Tissue specificity and utility of AAV vectors in hemophilia gene therapy

• Project/Area Number: 19591134
• 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 Jichi Medical University, 医学部, 講師 (20311938)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 遺伝子治療 / AAV ベクター / 組織特異性 / 免疫応答 / トランスジェニックマウス / 中和抗体 / AAVベクター / トランスジェニックスマウス

Research Abstract

様々な血清型に由来するAAV ベクターの組織特異性に関する検討を行った結果、骨格筋に対しては1型のベクターにCMV プロモーターを用いた場合が、肝臓には8型のベクターにhAAT プロモーターを用いるのが最も有効との結論を得た。また、in vivo のベクター投与において問題となる中和抗体検出系に関して検出方法・反応方法などの関連条件を検討することで、検出感度を著明に改善させることができた。

Research Products

• [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., Mizukami, H., Kume, A., Ookawara, S., Ikeda, U., Katayama, Y., Ozawa, K.
  • Journal Title: Gene Ther 16 Pages: 383-91
  • 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
  • Journal Title: Gene Therapy 16 Pages: 383-391
  • Peer Reviewed
• [Journal Article] Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice. (2008)
  • Author(s): Takei, Y., Saga, Y., Mizukami, H., Takayama, T., Ohwada, M., Ozawa, K., Suzuki, M.
  • Journal Title: Mol Cancer Ther 7 Pages: 704-11
  • Peer Reviewed
• [Journal Article] Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats. (2008)
  • Author(s): Nonaka-Sarukawa, M., Okada, T., Ito, T., Yamamoto, K., Yoshioka, T., Nomoto, T., Hojo, Y., Shimpo, M., Urabe, M., Mizukami, H., Kume, A., Ikeda, U., Shimada, K., Ozawa, K.
  • Journal Title: J Gene Med 10 Pages: 368-74
  • Peer Reviewed
• [Journal Article] Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice. (2008)
  • Author(s): Suzumura, K., Hirano, T., Son, G., Iimuro, Y., Mizukami, H., Ozawa, K., Fujimoto, J.
  • Journal Title: Hepatol Int 2 Pages: 80-88
  • Peer Reviewed
• [Journal Article] Protection Against Aminoglycoside-induced Ototoxicity by Regulated AAV Vector-mediated GDNF Gene Transfer Into the Cochlea. (2008)
  • Author(s): Liu, Y., Okada, T., Shimazaki, K., Sheykholeslami, K., Nomoto, T., Muramatsu, SI., Mizukami, H., Kume, A., Xiao, S., Ichimura, K., Ozawa, K.
  • Journal Title: Mol Ther 16 Pages: 474-80
  • Peer Reviewed
• [Journal Article] Overexpression of PTEN in ovarian cancer cells suppresses i. p. dissemination and extends survival in mice. (2008)
  • Author(s): Takei Y
  • Journal Title: Molecular Cancer Therapy 7 Pages: 704-11
  • Peer Reviewed
• [Journal Article] Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice. (2008)
  • Author(s): Suzumura K
  • Journal Title: Hepatology International 2 Pages: 80-88
  • Peer Reviewed
• [Journal Article] Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice (2008)
  • Author(s): Takei Y, et. al.
  • Journal Title: Mol Cancer Ther 7 Pages: 704-11
  • Peer Reviewed
• [Journal Article] Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. (2007)
  • Author(s): Ito, T., Okada, T., Miyashita, H., Nomoto, T., Nonaka-Sarukawa, M., Uchibori, R., Maeda, Y., Urabe, M., Mizukami, H., Kume, A., Takahashi, M., Ikeda, U., Shimada, K., Ozawa, K.
  • Journal Title: Circ Res 101 Pages: 734-41
  • Peer Reviewed
• [Journal Article] Adenoassociated virus-mediated prostacyclin synthase expression prevents pulmonary arterial hypertension in rats. (2007)
  • Author(s): Ito, T., Okada, T., Mimuro, J., Miyashita, H., Uchibori, R., Urabe, M., Mizukami, H., Kume, A., Takahashi, M., Ikeda, U., Sakata, Y., Shimada, K., Ozawa, K.
