Development of gene therapy using bone-marrow-derived mesenchymal stem cells

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390296
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: OZAWA Keiya 自治医科大学, 医学部, 教授 (30137707)
• Co-Investigator(Kenkyū-buntansha): URABE Masashi 自治医科大学, 医学部, 講師 (40213516) ; UCHIBORI Ryosuke 自治医科大学, 医学部, 助教 (20458285)
• Project Period (FY): 2009 – 2011
• Keywords: 間葉系幹細胞 / 癌 / 遺伝子治療 / 移植再生医療 / ゲノム

Research Abstract

The development of gene therapy technologies using mesenchymal stem cells(MSCs) was conducted. First, MSCs have the ability to accumulate at tumor sites, and we investigated the mechanisms using tumor-bearing nude mice. As a result, important information was obtained that will be useful when MSCs are utilized as a platform for cancer-targeted gene therapy. Second, in order to ensure the safety of genetic manipulation of MSCs, we conducted basic studies on the site-specific integration of transgenes using adeno-associated virus integration machinery for the AAVS1 locus on chromosome 19.

Research Products

• [Journal Article] Interleukin-10 expression induced by adeno-associated virus vector suppresses proteinuria in Zucker obese rats (2012)
  • Author(s): Ogura M, Urabe M, Akimoto T, Onishi A, Ito C, Ito T, Tsukahara T, Mizukami H, Kume A, Muto S, Kusano E, and Ozawa K.
  • Journal Title: Gene Ther Volume: 19巻 Pages: 476-82
  • DOI: DOI:10.1038/gt.2011.183.
  • Peer Reviewed
• [Journal Article] Recovery of neurogenic amines in phenylketonuria mice after liver-targeted gene therapy (2012)
  • Author(s): Yagi H, Sanechika S, Ichinose H, Sumi-Ichinose C, Mizukami H, Urabe M, Ozawa K, Kume A
  • Journal Title: Neuroreport Volume: 4巻 Pages: 30-4
  • Peer Reviewed
• [Journal Article] Development of a mouse model for lymph node metastasis with endometrial cancer (2011)
  • Author(s): Takahashi K, Saga Y, Mizukami H, Takei Y, Urabe M, Kume A, Suzuki M, and Ozawa K
  • Journal Title: Cancer Sci Volume: 102巻 Pages: 2272-7
  • DOI: DOI:10.1111/j.1349-7006.2011.02099.x.
  • Peer Reviewed
• [Journal Article] Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells (2011)
  • Author(s): Meguro A, Ozaki K, Hatanaka K, Oh I, Sudo K, Ohmori T, Matsu H, Tatara., Sato K, Sakata Y, Nakae S, Leonard W J, and Ozawa K
  • Journal Title: Bone Marrow Transplant Volume: 46巻 Pages: 1557-1565
  • DOI: DOI:10.1038/bmt.2010.342.
  • Peer Reviewed
• [Journal Article] Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation (2011)
  • Author(s): Tatara R, Ozak K., Kikuchi Y, Hatanaka K, Oh I, Meguro A, Matsu H, Sato K, and Ozawa K
  • Journal Title: Cytotherapy Volume: 13巻 Pages: 686-694
  • Peer Reviewed
• [Journal Article] Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector (2011)
  • Author(s): Yagi H, Ogura T, Mizukami H, Urabe M, Hamada H, Yoshikawa H, Ozawa K and Kume A
  • Journal Title: J. Gene Med Volume: 13巻 Pages: 114-122
  • DOI: DOI:10.1002/jgm.1543.
  • Peer Reviewed
• [Journal Article] Altered effector CD4+T cell function in IL-21R-/-CD4+T cell-mediated graft-versus-host disease (2010)
  • Author(s): Oh I, Ozaki K, Meguro A, Hatanaka K, Kadowaki M, Matsu H, Tatara R, Sato K, Iwakura Y, Nakae S, Sudo K, Teshima T, Leonard W J and Ozawa K
  • Journal Title: J. Immunol Volume: 185巻 Pages: 1920-1926
  • Peer Reviewed
• [Journal Article] IL-21 is critical for GVHD in a mouse model (2010)
  • Author(s): Meguro A, Ozaki K, Oh I, Hatanaka K, Matsu H, Tatara R, Sato. K, Leonard W J and Ozawa K
  • Journal Title: Bone Marrow Transplant Volume: 45巻 Pages: 723-729
  • Peer Reviewed
• [Journal Article] Mutant Macaque Factor IX T262A : A Tool for Hemophilia B Gene Therapy Studies in Macaques (2010)
  • Author(s): Ishiwata A, Mimuro J, Mizukami H, Kashiwakura Y, Yasumoto A, Sakata A, Ohmori T, Madoiwa S, Ono F, Shima M, Yoshioka A, Ozawa K, Sakata Y
  • Journal Title: Thromb Res Volume: 125巻 Pages: 533-7
  • Peer Reviewed
• [Journal Article] Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material (2010)
  • Author(s): Lock M, McGorray S, Auricchio A, Ayuso E, Beecham E J, Blouin V, Bosch F, Bose M, Byrne B, Caton T, Chiorini J, Chtarto A, Clark K R, Conlon T, Darmon C, Doria M, Douar A M, Flotte T R, Francis J, Francois A, Giacca M., Korn M., Korytov I, Leon X, Leuchs
