Patents Assigned to The Tokyo Metropolitan Institute of Medical Science
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Patent number: 9955675Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.Type: GrantFiled: April 25, 2013Date of Patent: May 1, 2018Assignees: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE, CHUGAI SEIYAKU KABUSHIKI KAISHA, PHOENIXBIO CO., LTD.Inventors: Michinori Kohara, Koichi Jishage, Yosuke Kawase, Chise Mukaidani, Hiroki Oshita, Satoko Hamamura
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Patent number: 9891229Abstract: Protein ubiquitylation, an essential post-translational modification, regulates almost every cellular process including protein degradation, protein trafficking, signal transduction, and DNA damage response in eukaryotic cells. The diverse functions of ubiquitylation are thought to be mediated by distinct chain topologies resulting from eight different ubiquitin linkages, chain lengths, and complexities. Currently, ubiquitin linkages are generally thought to be a critical determinant of ubiquitin signaling. However, ubiquitin chain lengths, another key element of ubiquitin signaling, have not been well documented especially in vivo situation during past three decades from the discovery of ubiquitin. The reason of this was simply because no method has been available for determination of ubiquitin chain length in endogenous ubiquitylated substrates. In the present invention, a practical technique for determining the actual length of substrate-attached polyubiquitin chains from biological samples is established.Type: GrantFiled: September 21, 2017Date of Patent: February 13, 2018Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Yasushi Saeki, Hikaru Tsuchiya, Ai Kaiho, Keiji Tanaka
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Patent number: 9891228Abstract: Protein ubiquitylation, an essential post-translational modification, regulates almost every cellular process including protein degradation, protein trafficking, signal transduction, and DNA damage response in eukaryotic cells. The diverse functions of ubiquitylation are thought to be mediated by distinct chain topologies resulting from eight different ubiquitin linkages, chain lengths, and complexities. Currently, ubiquitin linkages are generally thought to be a critical determinant of ubiquitin signaling. However, ubiquitin chain lengths, another key element of ubiquitin signaling, have not been well documented especially in vivo situation during past three decades from the discovery of ubiquitin. The reason of this was simply because no method has been available for determination of ubiquitin chain length in endogenous ubiquitylated substrates. In the present invention, a practical technique for determining the actual length of substrate-attached polyubiquitin chains from biological samples is established.Type: GrantFiled: November 5, 2014Date of Patent: February 13, 2018Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Yasushi Saeki, Hikaru Tsuchiya, Ai Kaiho, Keiji Tanaka
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Publication number: 20170357750Abstract: The present invention provides a method for evaluating (predicting, etc.) an individual difference (the tendency of every individual) in terms of drug sensitivity and disease vulnerability, comprising using a gene polymorphism of a cyclic AMP responsive element binding protein gene or the like. The method for evaluating drug sensitivity and the method for evaluating disease vulnerability according to the present invention comprise associating a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism with the drug sensitivity and disease vulnerability of an individual.Type: ApplicationFiled: July 10, 2017Publication date: December 14, 2017Applicant: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Kazutaka IKEDA, Daisuke NISHIZAWA, Kenichi FUKUDA
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Patent number: 9804174Abstract: A antibody has as a target molecule a ubiquitin protein comprising a phosphorylated serine residue at position 65. In addition, a method is provided for specifically detecting Parkinson's disease at an early stage, in which a target molecule is a ubiquitin protein comprising a phosphorylated serine residue at position 65, a pharmaceutical composition for definitively treating or preventing Parkinson's disease, and a method for screening for the pharmaceutical composition.Type: GrantFiled: February 13, 2015Date of Patent: October 31, 2017Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Noriyuki Matsuda, Fumika Koyano, Kei Okatsu, Etsu Go, Mayumi Kimura, Yasushi Saeki
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Patent number: 9802992Abstract: The present invention has the object of providing a cell into which a protein, which can serve as a polymerization nucleus of a protein polymer, or polymer thereof is introduced, and a method for producing the cell. The invention relates to a cell into which a protein, which can serve as a polymerization nucleus of a protein polymer, or a polymer thereof is introduced, a method for producing the cell, and a method of screening for a compound inhibiting an intracellular accumulation of a protein containing fibril structures, wherein the method comprises bringing a candidate substance into contact with the cell.Type: GrantFiled: December 6, 2006Date of Patent: October 31, 2017Assignee: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Takashi Nonaka, Sayuri Watanabe, Masami Masuda, Masato Hasegawa
