Development of molecular mechanism and therapy of Diamond-Blackfan anemia

• Project/Area Number: 23591554
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School
• Principal Investigator: KOICHI Miyake 日本医科大学, 医学部, 准教授 (90267211)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: リボゾーム蛋白 / 貧血 / 先天異常 / 先天性貧血 / siRNA / Diamond-Blackfan anemia / 遺伝子治療

Research Abstract

Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 gene. Recently, it was reported that other ribosomal proteins (RPL5, RPL11, RPS24, RPS17) were also mutated in DBA patients. We constructed lentiviral vector expressing siRNA against RPL5, RPL11, RPS24, and RPS17 to analyze the molecular mechanism of DBA. We established cell line model of DBA after transduction with these lentiviral vector. To develop DBA model mouse, first, we generated KRAB (Kruppel-associated box) gene transgenic mouse. Using this mouse, we have a plan to make a tetracycline inducible DBA model mouse.

Research Products

• [Journal Article] siRNA Knockdown of Tissue Inhibitor of Metalloproteinase-1 in Keloid Fibroblasts Leads to Degradation of Collagen Type I (2014)
  • Author(s): Aoki M, Miyake K, Ogawa R, Dohi T, Akaishi S, Hyakusoku H, Shimada T
  • Journal Title: J Invest Dermatol Volume: 134 Pages: 818-826
  • Peer Reviewed
• [Journal Article] miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability (2014)
  • Author(s): Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H
  • Journal Title: Brain Volume: 136 Pages: 2738-2750
  • Peer Reviewed
• [Journal Article] Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells (2014)
  • Author(s): Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H
  • Journal Title: Cerebellum Volume: 13 Pages: 29-41
  • Peer Reviewed
• [Journal Article] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells (2014)
  • Author(s): komiyama H, Miyake K, Asai K, Mizuno K, Shimada T
  • Journal Title: Cell Biochemistry & Function Volume: 32 Pages: 70-76
  • Peer Reviewed
• [Journal Article] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells (2014)
  • Author(s): Komiyama H, Miyake K, Asai K, Mizuno K, Shimada T.
  • Journal Title: Cell Biochem Funct. Volume: 32 Issue: 1 Pages: 70-76
  • DOI: 10.1002/cbf.2973
  • Peer Reviewed
• [Journal Article] Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar purkinje cells (2014)
  • Author(s): Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H.
  • Journal Title: Cerebellum Volume: 13 Issue: 1 Pages: 29-41
  • DOI: 10.1007/s12311-013-0516-5
  • Peer Reviewed
• [Journal Article] siRNA Knockdown of Tissue Inhibitor of Metalloproteinase-1 in Keloid Fibroblasts Leads to Degradation of Collagen Type I (2014)
  • Author(s): Aoki M, Miyake K, Ogawa R, Dohi T, Akaishi S, Hyakusoku H, Shimada T.
  • Journal Title: J Invest Dermatol. Volume: 134 Issue: 3 Pages: 818-826
  • DOI: 10.1038/jid.2013.396
  • Peer Reviewed
• [Journal Article] Direct Comparison of Administration Routes for AAV8-mediated Ocular Gene Therapy (2013)
  • Author(s): Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H.
  • Journal Title: Curr Eye Res Volume: 38 Pages: 569-577
  • Peer Reviewed
• [Journal Article] Team-based Learning Using an Audience Response System : A Possible New Strategy for Interactive Medical Education (2013)
  • Author(s): Fujikura T, Takeshita T, Homma H, Adachi K, Miyake K, Kudo M, Takizawa T, Nagayama H, Hirakawa K
  • Journal Title: J Nippon Med Sch Volume: 80 Pages: 63-69
  • NAID: 130004147207
  • Peer Reviewed
• [Journal Article] Direct comparison of administration routes for AAV8-mediated ocular gene therapy (2013)
  • Author(s): Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H.
