Development of mouse model and therapy of Diamond-Blackfan anemia

• Project/Area Number: 26461596
• 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: Miyake Koichi 日本医科大学, 医学部, 准教授 (90267211)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: リボゾーム蛋白 / 貧血 / 先天異常 / siRNA / レンチウイルスベクター / リボゾーム蛋白質 / ダイヤモンド・ブラックファン貧血 / リボゾームタンパク質

Outline of Final Research Achievements

We generated tetracycline inducible lentiviral vector expressing siRNA against RPL5, RPL11, RPS24, and RPS17 to analyze the molecular mechanism of DBA (Diamond-Blackfan anemia). To develop DBA model mouse, first, we generated KRAB (Kruppel-associated box) gene transgenic mouse. Bone marrow cells from KRAB mouse were transduced with the above lentiviral vectors and induced with tetracycline. Although expression of KRAB was detected, it was difficult to get enough inducible expression after tetracycline induction. Now, we have a plan to analyze the reason and have another strategy to make a DBA model mouse using CRISPR-Cas9 system.

Research Products

• [Journal Article] Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFα Treatment (2017)
  • Author(s): Hayato Tamai, Hiroki Yamaguchi, Koichi Miyake, Miyuki Takatori, Tomoaki Kitano, Satoshi Yamanaka, Syunsuke Yui, Keiko Fukunaga, Kazutaka Nakayama and Koiti Inokuchi
  • Journal Title: Cancer Research Volume: 77 Issue: 16 Pages: 4426-4433
  • DOI: 10.1158/0008-5472.can-16-2974
  • Peer Reviewed
• [Journal Article] D816V mutation in the KIT gene activation loop has greater cell-proliferative and anti-apoptotic ability than N822K mutation in core-binding factor acute myeloid leukemia (2017)
  • Author(s): Omori Ikuko、Yamaguchi Hiroki、Miyake Koichi、Miyake Noriko、Kitano Tomoaki、Inokuchi Koiti
  • Journal Title: Experimental Hematology Volume: 52 Pages: 56-64.e4
  • DOI: 10.1016/j.exphem.2017.05.003
  • Peer Reviewed
• [Journal Article] MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain (2017)
  • Author(s): Sakai Atsushi、Saitow Fumihito、Maruyama Motoyo、Miyake Noriko、Miyake Koichi、Shimada Takashi、Okada Takashi、Suzuki Hidenori
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 16079-16079
  • DOI: 10.1038/ncomms16079
  • Peer Reviewed / Open Access
• [Journal Article] Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys. (2017)
  • Author(s): Takahashi K, Igarashi T, Miyake K, Kobayashi M, Yaguchi C, Iijima O, Yamazaki Y, Katakai Y, Miyake N, Kameya S, Shimada T, Takahashi H, Okada T.
  • Journal Title: Mol Ther. Volume: 4；25 Issue: 1 Pages: 296-302
  • DOI: 10.1016/j.ymthe.2016.10.008
  • Peer Reviewed / Open Access
• [Journal Article] miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down-regulation. (2017)
  • Author(s): Ito N, Sakai A, Miyake N, Maruyama M, Iwasaki H, Miyake K, Okada T, Sakamoto A, Suzuki H.
  • Journal Title: British Journal of Pharmacology Volume: 174 Issue: 5 Pages: 386-395
  • DOI: 10.1111/bph.13698
  • Peer Reviewed / Open Access
• [Journal Article] Tyrosine triple mutated AAV2-BDNF gene therapy in a rat model of transient IOP elevation (2016)
  • Author(s): Igarashi T, Miyake K, Kobayashi M, Kameya S, Fujimoto C, Nakamoto K, Takahashi H, Igarashi T, Miyake N, Iijima O, Hirai Y, Shimada T, Okada T, Takahashi H.
  • Journal Title: Mol Vis. Volume: 16 Pages: 816-826
  • Peer Reviewed
• [Journal Article] Prevention of Lethal Murine Hypophosphatasia by Neonatal Ex Vivo Gene Therapy Using Lentivirally Transduced Bone Marrow Cells. (2015)
  • Author(s): Iijima O, Miyake K, Watanabe A, Miyake N, Igarashi T, Kanokoda C, Nakamura-Takahashi A, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millán JL, Okada T, Shimada T.
  • Journal Title: Hum Gene Ther. Volume: 26 Issue: 12 Pages: 801-12
  • DOI: 10.1089/hum.2015.078
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Enzyme replacement in the CSF to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary AAV1 vector. (2015)
  • Author(s): Hironaka K, Yamazaki Y, Hirai Y, Yamamoto M, Miyake N, Miyake K, Okada T, Morita A, Shimada T.
  • Journal Title: Sci Rep. Volume: 18 Issue: 1 Pages: 1-12
  • DOI: 10.1038/srep13104