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Patent number: 9632092Abstract: The present invention provides antibodies useful for diagnosing and treating tumors as well as methods of screening for antitumor agents. More specifically, tumors can be diagnosed and treated using an anti-phosphorylated p62 antibody that recognizes phosphorylation of serine at position 351 of an amino acid sequence of SEQ ID No. 1 or at a position corresponding thereto. An antitumor agent can be obtained by screening for a substance that inhibits the phosphorylation or that dephosphorylates the phosphorylated serine.Type: GrantFiled: July 9, 2015Date of Patent: April 25, 2017Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Masaaki Komatsu, Yoshinobu Ichimura
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Patent number: 9624279Abstract: The purpose of the present invention is to develop a method for amplifying in vitro to a large amount of a homogenous insoluble aggregate that is equivalent to an insoluble aggregate formed in the brain of a patient. A method of producing an insoluble aggregate including TDP-43 protein and fragments thereof according to the present invention includes the steps of: (1) introducing an insoluble fraction originated from the brain of a neurodegenerative disease patient into a cell culture in which the intact TDP-43 protein can be expressed in a constitutive manner; (2) culturing the cultured cell into which the insoluble fraction has been introduced; and (3) separating an insoluble fraction from the cultured cell. Optionally, the method may additionally include a step of amplifying the insoluble aggregate of the neurodegenerative-disease-related protein in the cultured cell.Type: GrantFiled: May 18, 2012Date of Patent: April 18, 2017Assignee: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Takashi Nonaka, Masami Masuda, Makiko Yamashita, Haruhiko Akiyama, Masato Hasegawa
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Patent number: 9315790Abstract: The present invention provides a pharmaceutical composition comprising a protein having ?-galactosidase activity for treating Fabry disease, which causes no allergic side effect, which is highly stable in blood (plasma) and which can readily be taken up by a cell of an affected organ. The pharmaceutical composition for treating Fabry disease of the invention comprises, for example, a protein which acquires an ?-galactosidase activity through alteration of the structure of the active site of wild-type human ?-N-acetylgalactosaminidase.Type: GrantFiled: September 13, 2013Date of Patent: April 19, 2016Assignees: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE, ALTIF LABORATORIES INC.Inventors: Hitoshi Sakuraba, Youichi Tajima, Ikuo Kawashima, Seiichi Aikawa, Fumiko Aikawa
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Patent number: 9193964Abstract: The present invention provides, as an enzyme which can be used for enzyme replacement therapy for Fabry disease, a protein having ?-galactosidase activity, which shows no allergic adverse side effect, shows a high stability in blood, and can be easily incorporated into a cell of an affected organ. The protein of the present invention is a protein which has acquired ?-galactosidase activity by changing the structure of the active site of wild-type human ?-N-acetylgalactosaminidase.Type: GrantFiled: January 23, 2014Date of Patent: November 24, 2015Assignees: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE, ALTIF LABORATORIESInventors: Hitoshi Sakuraba, Youichi Tajima, Mai Ito, Seiichi Aikawa, Fumiko Aikawa
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Patent number: 9175269Abstract: The present invention provides modified hepatitis C virus genomic RNA, comprising nucleotide sequences of genomic RNA portions of two or more types of hepatitis C viruses, which comprises a 5? untranslated region, a core protein coding sequence, an E1 protein coding sequence, a p7 protein coding sequence, an E2 protein coding sequence, an NS2 protein coding sequence, an NS3 protein coding sequence, an NS4A protein coding sequence, an NS4B protein coding sequence, an NS5A protein coding sequence, an NS5B protein coding sequence, and a 3? untranslated region, and which can be autonomously replicated. In particular, the present invention relates to modified hepatitis C virus genomic RNA, which can be autonomously replicated by substitution of the RNA sequence portion encoding NS3, NS4, NS5A, and NS5B proteins of hepatitis C virus genomic RNA with a partial RNA sequence encoding NS3, NS4, NS5A, and NS5B proteins of a JFH1 strain shown in SEQ ID NO: 1.Type: GrantFiled: January 4, 2013Date of Patent: November 3, 2015Assignees: TORAY INDUSTRIES, INC., TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Takaji Wakita, Takanobu Kato, Tomoko Date, Michiko Miyamoto, Ralf Bartenschlager, Jun-ichi Tanabe, Saburo Sone
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Patent number: 9128081Abstract: Disclosed is a transformed cell (a cell model) which can form a cytoplasmic inclusion body derived from TAR DNA-binding protein of 43 kDa (TDP-43) that is found in the brain of a patient suffering from a neurodegenerative disease such as FTLD and ALS. The transformed cell is characterized by having, introduced therein, a promoter capable of functioning in a host cell and a mutant TDP-43 gene.Type: GrantFiled: December 4, 2013Date of Patent: September 8, 2015Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Takashi Nonaka, Tetsuaki Arai, Haruhiko Akiyama, Masato Hasegawa, Makiko Yamashita
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Patent number: 9101618Abstract: The present invention was accomplished for the purpose of developing a method for effectively treating and/or preventing synucleinopathies, and is based on a discovery that an adiponectin receptor agonist suppresses ? (alpha)-synuclein aggregation, tau phosphorylation and a decrease in proteasomal activity. The method of the present invention for treating and/or preventing neurodegenerative diseases includes a step of administering an effective dose of at least one effective element selected from a group consisting of: adiponectin as an adiponectin receptor agonist; a compound inducing expression of adiponectin; globular adiponectin; and a compound inducing expression of globular adiponectin. The present invention further provides a screening method of the adiponectin receptor agonist for treating and/or preventing neurodegenerative diseases.Type: GrantFiled: August 20, 2012Date of Patent: August 11, 2015Assignee: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Makoto Hashimoto, Kazunari Sekiyama, Yoshiki Takamatsu, Masayo Fujita, Akio Sekigawa