  • Journal Title: Curr Eye Res. Volume: 38 Issue: 5 Pages: 569-577
  • DOI: 10.3109/02713683.2013.779720
  • Peer Reviewed
• [Journal Article] Role of survivin in acute lung injury: epithelial cells of mice and humans. (2013)
  • Author(s): Terasaki Y, Terasaki M, Urushiyama H, Nagasaka S,Kungi S, et al.
  • Journal Title: Lab Invest Volume: 93 Issue: 10 Pages: 1147-1163
  • DOI: 10.1038/labinvest.2013.103
  • Peer Reviewed
• [Journal Article] miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability (2013)
  • Author(s): Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H.
  • Journal Title: Brain Volume: 136 Issue: 9 Pages: 2738-2750
  • DOI: 10.1093/brain/awt191
  • Peer Reviewed
• [Journal Article] Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification (2012)
  • Author(s): Miyake K, Miyake N, Yamazaki Y, Shimada T, Hirai Y.
  • Journal Title: J Nippon Med Sch Volume: 79 Pages: 394-402
  • NAID: 130004057397
  • Peer Reviewed
• [Journal Article] Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of gata4, mef2c, and tbx5 (2012)
  • Author(s): Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M.
  • Journal Title: Circ Res Volume: 111 Pages: 1147-1156
  • Peer Reviewed
• [Journal Article] Successful gene therapy in utero for lethal murine hypophosphatasia (2012)
  • Author(s): Sugano H, Matsumoto T, Miyake K, Watanabe A, Iijima O, Migita M, Narisawa S, Millán JL, Fukunaga Y, Shimada T.
  • Journal Title: Hum Gene Ther Volume: 23 Pages: 399-406
  • Peer Reviewed
• [Journal Article] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice (2012)
  • Author(s): Tamai H, Miyake K, Yamaguchi H Takatori M, Dan K, Inokuchi K, Shimada T.
  • Journal Title: Blood Volume: 119 Pages: 64-71
  • Peer Reviewed
• [Journal Article] Serotype-independent Method of Recombinant Adeno-associated. Virus (AAV) Vector Production and Purification (2012)
  • Author(s): Miyake K, Miyake N, Yamazaki Y, Shimada T, Hirai Y
  • Journal Title: J Nippon Med Sch Volume: 79 Pages: 394-402
  • NAID: 130004057397
  • Peer Reviewed
• [Journal Article] Induction of Cardiomyocyte-like Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5 (2012)
  • Author(s): Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M
  • Journal Title: Circulation research Volume: 111 Issue: 9 Pages: 1147-56
  • DOI: 10.1161/circresaha.112.271148
  • Peer Reviewed
• [Journal Article] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice. (2012)
  • Author(s): Tamai, H.
  • Journal Title: Blood Volume: 119 Issue: 1 Pages: 64-71
  • DOI: 10.1182/blood-2011-05-354050
  • Peer Reviewed
• [Journal Article] Resistance of MLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 up-regulation (2011)
  • Author(s): Tamai H, Miyake K, Yamaguchi H Takatori M, Dan K, Inokuchi K, Shimada T.
  • Journal Title: Blood Cancer Journal Volume: 1
  • Peer Reviewed
• [Journal Article] Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia (2011)
  • Author(s): Wakita S, Yamaguchi H, Miyake K, Mitamura Y, Kosaka F, Dan K, Inokuchi K.
  • Journal Title: Leukemia Volume: 25 Pages: 1423-32
  • Peer Reviewed
• [Journal Article] Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease (2011)
  • Author(s): Yasuda T, Hayakawa H, Nihira T, Ren YR, Nakata Y, Nagai M, Hattori N, Miyake K, Takada M, Shimada T, Mizuno Y, Mochizuki H.
  • Journal Title: J Neuropathol Exp Neurol Volume: 70 Pages: 686-97
  • Peer Reviewed
• [Journal Article] Activated K-Ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model (2011)
  • Author(s): Tamai H, Miyake K, Takatori M, Miyake N Yamaguchi H, Dan K, Shimada T, Inokuchi K.