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeted gene transfer into ependymal cells through intraventricular injection of AAV1 vector and long-term enzyme replacement via the CSF. (2014)
  • Author(s): Yamazaki Y, Hirai Y, Miyake K, Shimada T.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 5506-5506
  • DOI: 10.1038/srep05506
  • Peer Reviewed / Open Access
• [Journal Article] Adeno-associated virus type 8 vector-mediated expression of siRNA targeting vascular endothelial growth factor efficiently inhibits neovascularization in a murine choroidal neovascularization model. (2014)
  • Author(s): Igarashi T, Miyake N, Fujimoto C, Yaguchi C, Iijima O, Shimada T, Takahashi H, Miyake K.
  • Journal Title: Mol Vis. Volume: 20 Pages: 488-96
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] nhibition of S100A6 induces graft versus leukemia effects in MLL/AF4-positive ALL in human PBMC-SCID mice. (2014)
  • Author(s): Tamai.H, Miyake K, Yamaguchi H, Shimada T, Dan K, Inokuchi K.
  • Journal Title: Bone Marrow Transplantation Volume: 49(5) Issue: 5 Pages: 699-703
  • DOI: 10.1038/bmt.2014.18
  • Peer Reviewed / Open Access
• [Journal Article] Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector. (2014)
  • Author(s): Miyake N, Miyake K, Asakawa N, Yamamoto M, Shimada T.
  • Journal Title: Gene Ther. Volume: 印刷中 Issue: 4 Pages: 427-433
  • DOI: 10.1038/gt.2014.17
  • Peer Reviewed / Open Access
• [Presentation] Successful treatment of neonatal metachromatic leukodystrophy model mice by intravenous injection of self-complementary AAV type 9 vector expressing ASA (2015)
  • Author(s): Noriko Miyake, Koichi Miyake, Motoko Yamamoto, Takashi Shimada, Takashi Okada
  • Organizer: The 21th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 大阪（国際会議場）
  • Year and Date: 2015-07-24
• [Presentation] The D816V c-kit mutation confers higher proliferation activity by JAK-STAT and Src family kinase pathways compared to N822K c-kit mutation in core-binding factor acute myeloid leukemia. (2015)
  • Author(s): Ikuko Omori1, Hiroki Yamaguchi1, Tomoaki Kitano, Noriko Miyake, Koichi Miyake, Kazuo Dan, Koiti Inokuchi.
  • Organizer: 20th Congress of European Hematology Association
  • Place of Presentation: Austria, Vienna
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] The D816V c-kit mutation confers higher proliferation activity by JAK-STAT and Src family kinase pathway compared to N822K c-kit mutation in core-binding factor acute myeloid leukemia. (2014)
  • Author(s): Omori I, Yamaguchi H, Kitano T, Miyake N, Miyake K, Inokuchi K.
  • Organizer: 56th ASH Annual Meeting & Exposition
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Long-term enzyme supplementation into the CSF to treat metachromatic leukodystrophy by intraventricular injection of AAV1 vector. (2014)
  • Author(s): Yamazaki Y, Hironaka K, Miyake N, Hirai Y, Miyake K, Okada T, Shimada T.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 東京
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Trans-BBB gene therapy for metachromatic leukodystrophy using self-complementary type 9 AAV vector. (2014)
  • Author(s): Miyake N, Miyake K, Yamamoto M, Okada T, Shimada T.
  • Organizer: The 20th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: 東京
  • Year and Date: 2014-08-06 – 2014-08-08
• [Presentation] Efficient Protection of Retina By Tyrosine-Mutated Self-Complementary AAV2 Vector Encoding BDNF in a Rat Retinal Ischemic Injury Model. (2014)
  • Author(s): Igarashi T, Miyake K, Kobayashi M, Takahashi K, Miyake N, Iijima O, Nakamoto K, Hirai Y, Shimada T, Takahashi H.
  • Organizer: 17th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Washington DC
  • Year and Date: 2014-05-21 – 2014-05-24
• [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, Shimada T.
  • Organizer: 17th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Washington DC
  • Year and Date: 2014-05-21 – 2014-05-24
• [Book] Gene Therapy - Principles and Challenges (2015)
  • Author(s): Koichi Miyake, Noriko Miyake and Takashi Shimada
  • Total Pages: 208
  • Publisher: INTECh