  • Journal Title: Hypertension 50 Pages: 531-6
  • Peer Reviewed
• [Journal Article] Prevention of diabetic retinopathy by intraocular soluble flt-1 gene transfer in a spontaneously diabetic rat model. (2007)
  • Author(s): Ideno, J., Mizukami, H., Kakehashi, A., Saito, Y., Okada, T., Urabe, M., Kume, A., Kuroki, M., Kawakami, M., Ishibashi, S., and Ozawa, K.
  • Journal Title: Int J Mol Med 19 Pages: 75-9
  • Peer Reviewed
• [Journal Article] Suppression of ovarian cancer by muscle-mediated expression of soluble VEGFR-1/Flt-1 using adeno-associated virus serotype 1-derived vector. (2007)
  • Author(s): Takei, Y., Mizukami, H., Saga, Y., Yoshimura, I., Hasumi, Y., Takayama, T., Kohno, T., Matsushita, T., Okada, T., Kume, A., Suzuki, M., Ozawa, K.
  • Journal Title: Int J Cancer 120 Pages: 27-84
  • Peer Reviewed
• [Journal Article] Tendon healing in vitro: Adeno-associated virus-2 effectively transduces intrasynovial tenocytes with persistent expression of the transgene, but other serotypes do not. (2007)
  • Author(s): Wang, X.T., Liu, P.Y., Tang, J.B., Mizukami, H., Xin, KQ., Ozawa, K., Ushijima, H.
  • Journal Title: Plast Reconstr Surg 119 Pages: 227-34
  • Peer Reviewed
• [Journal Article] Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. (2007)
  • Author(s): Ito T, et. al.
  • Journal Title: Circulation Research 101 Pages: 734-41
  • Peer Reviewed
• [Journal Article] Adenoassociated virus-mediated prostacyclin synthase expression prevents pulmonary arterial hypertension in rats 50:,2007. (2007)
  • Author(s): Ito T, et. al.
  • Journal Title: Hypertension 50 Pages: 531-6
  • Peer Reviewed
• [Presentation] 遺伝子治療の現状と課題 (2008)
  • Author(s): 水上浩明、小澤敬也
  • Organizer: 第28 回 医療情報学連合大会
  • Place of Presentation: オーガナイズドセッション「ゲノムインフォマティクス」横浜
  • Year and Date: 2008-11-23
• [Presentation] Therapeutic efficacy of AAV vectors encoding sflt-4 against endometrial cancer model with lymph node metastasis. (2008)
  • Author(s): Takahashi K, Mizukami H, Saga Y, Takei Y, Urabe M, Kume A, Suzuki M, Ozawa K
  • Organizer: The 67^<th> annual meeting of the Japanese Cancer Association(EW11-2, Abstract p495)
  • Place of Presentation: Nagoya
  • Year and Date: 2008-10-28
• [Presentation] Role of inflammatory cytokines in tumor tropism of mesenchimal stromal cells. (2008)
  • Author(s): Uchibori R, Ito T, Mizuguchi H, Urabe M, Mizukami H, Kume A, Ozawa K
  • Organizer: The 67^<th> annual meeting of the Japanese Cancer Association(O-369, Abstract p300)
  • Place of Presentation: Nagoya
  • Year and Date: 2008-10-27
• [Presentation] Inhibitory actions of very low titer neutralizing antibody against AAV8 capsid upon transgene expression in monkey. (2008)
  • Author(s): Mizukami H, Urabe M, Kume A, Ozawa K
  • Organizer: The 67^<th> annual meeting of the Japanese Cancer Association(O-162, Abstract p91)
  • Place of Presentation: Nagoya
  • Year and Date: 2008-10-26
• [Presentation] AAV に対する中和抗体の遺伝子導入に及ぼす影響・カニクイザルにおける検討 (2008)
  • Author(s): 水上浩明、八木洋也、卜部匡司、久米晃啓、小澤敬也
  • Organizer: 第56 回日本ウイルス学会学術集会(抄録集p229)
  • Place of Presentation: 岡山
  • Year and Date: 2008-10-26
• [Presentation] AAVベクターを用いた遺伝子導入法と免疫反応-血友病Bに関する検討を中心に (2008)
  • Author(s): 水上浩明
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-10
• [Presentation] Inhibitory actions of very low titer neutralizing antibody against AAV8 capsid upon liver-mediated factor IX expression in non-human primates (2008)
  • Author(s): Mizukami H, Mimuro J, Ishiwata A, Ono F, Yagi H, Urabe M, Ito T, Kume A, Terao K, Yasutomi Y, Sakata Y, Ozawa K.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #65)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-14
• [Presentation] Full reconstitution of in vivo oxidative activity for phenylalanine in self-complementary AAV vector-treated phenylketonuria mice. (2008)
  • Author(s): Kume A, Yagi H, Mizukami H, Urabe M, Ito T, Ozawa, K.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #70)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-14
• [Presentation] Establishment of a lymph node metastasis model with endometrial cancer and therapeutic efficacy of AAV vectors encoding sflt-4. (2008)
  • Author(s): Takahashi, T., Mizukami, H., Saga, Y., Takei, Y., Urabe, M., Kume, A., Suzuki, M., Ozawa, K.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #74)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-14
• [Presentation] Immune responses in gene herapy using adeno-associated vectors (2008)
  • Author(s): Mizukami, H.