  • Journal Title: Leukemia Volume: 25 Pages: 888-91
  • Peer Reviewed
• [Journal Article] Direct comparison of four adeno-associated virus serotypes in mediating the production of antiangiogenic proteins in mouse muscle (2011)
  • Author(s): Isotani M, Miyake K, Miyake N, Hirai Y, Shimada T.
  • Journal Title: Cancer Invest Volume: 29(5) Pages: 353-359
  • Peer Reviewed
• [Journal Article] Direct Comparison of Four Adeno-Associated Virus Serotypes in Mediating the Production of Antiangiogenic Proteins in Mouse Muscle (2011)
  • Author(s): Mayu Isotani, Koichi Miyake, Noriko Miyake, Yukihiko Hirai, Takashi Shimada
  • Journal Title: Cancer Investigation Volume: 29 Issue: 5 Pages: 353-359
  • DOI: 10.3109/07357907.2011.584585
  • Peer Reviewed
• [Presentation] Successful Treatment of Adult MLD Model Mice By Intravenous Injection of Self-Complementary Type 9 AAV Vector Expressing ASA (2014)
  • Author(s): Miyake N, Miyake K, Yamamoto M and Shimada T.
  • Organizer: 17th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Washington DC
• [Presentation] Minimally invasive gene therapy of MLD model mice by intrathecal and intravenous injection of AAV9 vector (2014)
  • Author(s): Miyake N, Miyake K, and Shimada T.
  • Organizer: 10th WORLDSymposium™
  • Place of Presentation: San Diego,CA
• [Presentation] Minimally invasive gene therapy of MLD model mice by intrathecal and intravenous injection of AAV9 vector (2014)
  • Author(s): Miyake N, Miyake K, Shimada T.
  • Organizer: 10th WORLDSymposium™ 2014
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Adeno−Associated Vector (Type 8)−Mediated Expression of siRNA Targeting Vascular Endothelial Growth Factor Efficiently Inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • Author(s): Igarashi T, Miyake K, Miyake N, Iijima O, Yaguchi C, Shimada T and Takahashi H.
  • Organizer: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Salt Lake City, Utah
• [Presentation] Long−Term Secretion of Arylsulfatase A without Antibody Formation after AAV Mediated Neonatal Gene Transfer into MLD Model Mice (2013)
  • Author(s): Miyake N, Miyake K, Yamamoto M and Shimada T.
  • Organizer: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Salt Lake City, Utah
• [Presentation] Adeno－Associated Vector (Type 8)－Mediated Expression of siRNA Targeting Vascular Endothelial Growth Factor Efficiently Inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • Author(s): Igarashi T, Miyake K, Miyake N, Iijima O, Yaguchi C, Shimada T, Takahashi H.
  • Organizer: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Salt Lake City, Utah, USA
• [Presentation] Long－Term Secretion of Arylsulfatase A without Antibody Formation after AAV Mediated Neonatal Gene Transfer into MLD Model Mice (2013)
  • Author(s): Miyake N, Miyake K, Yamamoto M, Shimada T.
  • Organizer: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Salt Lake City, Utah, USA
• [Presentation] Targeted Gene Transfer into the Ependymal Cells and Long-Term Enzyme Replacement in the CSF by Intraventricular Injection of AAV Vector Serotype 1 (2013)
  • Author(s): Yamazaki Y, Hironaka K, Hirai Y, Miyake K, Shimada T.
  • Organizer: 16th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Salt Lake City, Utah, USA
• [Presentation] siRNA Targeting Vascular Endothelial Growth Factor by adeno-associated vector (type 8) efficiently inhibits Neovascularization in a Murine Choroidal Neovascularization Model (2013)
  • Author(s): Igarashi T, Miyake N, Iijima O, Yaguchi C, Shimada T, Takahashi H, Miyake K.
  • Organizer: The 19th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama,Japan
• [Presentation] Tolerance induction to arylsulfatase A by AAV mediated neonatal gene transfer into MLD model mice (2013)
  • Author(s): Miyake N, Miyake K, Yamamoto M, Shimada T.