  • Journal Title: Human Gene Therapy Volume: 21巻 Pages: 1723-85
  • Peer Reviewed
• [Journal Article] A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease (2010)
  • Author(s): Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, Kawakami T, Urabe M, Kume A, Sato T, Watanabe E, Ozawa K, Nakano I
  • Journal Title: Mol Ther Volume: 18巻 Pages: 1731-5
  • Peer Reviewed
• [Journal Article] Gene therapy for Parkinson's disease. Strategies for the local production of dopamine (2010)
  • Author(s): Muramatsu S, Asari S, Fujimoto K, Ozawa K and Nakamo I.
  • Journal Title: Gene Therapy & Regulation Volume: 5巻 Pages: 57-65
  • Peer Reviewed
• [Journal Article] Establishment and characterization of transplantable, luminescence labeled rat renal cell carcinoma cell lines (2010)
  • Author(s): Kobayashi M, Murakami T, Uchibori R, Chun NA, Kobayashi E, Morita T, Ozawa K.
  • Journal Title: J Urol Volume: 183巻 Pages: 2029-2035
  • Peer Reviewed
• [Journal Article] Liver-restricted expression of the canine factor VIII gene facilitates prevention of inhibitor formation in factor VIII-deficient mice (2009)
  • Author(s): Ishiwata A, Mimuro J, Mizukami H, Kashiwakura Y, Takano K, Ohmori T, Madoiwa S, Ozawa K and Sakata Y
  • Journal Title: J. Gene Med Volume: 11巻 Pages: 1020-1029
  • Peer Reviewed
• [Journal Article] Generation of adeno-associated virus vector enabling functional expression of oxytocin receptor and fluorescence marker genes using the human eIF4G internal ribosome entry site element (2009)
  • Author(s): Sato K, Date S, Aoyagi Y, Kasahara Y, Nawa A, Mizukami H, Hidema S, Ozawa K, Nishimori K
  • Journal Title: Biosci. Biotechnol. Biochem Volume: 73巻 Pages: 2145-2148
  • Peer Reviewed
• [Journal Article] A convenient enzyme-linked immunosorbent assay for rapid screeningof anti-adeno-associated virus neutralizing antibodies (2009)
  • Author(s): Ito T, Yamamoto S, Hayashi T, Kodera M, Mizukami H, Ozawa K, Muramatsu S.
  • Journal Title: Ann. Clin. Biochem Volume: 46巻 Pages: 508-510
  • Peer Reviewed
• [Journal Article] Cotransplantation with MSCs improves engraftment of HSCs after autologous intra-bone marrow transplantation in nonhuman primates (2009)
  • Author(s): Masuda S, Ageyama N, Shibata H, Obara Y, Ikeda T, Takeuchi K, Ueda Y, Ozawa K., Hanazono Y
  • Journal Title: Exp. Hematol Volume: 37巻 Pages: 1250-1257
  • Peer Reviewed
• [Journal Article] Scalable purification of adeno-associated virus serotype 1(AAV1) and AAV8 vectors, using dual ion-exchange adsorptive membranes (2009)
  • Author(s): Okada T, Nonaka-Sarukawa M, Uchibori R, Kinoshita K, Hayashita-Kinoh H, Nitahara-Kasahara Y, Takeda S, and Ozawa K
  • Journal Title: Hum. Gene Ther Volume: 20巻 Pages: 1013-1021
  • Peer Reviewed
• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy (2009)
  • Author(s): Uchibori R, Okada T, Ito T, Mizukami H, Kume A and Ozawa, K
  • Journal Title: J. Gene Med Volume: 11巻 Pages: 373-381
  • Peer Reviewed
• [Journal Article] Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat (2009)
  • Author(s): Nomoto T, Okada T, Shimazaki K, Yoshioka T, Nonaka-Sarukawa M, Ito T, Takeuchi K, Katsura K I, Mizukami H, Kume A, Ookawara S, Ikeda U, Katayama Y, and Ozawa K
  • Journal Title: Gene Ther Volume: 16巻 Pages: 383-91
  • Peer Reviewed
• [Presentation] The adeno-associated virus p5 promoter sequence mediated integration of transgene into the AAVS1 site (2011)
  • Author(s): Urabe M
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2011-12-13
• [Presentation] Synergistic effect on the tumor-killing activity of soluble TRAIL-expressing MSCs (2011)
  • Author(s): Uchibori R
  • Organizer: 第70回に本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2011-10-04
• [Presentation] The p5 promoter of adeno-associated virus for AAVS1-specific integration (2011)
  • Author(s): Urabe M
  • Organizer: The XVth International Congress of Virology
  • Place of Presentation: 札幌コンベンションセンター(札幌)
  • Year and Date: 2011-09-13
• [Presentation] The role of the p5 promoter of adeno-associated virus in AAVS1-directed integration (2011)
