Improvement of neutralizing antibody assay against AAV vectors and application to hemophilia gene therapy

• Project/Area Number: 21591248
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: MIZUKAMI Hiroaki 自治医科大学, 医学部, 准教授 (20311938)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遺伝子 / ウイルス / バイオテクノロジー / 免疫学 / 遺伝子治療

Research Abstract

Significant improvement in neutralizing antibody assay against AAV vectors was achieved. In the cases of AAV8 and 9, the cells were successfully transduced at 1000 genome copies per cell, which is ten times lower than that reported earlier. Moreover, all of the 9 monkeys screened by this method showed transgene expression after IV injection of AAV8 vectors, suggesting the utility of this assay.

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, Ozawa K
  • Journal Title: Gene Ther Volume: 19 Pages: 476-82
  • Peer Reviewed
• [Journal Article] Recovery of neurogenic amines in phenylketonuria mice following 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: 23 Pages: 30-4
  • Peer Reviewed
• [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 Issue: 5 Pages: 476-82
  • DOI: 10.1038/gt.2011.183
  • 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., Ozawa, K.
  • Journal Title: Cancer Sci Volume: 102 Pages: 2272-7
  • NAID: 10030246395
  • 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., Kume, A.
  • Journal Title: J Gene Med Volume: 13 Pages: 114-22
  • 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, et al.
  • Journal Title: J Gene Med Volume: 13 Pages: 114-22
  • 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 Pages: 1731-5
  • 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., Gi
  • Journal Title: Human Gene Therapy Volume: 21 Pages: 1723-85
  • 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 Pages: 533-7
  • 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, et al.
  • Journal Title: Mol Ther Volume: 18 Pages: 1731-5
  • Peer Reviewed
• [Journal Article] Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material. (2010)
  • Author(s): Lock M, et al.
  • Journal Title: Human Gene Therapy Volume: 21 Pages: 1273-85
  • Peer Reviewed
• [Journal Article] Mutant Macaque Factor IX T262A : A Tool for Hemophilia B Gene Therapy Studies in Macaques. (2010)
  • Author(s): Ishiwata A, et al.
  • Journal Title: Thromb Res. Volume: 125 Pages: 533-7
  • 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., Sakata, Y.
  • Journal Title: J Gene Med Volume: 11 Pages: 1020-9
  • 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., Urabe, M., Mizukami, H., Kume, A., Ozawa, K.
  • Journal Title: J Gene Med Volume: 11 Pages: 373-81
  • Peer Reviewed
• [Journal Article] Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival (2009)
  • Author(s): Takahashi, K., Saga, Y., Mizukami, H., Takei, Y., Machida, S., Fujiwara, H., Ozawa, K., Suzuki, M.
  • Journal Title: Int J Oncol Volume: 35 Pages: 725-9
  • 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, et al.
  • Journal Title: J Gene Med 11 Pages: 1020-9
  • Peer Reviewed
• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy (2009)
  • Author(s): Uchibori R, et al.
  • Journal Title: J Gene Med 11 Pages: 373-81
  • Peer Reviewed
• [Journal Article] Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival (2009)
  • Author(s): Takahashi K, et al.
  • Journal Title: Int J Oncol 35 Pages: 725-9
  • Peer Reviewed
• [Presentation] Optimization of efficacy in AAV-mediated siRNA expression (2011)
  • Author(s): Mizukami H, et al
  • Organizer: 19^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Brighton, UK
  • Year and Date: 2011-10-29
• [Presentation] Consistent Factor IX Expression in NAb-negative Macaques following IV Administration of AAV8 Vector (2011)
  • Author(s): Mizukami H, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Presentation] Relationship between neutralizing antibody and factor IX expression in non-human primates following IV administration of AAV8 vectors (2011)
  • Author(s): Mizukami H, et al
  • Organizer: American Society of Gene and Cell Therapy's 14th Annual Meeting
  • Place of Presentation: Seattle, USA