  • Organizer: The 19th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Okayama, Japan
• [Presentation] AAV9 mediated gene therapy of MLD model mice (2012)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • Organizer: 20th Annual Meeting of the European Society of Gene & Cell Therapy
  • Place of Presentation: Versailles, France
• [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • Organizer: 15th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Philadelphia, Pennsylvania
• [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • Organizer: 15th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Philadelphia, USA
• [Presentation] Successful gene therapy in utero for lethal murine hypophosphatasia (2012)
  • Author(s): Sugano H, Miyake K, Watanabe A, Iijima O, Narisawa S, Millán JL, Fukunaga Y, Shimada T
  • Organizer: 6th Alkaline Phosphatasie and Hypophosphatasia International Symposium
  • Place of Presentation: Huningue, France
• [Presentation] Ex vivo gene therapy of severe infantile hypophosphatasia model mice using lentiviral transduced bone marrow cells (2012)
  • Author(s): Iijima O, Sugano H, Watanabe A, Miyake K, Shimada T
  • Organizer: 6th Alkaline Phosphatasie and Hypophosphatasia International Symposium
  • Place of Presentation: Huningue, France
• [Presentation] Ex vivo gene therapy of severe infantile hypophosphatasia model mice using lentiviral transduced bone marrow cells (2012)
  • Author(s): Iijima O, Sugano H, Watanabe A, Miyake K, Shimada T
  • Organizer: The 18th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 熊本
• [Presentation] Successful treatment of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • Organizer: The 18th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 熊本
• [Presentation] DRG神経におけるmiR-7a過剰発現は神経障害性疼痛を特異的に抑制する (2012)
  • Author(s): 坂井敦、齋藤文仁、三宅紀子、三宅弘一、島田隆、鈴木秀典
  • Organizer: 第35回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] 骨髄細胞移植による低フォスファターゼ症のex vivo遺伝子治療 (2012)
  • Author(s): 飯島修、菅野華子、鹿子田千津、渡邉淳、三宅弘一、島田隆
  • Organizer: 第57回日本人類遺伝学会学術集会
  • Place of Presentation: 東京
• [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector (2012)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, Shimada T
  • Organizer: 第4回国際ライソゾーム病フォーラム・第17回日本ライソゾーム病研究会
  • Place of Presentation: 東京
• [Presentation] Rescue of lethal hypophosphatasia mice by neonatal ex vivo gene therapy using lentivirally transduced bone marrow cells (2012)
  • Author(s): Iijima O, Miyake K, Sugano H, Tsutomu I, Chizu K, Watanabe A, Shimada T
  • Organizer: 54th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta, USA
• [Presentation] Intrathecal Administration of Type 9 AAV Vector Expressing Arylsulfatase A Is Effective for Reduction of Sulfatide Storage but Not for Correction of Neurological Deficits in Adult Metachromatic Leukodystrophy Model Mice with Overt Neurological Symptoms (2011)
  • Author(s): Miyake N, Miyake K, Sakai A, Yamamoto M, Endo A, Suzuki H, and Shimada T.
  • Organizer: 14th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Seattle, WA
• [Presentation] Development of cell targeting strategy using HIV vector pseudtyped with HIV envelope (2011)
  • Author(s): Koichi Miyake, Takashi Shimada
  • Organizer: The 17th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 福岡
• [Book] Development of Muscle-Directed Systemic Cancer Gene Therapy. Novel Gene Therapy Approaches (2013)
  • Author(s): Miyake K, Shimada T
  • Publisher: Edited by Ming Wei and David Good, Published by InTech
• [Book] Novel Gene Therapy Approaches (2013)
  • Author(s): Miyake K, Shimada T
  • Total Pages: 450
  • Publisher: InTech
• [Book] Development and Application of HIV Vectors Pseudotyped with HIV Envelopes. Viral Gene Therapy (2011)
  • Author(s): Miyake K, Shimada T
  • Publisher: Edited by Ke Xu, Published by InTech
• [Book] Viral gene therapy (2011)
  • Author(s): Koichi Miyake, Takashi Shimada
  • Total Pages: 16
  • Publisher: Intec