  • Organizer: Educational seminar IV "AAV vectors" The 14^<th> Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-13
• [Presentation] Unexpected silencing of transgene integrated at AAVS1 locus using AAV machinary. (2008)
  • Author(s): Obara Y, Urabe M, Ito T, Mizukami H, Kume A, Ozawa K.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #11)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-13
• [Presentation] AAV vector-mediated systemic interleukin-10 expression ameliorates the metabolic syndrome in Zucker fatty rats. (2008)
  • Author(s): Ito T, Nakata M, Uchibori R, Urabe M, Mizukami H, Kume A, Yada T, Shimada K, Ozawa K.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #32)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-13
• [Presentation] “Immune responses in gene therapy using adeno-associated vectors"Educational seminar IV, “AAV vectors". (2008)
  • Author(s): Mizukami H
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 札幌
  • Year and Date: 2008-06-13
• [Presentation] Aromatic L-amino acid decarboxylase gene transfer for parkinson's disease: preliminary results of an open-label safety study. (2008)
  • Author(s): Muramatsu S, Fujimoto K, Kato S, Mizukami H, Ikeguchi K, Kawakami T, Urabe M, Kume A, Sato T, Watanabe E, Ozawa K, Nakano I.
  • Organizer: The 14^<th> Annual Meeting of Japan Society of Gene Therapy(Abstract #4)
  • Place of Presentation: Sapporo
  • Year and Date: 2008-06-12
• [Presentation] Liver-mediated factor IX expression and neutralizing antibody in non-human primates. (2008)
  • Author(s): Mizukami H
  • Organizer: The 11^<th> Annual Meeting of American Society of Gene Therapy
  • Place of Presentation: Boston, USA
  • Year and Date: 2008-05-29
• [Presentation] 「AAV ベクターを用いた遺伝子治療の現状と展望」自治医科大学21 世紀COE プログラム (2008)
  • Author(s): 水上浩明、小澤敬也
  • Organizer: 第5回合同シンポジウム
  • Place of Presentation: 自治医科大学
  • Year and Date: 2008-02-02
• [Presentation] 間葉系幹細胞と造血幹細胞の相互作用の分子メカニズム (2008)
  • Author(s): 菊池裕二、久米晃啓、卜部匡司、水上浩明、鈴木隆浩、尾崎勝俊、小澤敬也
  • Organizer: 第6回幹細胞シンポジウム
  • Place of Presentation: 東京
• [Presentation] カニクイザルを用いたAAV ベクターの有効性評価 (2007)
  • Author(s): 水上浩明
  • Organizer: 第3回霊長類医科学フォーラム
  • Place of Presentation: つくば
  • Year and Date: 2007-12-06
• [Presentation] Low seropositivity against AAV serotypes 1,8 and 9 in specific pathogen-free cynomolgus monkey colony (2007)
  • Author(s): Mizukami H, et. al.
  • Organizer: European Society for Gene and Cell Therapy
  • Place of Presentation: Rotterdam,Netherland
  • Year and Date: 2007-10-29
• [Presentation] "AAV-mediated gene transfer: current status and future perspectives" The department of Microbiology (2007)
  • Author(s): Mizukami, H.