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Patent number: 9090681Abstract: The present invention provides antibodies useful for diagnosing and treating tumors as well as methods of screening for antitumor agents. More specifically, tumors can be diagnosed and treated using an anti-phosphorylated p62 antibody that recognizes phosphorylation of serine at position 351 of an amino acid sequence of SEQ ID No. 1 or at a position corresponding thereto. An antitumor agent can be obtained by screening for a substance that inhibits the phosphorylation or that dephosphorylates the phosphorylated serine.Type: GrantFiled: June 5, 2013Date of Patent: July 28, 2015Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Masaaki Komatsu, Yoshinobu Ichimura
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Patent number: 9057048Abstract: An objective of this invention is to provide an HCV strain with a high capacity for virus production in a cell culture system. This invention provides a nucleic acid encoding a polyprotein precursor of the hepatitis C virus JFH1 strain having one or more amino acid substitutions, wherein the polyprotein precursor comprises at least substitution of glutamine at position 862 with arginine, as determined with reference to the amino acid sequence as shown in SEQ ID NO: 2 in the Sequence Listing.Type: GrantFiled: March 25, 2011Date of Patent: June 16, 2015Assignees: THE UNIVERSITY OF TOKYO, NIHON UNIVERSITY, INSTITUTE OF MICROBIOLOGY, CHINESE ACADEMY OF SCIENCES, TORAY INDUSTRIES, INC., JAPAN AS REPRESENTED BY DIRECTOR-GENERAL OF NATIONAL INSTITUTE OF INFECTIOUS DISEASES, TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCEInventors: Yoshihiro Kitamura, Yoko Shimizu, Chie Aoki, Lijuan Yu, Takaji Wakita
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Publication number: 20150128298Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.Type: ApplicationFiled: April 25, 2013Publication date: May 7, 2015Applicants: TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE, PHOENIXBIO CO., LTD., CHUGAI SEIYAKU KABUSHIKI KAISHAInventors: Michinori Kohara, Koichi Jishage, Yosuke Kawase, Chise Mukaidani, Hiroki Oshita, Satoko Hamamura
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Patent number: 9000136Abstract: Provided is a recombinant virus which is efficacious in preventing the onset of hepatitis C infection and has a high safety. Also provided is a vaccine for hepatitis C virus which contains the recombinant virus. A recombinant vaccinia virus which can express hepatitis C virus gene. The hepatitis C virus vaccine as described above contains the recombinant virus as described above.Type: GrantFiled: March 6, 2009Date of Patent: April 7, 2015Assignees: Tokyo Metropolitan Institute of Medical Science, The Chemo-Sero-Therapeutic Research InstituteInventors: Michinori Kohara, Fukashi Murai
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Patent number: 8957199Abstract: The present inventors focused on siE sequences that have been thought to show RNAi activity against HCV viral RNAs, and mainly selected the D5-50 and D5-197 regions present within the IRES region, and carried on the analysis. As a result, the present inventors successfully identified siRNA sequences that exhibit a more effective RNAi activity against hepatitis C virus RNAs. Furthermore, the siRNAs were demonstrated to have a significant inhibitory effect on HCV propagation in an in vivo system.Type: GrantFiled: November 26, 2009Date of Patent: February 17, 2015Assignees: Chugai Seiyaku Kabushiki Kaisha, Tokyo Metropolitan Institute of Medical ScienceInventors: Michinori Kohara, Masayuki Sudo
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Patent number: 8940872Abstract: The present invention provides an antibody that specifically binds to an abnormal TDP-43 protein aggregate, an agent comprising the antibody for detecting a TDP-43 proteinopathy lesion, and a method for detecting or diagnosing a TDP-43 proteinopathy lesion by using the antibody.Type: GrantFiled: July 7, 2008Date of Patent: January 27, 2015Assignee: Tokyo Metropolitan Institute of Medical ScienceInventors: Masato Hasegawa, Tetsuaki Arai, Takashi Nonaka, Fuyuki Kametani, Haruhiko Akiyama
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Patent number: 8834893Abstract: The present invention provides a nucleic acid comprises a 5? untranslated region, an NS3 protein coding region, an NS4A protein coding region, an NS4B protein coding region, an NS5A protein coding region, an NS5B protein coding region, and a 3? untranslated region of a hepatitis C virus genome, wherein the nucleic acid has nucleotide substitutions causing one or more amino acid substitutions selected from the group consisting of M(1205)K, F(1548)L, C(1615)W, T(1652)N, A(2196)T, A(2218)S, H(2223)Q, Q(2281)R, K(2520)N, and G(2374)S, as defined using the amino acid sequence shown in SEQ ID NO: 6 in the Sequence Listing as a reference sequence, in the NS3 protein coding region, the NS5A protein coding region, or the NS5B protein coding region.Type: GrantFiled: December 25, 2009Date of Patent: September 16, 2014Assignees: Toray Industries, Inc., Japan as Represented by Director-General of National Institute of Infectious Diseases, Tokyo Metropolitan Institute of Medical ScienceInventors: Takaji Wakita, Tomoko Date, Hitoshi Takahashi