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DISEASE MODEL ANIMAL AND DISEASE THERAPEUTIC AGENT コモンズ

外国特許コード F180009394
整理番号 (NU-665)
掲載日 2018年4月20日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2017JP025273
国際公開番号 WO 2018012497
国際出願日 平成29年7月11日(2017.7.11)
国際公開日 平成30年1月18日(2018.1.18)
優先権データ
  • 特願2016-139308 (2016.7.14) JP
発明の名称 (英語) DISEASE MODEL ANIMAL AND DISEASE THERAPEUTIC AGENT コモンズ
発明の概要(英語) 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.
従来技術、競合技術の概要(英語) 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.).
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • NAGOYA UNIVERSITY
  • 発明者(英語)
  • SOBUE Gen
  • ISHIGAKI Shinsuke
  • YOKOI Satoshi
国際特許分類(IPC)
指定国 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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