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THERAPEUTIC AGENT FOR INTRACELLULAR TDP-43 CONTENT-RELATED DISEASE

Foreign code F170009124
File No. (S2016-0233-N0)
Posted date Jul 13, 2017
Country WIPO
International application number 2016JP088738
International publication number WO 2017111166
Date of international filing Dec 26, 2016
Date of international publication Jun 29, 2017
Priority data
  • P2015-253332 (Dec 25, 2015) JP
Title THERAPEUTIC AGENT FOR INTRACELLULAR TDP-43 CONTENT-RELATED DISEASE
Abstract According to the present invention, a drug for treating an intracellular TDP-43 content-related disease is developed and provided . In the binding of TDP-43 to a specific mt-tRNA, the binding sites of the respective substances are identified. On the basis of the result of the identification, a binding inhibitor capable of selectively inhibiting the binding of TDP-43 to the specific mt-tRNA is developed.
Outline of related art and contending technology BACKGROUND ART
Amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis: hereinafter, referred to herein is often '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, of development, normal, relatively fast, 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. Familial ALS interrupt is about 2, 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, (non-patent document 2) (angiogenin) , vesicle membrane binding protein (VAMP: vesicle-associated membrane protein) / synaptic vesicle binding protein B(synaptobrevin-associated membrane protein B) (non-patent document 3), 43(TAR DNA-binding protein-43 TAR DNA binding protein: hereinafter, often referred to herein as' TDP-43' referred to) (non-patent document 4), fused in sarcoma/translated in liposarcoma(FUS/TLS) (and non-patent document 5) have been reported such as gene. 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 of the 3 familial ALS patient example, 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, mutated in rather TDP-43 gene has been 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 (often abbreviated as' Glu ' or less) 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, loss of astrocytes Glu uptake is believed to be the cause. Therefore, poison Glu, in particular glutamate receptor sub-type α - hydroxy -5 - methyl -4 - amino -3 - acid (AMPA) receptor-mediated Glu Glu by toxins neuropathy due to an increase in a result generated, consistent with the hypothesis that the onset of sporadic ALS is promising. For example, in human ALS motor neurons, AMPA receptor subunit RNA editing rate is low and the GluR2 Q/R site, sporadic ALS play an important role in the pathology report to the effect that the (non-patent document 8-12), supporting the hypotheses.
(Non-patent document 13) Lacomblez et al. is, 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, a high concentration of methylcobalamin is, by adenosylmethionine S- competitively inhibit methylation of DNA for, high retention become possible gene transcription (non-patent document 15). Therefore, it is necessary for nerve regeneration by promoting the synthesis of the protein, cerebral spinal cord from reaching the movement of the protection of neuronal cells or not, is assumed to be, 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, medical history and neurological findings totally judgment, onset of diagnosis and accurate diagnosis is difficult.
So far as one of the causal genes ALS, sporadic and familial ALS ALS high mutation frequency in any of the suggested that TDP-43 gene (non-patent document 16-23), further ALS patient lesion cells including TDP-43 cytoplasmic accumulation of the deposits also known (non-patent document 17). However, TDP-43 TDP-43 functions within the cells and the mutation relates to how the onset ALS, the mechanism will be, from the known up to now.
Scope of claims (In Japanese)[請求項1]
TAR DNA結合タンパク質-43とmt-tRNAとの結合阻害剤であって、
(a)mt-tRNAにおける可変領域の全部又は一部からなる領域に結合する分子、
(b)mt-tRNAにおける可変領域の全部又は一部からなる領域を遮蔽する分子、
(c)配列番号1で示すアミノ酸配列において136位のリジン、145位のリジン、147位のフェニルアラニン及び149位のフェニルアラニンからなる群から選択されるアミノ酸を少なくとも1つ含むTAR DNA結合タンパク質-43の一部からなる領域に結合する分子、又は
(d)配列番号1で示すアミノ酸配列における136位のリジン、145位のリジン、147位のフェニルアラニン及び149位のフェニルアラニンからなる群から選択されるアミノ酸の少なくとも1つ含むTAR DNA結合タンパク質-43の一部からなる領域を遮蔽する分子、
からなり、
前記mt-tRNAは、mt-tRNAAsn、mt-tRNAGln、mt-tRNAPro及びmt-tRNAGluからなる群から選択されるいずれかのmt-tRNAである、
前記結合阻害剤。
[請求項2]
前記分子が核酸、ペプチド、低分子化合物、又はそれらの組み合わせで構成される、請求項1に記載の結合阻害剤。
[請求項3]
前記核酸が配列番号2(guguuugugg)、配列番号3(cagggau)、配列番号4(auggugg)及び配列番号5(uuggucg)で示すいずれか一の塩基配列を含むヌクレオチドからなり、TAR DNA結合タンパク質-43と結合する、請求項2に記載の結合阻害剤。
[請求項4]
前記核酸が前記mt-tRNAにおける可変領域の全部又は一部からなる領域に相補的な塩基配列を含むヌクレオチドからなり、前記いずれか一のmt-tRNAに結合する、請求項2に記載の結合阻害剤。
[請求項5]
前記mt-tRNAにおける可変領域が配列番号6(cuaaguguuuguggg)、配列番号7(uucucagggauggg)、配列番号8(gcuaaugguggagu)、及び配列番号9(aucauuggucgugg)で示すいずれか一の塩基配列からなる、請求項4に記載の結合阻害剤。
[請求項6]
前記ペプチドが配列番号1で示すアミノ酸配列において136位~149位のアミノ酸配列を含み、全長100アミノ酸以下のペプチドからなる、前記いずれか一のmt-tRNAに結合する、請求項2に記載の結合阻害剤。
[請求項7]
前記核酸が請求項6に記載のペプチドをコードするポリヌクレオチドを含む遺伝子発現系である、請求項2に記載の結合阻害剤。
[請求項8]
請求項1~7のいずれか一項に記載のTAR DNA結合タンパク質-43とmt-tRNAとの結合阻害剤を有効成分とするTAR DNA結合タンパク質-43細胞内存在量関連疾患治療用医薬組成物。
[請求項9]
前記TAR DNA結合タンパク質-43細胞内存在量関連疾患が筋萎縮性側索硬化症、前頭側頭葉変性症、アルツハイマー病、及びパーキンソン病からなる群から選択される、請求項8に記載の医薬組成物。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY
  • TOKYO METROPOLITAN UNIVERSITY
  • Inventor
  • IZUMIKAWA Keiichi
  • TAKAHASHI Nobuhiro
  • ISHIKAWA Hideaki
  • ISOBE Toshiaki
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 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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