  • Year and Date: 2011-05-21
• [Presentation] Relationship between neutralizing antibody and factor IX expression in non-human primates following IV administration of AAV8 vectors (2011)
  • Author(s): Mizukami H, et al
  • Organizer: American Society of Gene Therapy 14th Annual Meeting
  • Place of Presentation: Seattle, USA
  • Year and Date: 2011-05-21
• [Presentation] Optimization of efficacy in AAV-mediated siRNA expression (2010)
  • Author(s): Mizukami H, et al, Tomonori Tsukahara, Akihiro Kume, Keiya Ozawa, Hiroaki Mizukami, Masashi Urabe
  • Organizer: 19^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Brighton, UK
  • Year and Date: 2010-10-23
• [Presentation] Unswerving Factor IX Expression in NAb-negative Macaques following IV Administration of AAV8 Vector (2010)
  • Author(s): Mizukami H, et al
  • Organizer: 18^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Milan, Italy
  • Year and Date: 2010-10-23
• [Presentation] Improved assay system for NAb against AAV vectors and prevalence in non-human primates (2010)
  • Author(s): Mizukami H, et al
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Immune responses in AAVmediated gene transfer (2010)
  • Author(s): Mizukami H.
  • Organizer: 第16回日本遺伝子治療学会
  • Place of Presentation: 宇都宮
  • Year and Date: 2010-07-03
• [Presentation] IMMUNE RESPONSES IN AAV-MEDIATED GENE TRANSFER (2010)
  • Author(s): Mizukami H, et al.
  • Organizer: Japan Society of Gene Therapy 16^<th> Annual Meeting
  • Place of Presentation: 宇都宮
  • Year and Date: 2010-07-03
• [Presentation] Robust and Sustained Factor IX Expression by IV Administration of AAV8-based Vectors in Macaques (2010)
  • Author(s): Mizukami H, et al
  • Organizer: American Society of Gene and Cell Therapy's 13th Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2010-05-27
• [Presentation] Robust and Sustained Factor IX Expression by IV Administration of AAV8-based Vectors in Macaques (2010)
  • Author(s): Mizukami H, et al.
  • Organizer: American Society of Gene Therapy 13th Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2010-05-21
• [Presentation] Relationship between neutralizing antibody and liver-mediated factor IX expression in non-human primates using AAV vectors (2009)
  • Author(s): Mizukami H, et al
  • Organizer: 17^<th> Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Hannover, Germany
  • Year and Date: 2009-11-22
• [Presentation] Robust and sustained factor IX expression following IV injection of AAV8-based vectors in macaques (2009)
  • Author(s): Mizukami H, et al
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2009-10-23
• [Presentation] Neutralizing antibody affects liver-mediated factor IX expression in non-human primates by AAV vectors (2009)
  • Author(s): Mizukami H, et al
  • Organizer: American Society of Gene and Cell Therapy's 13th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2009-05-30
• [Presentation] Neutralizing antibody affects liver-mediated factor IX expression in non-human primates by AAV vectors (2009)
  • Author(s): Mizukami H, et al.
  • Organizer: American Society of Gene Therapy 12th Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2009-05-30
• [Book] 血友病の遺伝子治療血液フロンティア (2012)
  • Author(s): 水上浩明
  • Publisher: 医薬ジャーナル社
• [Book] Gene Therapy for Diabetic Retinopathy in Animal Models and Humans. In, The Open Diabetes Journal? Novel rat model of diabetes, SDT rat and SDT fatty rat.(ed. By Kahehashi, A.) (2011)
  • Author(s): Mizukami, H., Urabe, M., Kume, A. Ozawa, K.
• [Book] 網膜疾患に対する遺伝子治療の現状と展望 (2011)
  • Author(s): 水上浩明
  • Publisher: 医歯薬出版
• [Book] 筋疾患に対する遺伝子治療生体の科学 (2011)
  • Author(s): 水上浩明
  • Publisher: 医学書院
• [Book] 遺伝子導入とベクターBIO Clinica (2011)
  • Author(s): 水上浩明
  • Publisher: 北隆館
• [Book] Gene Therapy for Diabetic Retinopathy in Animal Models and Humans. In, The Open Diabetes Journal-Novel rat model of diabetes, SDT rat and SDT fatty rat.(ed.By Kahehashi, A.) (2011)
  • Author(s): Mizukami H, et al
  • Total Pages: 122
  • Publisher: Bentham
• [Remarks]
  • URL: http://www.jichi.ac.jp/idenshi/index.html
• [Remarks]
  • URL: http://www.jichi.ac.jp/idenshi/index.html