  • Organizer: Molecular Genetics and Immunology Seminar Series
  • Place of Presentation: The University of Kansas Medical Center, Kansas City (USA)
  • Year and Date: 2007-05-29
• [Presentation] 肝臓特異的にFVIII を高発現するAAV8 ベクターを用いた血友病A マウスへのFVIII 遺伝子導入 (2007)
  • Author(s): 石渡彰、三室淳、柏倉裕志、大森司、諏合輝子、窓岩清治、水上浩明、久米晃啓、小澤敬也、坂田洋一
  • Organizer: 第30 回日本血栓止血学会総会(抄録集p462)
  • Place of Presentation: 志摩
• [Presentation] 血友病B 遺伝子治療の非ヒト霊長類モデルにおける基礎的検討 (2007)
  • Author(s): 石渡彰、三室淳、水上浩明、小野文子、柏倉裕志、大森司、諏合輝子、窓岩清治、寺尾恵治、小澤敬也、坂田洋一
  • Organizer: 第69 回日本血液学会総会・第49 回日本臨床血液学会合同総会(抄録集p190)
  • Place of Presentation: 横浜
• [Presentation] Sustained expression of prostacyclin synthase by an intramuscular injection of an AAV vector attenuates obesity in Zucker fatty rats. (2007)
  • Author(s): Ito, T., Okada, T., Mimuro, J., Nakata, M., Uchibori, R., Urabe, M., Mizukami, H., Kume, A., Sakata, Y., Yada, T., Shimada, K., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(Abstract #092)
  • Place of Presentation: Nagoya
• [Presentation] Efficient and stable liver transduction by a self-complementary adeno-associated virus vector for phenylketonuria gene therapy. (2007)
  • Author(s): Kume, A., Matsushita, T., Mizukami, H., Urabe, M., Okada T., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(J Gene Med 10:443-444, 2008)
  • Place of Presentation: Nagoya
• [Presentation] Prevalence of neutralizing antibody against AAV serotypes 1, 8 and 9 in cynomolgus monkey colonies. (2007)
  • Author(s): Mizukami, H., Ishiwata, A., Ono, F., Takano, J., Fujimoto, K., Mimuro, J., Urabe, M., Kume, A., Terao, K., Sakata, Y., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(J Gene Med 10:453, 2008)
  • Place of Presentation: Nagoya
• [Presentation] Safety of intracranial AAV vector injection in cynomolgus monkeys. (2007)
  • Author(s): Mizukami, H., Muramatsu, S., Ono, F., Mimuro, J., Sakata, Y., Urabe, M., Kume, A., Tera,o K., Nakano, I., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(J Gene Med 10:454, 2008)
  • Place of Presentation: Nagoya
• [Presentation] Overexpression of PTEN in ovarian cancer cells suppresses peritoneal dissemination and extends survival in mice. (2007)
  • Author(s): Takei, Y., Saga, Y., Mizukami, H., Ozawa, K., Suzuki, M.
  • Organizer: The 66th Annual Meeting of the Japanese Cancer Association2007.(Proceedings of the 66th Annual Meeting of the Japanese Cancer Association, p245)
  • Place of Presentation: Yokohama
• [Presentation] Tumor tracking and therapeutic gene amplification by using retroviral vector-producing Mesenchymal stem cells for reinforcement of suicide cancer gene therapy. (2007)
  • Author(s): Uchibori, R., Okada, T., Ito, T., Matsushita, T., Urabe, M., Mizukami, H., Kume, A., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(J Gene Med 10:478-479, 2008)
  • Place of Presentation: Nagoya
• [Presentation] Production of more potent type 1 adeno-associated virus vectors in insect cells. (2007)
  • Author(s): Urabe, M., Mizukami, H., Bakker, A., Kume, A., Hermens, W., Ozawa, K.
  • Organizer: The 13th Annual Meeting of Japan Society of Gene Therapy(Abstract #010)
  • Place of Presentation: Nagoya
• [Book] 『糖尿病学-基礎と臨床』 (2007)
  • Author(s): 水上 浩明(分担執筆)
  • Total Pages: 1200
  • Publisher: 西村書店