  • Author(s): Urabe M
  • Organizer: The 17th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 九州大学医学部百年講堂(福岡)
  • Year and Date: 2011-07-17
• [Presentation] Trichostatin A sensitize apoptosis induced by soluble TRAIL-expressing MSCs (2011)
  • Author(s): Uchibori R
  • Organizer: The 17th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 九州大学医学部百年講堂(福岡)
  • Year and Date: 2011-07-16
• [Presentation] The p5 promoter sequence of AAV genome regulates the direction of transgene insertion into the AAVS1 site (2011)
  • Author(s): Urabe M
  • Organizer: The 14th Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: The Washington State Convention Center(Seattle)
  • Year and Date: 2011-05-21
• [Presentation] Enhancement of Tumor-Killing Activity of TRAIL-Expressing MSCs by Using Trichostatin A (2011)
  • Author(s): Uchibori R
  • Organizer: The 14th Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: The Washington State Convention Center(Seattle)
  • Year and Date: 2011-05-20
• [Presentation] Analysis of cis elements required for AAVS1-specific integration of adeno-associated virus (2010)
  • Author(s): Urabe M
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2010-12-07
• [Presentation] アデノ随伴ウイルスの部位特異的組込み機構の解析 (2010)
  • Author(s): Urabe M
  • Organizer: 第58回日本ウイルス学会学術総会
  • Place of Presentation: あわぎんホ-ル(徳島)
  • Year and Date: 2010-11-09
• [Presentation] The effect of DMXAA(TNF-α inducer) on MSC accumulation at tumor sites (2010)
  • Author(s): Uchibori R
  • Organizer: 第16回日本癌学会総会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2010-09-24
• [Presentation] Mesenchymal stem cells as a cellular vehicle for cancer-targeted gene therapy (2010)
  • Author(s): Uchibori R
  • Organizer: The 16th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 栃木県総合文化センター(宇都宮)
  • Year and Date: 2010-07-02
• [Presentation] Editing cis elements required for AAV integration to enhance AAVS1-targeted integration (2010)
  • Author(s): Urabe M
  • Organizer: The 16th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 栃木県総合文化センター(宇都宮)
  • Year and Date: 2010-07-01
• [Presentation] The effect of DMXAA(56-dimethylxanthenone-4-acetic acid) on MSC accumulation in tumor sites (2010)
  • Author(s): Uchibori R
  • Organizer: The 16th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 栃木県総合文化センター(宇都宮)
  • Year and Date: 2010-07-01
• [Presentation] NF-κB activity regulates MSC accumulation at tumor sites (2010)
  • Author(s): Uchibori R
  • Organizer: The 13th Annual Meeting of the American Society of Gene Therapy
  • Place of Presentation: Marriott Wardman Park Hotel(Washington, D. C.)
  • Year and Date: 2010-05-20
• [Presentation] Mechanism of MSC(mesenchymal stem/stromal cell) accumulation at the sites of tumors (2009)
  • Author(s): Uchibori R
  • Organizer: The 14th Congress of the European Hematology Association
  • Place of Presentation: Germany
  • Year and Date: 20090600
• [Presentation] Mesenchymal stem cells(MSCs) as a platform for cancer gene therapy (2009)
  • Author(s): Uchibori R
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2009-10-23
• [Presentation] VCAM-1 expression following TNF-alpha stimulation is required, for tumor tropism of mesenchymal stem cells (2009)
  • Author(s): Uchibori R
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2009-10-03
• [Presentation] Cancer-targeted gene therapy using MSCs as a platform (2009)
  • Author(s): Uchibori R
  • Organizer: Annual Meeting of the International Society for Cell and Gene Therapy of Cancer
  • Place of Presentation: Ireland
  • Year and Date: 2009-09-03
• [Presentation] Mechanism of MSC(Mesenchymal stem/stromal cell) accumulation at tumor sites (2009)
  • Author(s): Uchibori R
  • Organizer: The 15th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 大阪大学コンベンションセンター(大阪)
  • Year and Date: 2009-07-11
• [Presentation] Roles of inflammatory cytokines in tumor tropism of mesenchimal stromal cells (2009)
  • Author(s): Uchibori R
  • Organizer: The 12th Annual Meeting of the American Society of Gene Therapy
  • Place of Presentation: San Diego Convention Center(San Diego)
  • Year and Date: 2009-05-28