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METHOD FOR DESIGNATING DISEASE RELATING TO AMOUNT OF TDP-43 EXISTING IN CELLS 新技術説明会

外国特許コード F130007671
整理番号 S2012-0454-N0
掲載日 2013年10月17日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2013JP055497
国際公開番号 WO 2013129603
国際出願日 平成25年2月28日(2013.2.28)
国際公開日 平成25年9月6日(2013.9.6)
優先権データ
  • 特願2012-042256 (2012.2.28) JP
発明の名称 (英語) METHOD FOR DESIGNATING DISEASE RELATING TO AMOUNT OF TDP-43 EXISTING IN CELLS 新技術説明会
発明の概要(英語) The present invention addresses the problem of developing and providing a method for designating a disease that relates to the amount of TDP-43 existing in cells and a method for producing a TDP-43 binding inhibitor. By collecting cells from a subject and measuring the existing amount of a test substance in the cells, the binding amount of the test substance to TDP-43 in the cells, etc., whether or not the subject suffers from a disease that relates to the amount of TDP-43 existing in cells is designated. By adding a medicine candidate, a medicine capable of significantly reducing the binding of the test substance to TDP-43 is produced.
従来技術、競合技術の概要(英語) BACKGROUND ART
Amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis: hereinafter, often abbreviated as' ALS ') is, the brain stem, spinal cord, the motor neuron disorder of upper motor neuron lesions, with the advance of the lower motor neuron disorder, muscle atrophy and muscle weakness associated with the cause of dysfunction of the upper limb movements, gait impairment, dysarthria, dysphagia, disordered breathing such as refractory disease symptoms appear. A relatively long-term survival ventilator also known for the sake of example, are usually relatively fast development of , average 3.5 years after the onset of paralysis of the respiratory muscles mainly in many cases of mortality.
ALS is one of 5-10%, a family history of familial amyotrophic lateral sclerosis involves Amyotrophic Lateral Sclerosis (familial ALS) called. Is about 2 to interrupt the familial ALS, a free radical scavenging enzyme superoxide dismutase cu/Zn (SOD1: superoxide dismutase 1) (ALS1) reported that mutations in the gene (non-patent document 1) and, ALS 1 SOD1 gene are considered to be one of the causal genes. In addition, as the causal genes other ALS, angiogenin (non-patent document 2), vesicle membrane binding protein (VAMP: vesicle-associated membrane protein) / synaptic vesicle binding protein B (VAPB: synaptobrevin-associated membrane protein B) (non-patent document 3), TAR DNA binding protein 43 (TDP-43: TAR DNA-binding protein) (non-patent document 4), non-patent document 5 and fused in sarcoma/translated in liposarcoma(FUS/TLS) () such as gene have been reported. However, due to the abnormality of these genes, how to develop ALS, or to the progress of the disease state, is known about the specific mechanism is not.
Maruyama et al. (non-patent document 6) is, in the example 6 familial ALS patient of example 3, involved in intracellular signaling to suppress NFκB optineurin gene (optineurin) disclosed a variation. Mutant optineurin, leading to a loss of the suppressive activity of NFκB it, ALS NFκB inhibitor is likely to have a therapeutic effect has been suggested. However, the 90-95% of the ALS, sporadic and, in many ALS patients than the optineurin gene, a mutation in the gene rather TDP-43 are found. Therefore, even if the inhibitor has an effect in the treatment of ALS NFκB even, its therapeutic effect is, only a small part of ALS can be expected in a patient.
Rothstein et al. (non-patent document 7) is, the mutant SOD1 gene in the patient's cerebrospinal fluid ALS, wild-type SOD1 gene healthy in comparison to glutamic acid (hereinafter often simply referred to as' Glu ') can be nearly a fourfold increase in the concentration of 3, and the population studies in sporadic ALS spinal Glu 40% of the patients an increase of from each other, along with increase of the fuel-Glu Glu ALS play an important role in the mechanism of development suggests that are responsible for. An increase in a patient such Glu ALS, due to a loss of astrocytes Glu believed uptake and, therefore, sporadic ALS is, poison Glu, a subtype of the glutamate receptors in particular α - hydroxy -5 - methyl -4 - amino -3 - acid (AMPA) receptor-mediated Glu Glu due to an increase in the nerve poison adversely affected and promising hypothesis that develops as a result. In human ALS motor neurons, AMPA receptor subunit RNA editing rate is low and the GluR2 Q/R site, sporadic ALS and play an important role in the pathology and also reports (non-patent document 8-12), supporting this hypothesis.
(Non-patent document 13) is Lacomblez et al., Riluzole ALS (Riluzole) survival of the patient is in a small amount can be significantly extended clinical test results disclosed. Riluzole is, said hypothesis is developed based on the glutamic acid antagonist. At present, only this Riluzole ALS as a therapeutic drug approved in Japan and Europe (trade name: ). However, riluzole is, to suppress an increase in the cause of ALS is not Glu, due to an increase in handling the effect of reducing the poison Glu Glu therapy but only, in the cardinal symptoms of ALS or other muscle weakness is not a validity with respect to clinical symptoms.
Is Patent Document 1, large doses of methylcobalamin ALS (Methylcobalamin) by a certain improvement effect in the clinical symptoms of disclosed is observed, the current, double-blind comparison tests of methylcobalamin has been promoted. However, a glutamate Agent to be mainly cell death inhibitory effect (non-patent document 14) based on, the effect of Riluzole can not be expected to improve. However, its effect on ALS is methylcobalamin of, in addition to the toxic effects of suppressing Glu, due to the high concentration of methylcobalamin is adenosylmethionine S- competitively inhibit methylation of DNA from, gene transcription (non-patent document 15) maintained at a high value, thereby the synthesis of proteins necessary for nerve regeneration is promoted as a result, the protection of cerebral spinal cord motor neurons in the barrier layer from reaching the, and been suspected. However, actually ALS pathology, indicating a relationship of the onset mechanism and there is no evidence, merely generally remains stoichiometric inference.
In addition, a diagnosis of ALS can be confirmed diagnosis to date no specific clinical inspection method, conventionally, by the observation that generally determines the medical history or nerve and, prior to the onset of the expected, the accuracy of the onset of diagnosis is the diagnosis and after the onset, difficult.
As described above, ALS is, a high precision diagnosis method up to now, curative therapy, and to suppress the progression or delay the progression is not established therapy, has been its development is strongly desired.
  • 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
  • NATIONAL UNIVERSITY CORPORATION TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY
  • TOKYO METROPOLITAN UNIVERSITY
  • 発明者(英語)
  • TAKAHASHI Nobuhiro
  • IZUMIKAWA Keiichi
  • ISHIKAWA Hideaki
  • YOSHIKAWA Harunori
  • ISHOBE Thoshiaki
  • TAOKA Masato
  • NAKAYAMA Hiroshi
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 DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT 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 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 ML MR NE SN TD TG
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