The present invention provides a model animal that presents a symptom of a disease (e.g., frontotemporal lobar degeneration (FTLD)) accompanied by a synapse abnormality, which animal is characterized by being produced by specifically knocking out the FUS gene in the brain, for example, by using the Cre-loxP system and CamK2 promotor, for example and a method for producing same, or a screening method for the therapeutic agent for said disease, in which said model animal is used or the like.
Outline of related art and contending technology BACKGROUND ART
In recent years, medical and scientific advances, particularly in industrialized countries to increase the average life is extended. However, in accordance with this, in the past the problem was not caused by a decrease in the various functions of the brain aging, disease, and the pathology has been a great social problem. Among them the dementia is, the patient assesses the quality of the principal, offer, life is significantly reduced, in addition, a very large burden on the family care. Dementia symptoms include, memory impairment, visual impairment, language impairment, problem behavior, sleep disorders, such as a wide range of depressive symptoms. Such as a degenerative disease of the brain affected dementia, Alzheimer's disease, Lewy body dementia, vascular dementia, frontotemporal leaves (FTLD: Frontotemporal lobar degeneration) macular degeneration are known.
By the dementia FTLD, particularly in Europe, then the progressive dementia Alzheimer's disease in many cases. The principal features of FTLD, temporal lobe and frontal lobe and the modified site, the tissue pathological findings, the frontal lobe of the modified type, Pick's disease type, motor neuron disease type one 3. As symptoms, personality and social behaviors such as the abnormality of the abnormal behavior due to the higher order brain can be seen. However, is very complex and FTLD condition, diagnostic methods to this, studies relating to the order was not sufficiently advanced, fundamental therapy is not yet been established.
Exhibits a very complex condition for further detailed study of FTLD is advanced, the pathology requires the presence of a uniform model animal system is essential. Such a model as the animals, transgenic animal models, for example, it is preferable that the knock-out mice. Conventional, FTLD is, in the nerve cells and abnormal protein aggregation FUS TDP-43, neurodegenerative localization or abnormal accumulation is called as a cause. Therefore, the model animal FTLD such as dementia, dementia-related gene by overexpression of, for example, a knock has been produced by the gene. However, they may be the high expression of specific genes by toxicity, cause neurodegeneration possibility cannot be negative, abnormal findings depend on the model itself is data indicating whether or not there was criticized.
Patent Document 1 is, Amyotrophic Lateral Sclerosis and/or muscular atrophy in frontotemporal leaves a mouse model of macular degeneration is disclosed. The model mouse, endogenous alleles of at least one TDP-43 of the variants in the TDP-43 knock-in mice were replaced. The model mouse, amyotrophic lateral sclerosis and neurodegenerative disease and frontotemporal leaf exhibits a similar, since knock-in mice, according to the findings of the model itself may determine whether or not the abnormality is difficult to determine.
The group of the inventors of the present invention, the above conditions using a mouse and a study of FTLD, as a result, in the mouse brain (Fused in sarcoma) genes FUS, shRNA knockdown expression lentivivus using mice, as shown in the pathology of FTLD (see Non-Patent Document 1.). Knocked down genes FUS further in cultured cells, present in the synapse GluA1 glutamate receptor can be a significant decrease in the amount of protein, specific mRNA GluA1 of the FUS is coupled to a serves to stabilize, then the above-described mouse knock down FUS FTLD-like condition is, by the introduction of gene GluA1 indicated.
In the experiments described above to suppress the expression of the (loss of function) has been suggested as a cause of FTLD for genes FUS, more precisely to the study proceeds, the need for the production of knockout mice FUS. However, gene knockout mice FUS, because the lethal embryonic usually, this is reported to the creation of the hybrid and of the mouse (in the example, non-patent document 2, see Non-Patent Document 3.), Otherwise the report is not found. In addition, having substantially the same genetic background of the inbred mice knockout mice and more difficult to manufacture, there was no report so far. FTLD-type dementia is, has a very complicated condition, in order to obtain reliable results of the experiment, a large individual difference is limited in the hybrid.
On the other hand, is SynGAP (Synaptic Ras GTPase activating Protein), thick post-synaptic (PSD) and a protein present, the downstream activation of glutamate receptor g protein signaling a small molecule known in the negative control. Is SynGAP protein, mammalian to the higher from a nematode been found to be present. In addition, the protein is SynGAP, a plurality of types of the current C-terminal domain to the (α1, α2, β, γ or the like) and, a plurality of types of N-terminal domain (A, B, C or the like) composed of a combination of splicing and indicated the presence of various, suggesting that a variety of functions (for example, Non-Patent Document 4, see Non-Patent Document 5.).
Scope of claims (In Japanese)[請求項1]
脳におけるFUS遺伝子の特異的ノックアウトにより作製されることを特徴とする、シナプス異常を伴う疾患の症状を呈するモデル動物。
[請求項2]
ノックアウトが、Cre-loxPシステムとCamK2プロモーターとを用いて行われる、請求項1に記載のモデル動物。
[請求項3]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項1または2に記載のモデル動物。
[請求項4]
動物がマウスである、請求項1~3のいずれか一項に記載のモデル動物。
[請求項5]
動物が近交系である、請求項1~4のいずれか一項に記載のモデル動物。
[請求項6]
請求項1~5のいずれか一項に記載のモデル動物から取得されるモデル神経細胞またはモデル神経細胞株。
[請求項7]
脳におけるFUS遺伝子を特異的にノックアウトする操作工程を有することを特徴とする、シナプス異常を伴う疾患の症状を呈するモデル動物の製造方法。
[請求項8]
脳におけるFUS遺伝子を特異的にノックアウトする操作工程が、Cre-loxPシステムとCamK2プロモーターとを用いるものである、請求項7に記載の製造方法。
[請求項9]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項7または請求項8に記載の製造方法。
[請求項10]
動物がマウスである、請求項7~9のいずれか一項に記載の製造方法。
[請求項11]
動物が近交系である、請求項7~10のいずれか一項に記載の製造方法。
[請求項12]
請求項1~5のいずれか一項に記載のモデル動物、または請求項6に記載のモデル神経細胞もしくはモデル神経細胞株を用いる工程を有することを特徴とする、シナプス異常を伴う疾患の治療薬を探索するためのスクリーニング方法。
[請求項13]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項12に記載のスクリーニング方法。
[請求項14]
対象薬物の適用によるSynGAPα2の増減を測定する工程を有することを特徴とする、シナプス異常を伴う疾患の治療薬を探索するためのスクリーニング方法。
[請求項15]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項14に記載のスクリーニング方法。
[請求項16]
SynGAPα2をコードする遺伝子もしくはSynGAPα2タンパク質、または脳におけるSynGAPα2遺伝子の発現を促進する薬物もしくはSynGAPα2タンパク質を増加しうる薬物を有効成分として含有することを特徴とする、シナプス異常を伴う疾患の治療剤。
[請求項17]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項16に記載の治療剤。
[請求項18]
SynGAPα2を脳に補充または増加させる工程を有することを特徴とする、シナプス異常を伴う疾患の治療方法。
[請求項19]
シナプス異常を伴う疾患が、前頭側頭葉変性症(FTLD)または運動ニューロン疾患である、請求項18に記載の治療方法。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NAGOYA UNIVERSITY
  • Inventor
  • SOBUE Gen
  • ISHIGAKI Shinsuke
  • YOKOI Satoshi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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