重篤な遺伝病に対する周産期遺伝子治療

2012 年度 研究成果報告書

• 研究課題/領域番号: 22390212
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 小児科学
• 研究機関: 日本医科大学
• 研究代表者: 島田 隆 日本医科大学, 大学院・医学研究科, 教授 (20125074)
• 連携研究者: 三宅 弘一 日本医科大学, 医学部, 准教授 (90267211) ; 右田 真 日本医科大学, 医学部, 准教授 (50256963) ; 渡邉 淳 日本医科大学, 医学部, 准教授 (10307952)
• 研究期間 (年度): 2010 – 2012
• キーワード: 遺伝子 / 遺伝子治療 / 遺伝病

研究概要

遺伝性神経脱髄疾患である異染性白質ジストロフィー(MLD)と、遺伝性骨系統疾患である低フォスファターゼ症(HPP)のモデルマウスを使い、アデノ随伴ウイルスベクター(AAV)による胎児/新生児遺伝子治療の可能性を検討した。新生児MLDマウスにAAVベクターを静脈内投与すると、ベクターは血液脳関門(BBB)を越えて中枢神経系に侵入し、広範囲な脳組織への遺伝子導入が認められた。その結果、モデルマウスの神経症状が改善した。HPPモデルマウスの胎児の腹腔内にAAVベクターを投与する実験では、出生児の骨形成不全の改善と生存期間の延長が認められた。これらの結果は周産期の遺伝子治療が重篤な遺伝病の治療法として有用であることを示している。

研究成果

• [雑誌論文] Direct Comparison of Administration Routes for AAV8-Mediated Ocular Gene Therapy. (2013)
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• [雑誌論文] Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers. (2011)
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• [雑誌論文] Intraperitoneal AAV9-shRNA inhibits target expression in neonatal skeletal and cardiac muscles. (2011)
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• [雑誌論文] Global gene transfer into the CNS across the BBB after neonatal systemic delivery of single-stranded AAV vectors. (2011)
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• [雑誌論文] Rescue of Severe Infantile Hypophosphatasia Mice by AAV Mediated Sustained Expression of Soluble Alkaline Phosphatase. (2011)
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• [雑誌論文] Direct comparison of four adeno-associated virus serotypes in mediating the production of anti-angiogenic proteins in mouse muscle. (2011)
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• [雑誌論文] Neuron-Specific Gene Transfer through Retrograde Transport of Lentiviral Vector Pseudotyped with a Novel Type of Fusion Envelope Glycoprotein. (2011)
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• [雑誌論文] Adeno-associated viral vector-mediated gene transduction in mesencephalic slice culture. (2011)
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• [雑誌論文] Overexpression of GDNF in the Uninjured DRG Exerts Analgesic Effects on Neuropathic Pain Following Segmental Spinal Nerve Ligation in Mice. (2011)
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• [雑誌論文] Hematopoiesis in regenerated bone marrow within hydroxyapatite scaffold. (2010)
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• [雑誌論文] Adeno-associated vector (type8)-mediated expression of soluble Flt-1 efficiently inhibits neovascularization in a murine choroidalneovascularization model. (2010)
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• [雑誌論文] Successful treatment of metachromatic leukodystrophy using bone marrow transplantation of HoxB4 overexpressing cells. (2010)
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• [雑誌論文] Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. (2010)
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• [雑誌論文] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells.
  • 著者名/発表者名: Komiyama, H., Miyake, K., Asai, K., Mizuno, K., Shimada, T.
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• [学会発表] AAV9 mediated gene therapy of MLD model mice. (2012)
  • 著者名/発表者名: Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • 学会等名: 20th Annual Meeting of the European Society of Gene & Cell Therapy.
  • 発表場所: Versailles, France
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• [学会発表] Gene therapy for lethalmurine hyopophosphatasia. (2012)
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  • 学会等名: 6th International Alkaline Phosphatase And Hypophosphatasia Symposium.
  • 発表場所: Huningue, Alsace, France
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• [学会発表] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector. (2012)
  • 著者名/発表者名: Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • 学会等名: 15th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Philadelphia, Pennsylvania
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• [学会発表] A single injection of AAV-8 vector expressing IL-24 efficiently suppressestumor growth mediated by multiple anti-tumor mechanisms in MLL/AF4 positive ALL model mice. (2011)
  • 著者名/発表者名: Tamai, H., Miyake, K., Yamaguchi, H., Inokuchi, K., Shimada, T., Dan, K.
  • 学会等名: 2011European Hematology AssociationCongress.
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• [学会発表] Successful Treatment of Hypophosphatasia Model Mice by a Single Intramuscular Injection of AAV Type 8 Vector Expressing Tissue-Nonspecific Alkaline Phosphatase. (2011)
  • 著者名/発表者名: Matsumoto, T., Miyake, K., Miyake, N., Orimo, H., Narisawa, S., Millan, J.L. Fukunaga, Y., Shimada. T.
  • 学会等名: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Seattle, WA
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• [学会発表] Fetal Gene Therapy for Lethal Murine Hypophosphatasia. (2011)
  • 著者名/発表者名: Sugano, H., Matsumoto, T., Miyake, K., Watanabe, A., Narisawa, S.,Millan, J.L., Fukunaga, Y., Shimada, T.
  • 学会等名: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Seattle, WA
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• [学会発表] Direct Comparison of Administration Routes for AAV 8 Mediated Ocular Gene Therapy. (2011)
  • 著者名/発表者名: Igarashi, T., Miyake, K., Asakawa, N., Shimada, T., Takahashi, H.
  • 学会等名: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Seattle, WA
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• [学会発表] IntrathecalAdministration 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)
  • 著者名/発表者名: Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • 学会等名: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Seattle, WA
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• [学会発表] Systemic injection of AAV type 9 in utero facilitates global gene expression in the CNS. (2010)
  • 著者名/発表者名: Sugano H, Miyake N, Endo A , Miyake K , Shimada T.
  • 学会等名: International workshop of lysosomal storage disease.
  • 発表場所: Prague, Czech
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• [学会発表] Systemic injection of AAV type 9 in utero facilitates global gene expression in the CNS. (2010)
  • 著者名/発表者名: Sugano H, Miyake N, Endo A , Miyake K , Shimada T.
  • 学会等名: 18th European Society of Gene and Cell Therapy Annual Congress.
  • 発表場所: Milano,Italy
  • 年月日: 20101000
• [学会発表] Global gene transfer in the CNS and phenotypic correction of MLD model mice by systemic neonatal injection of serotype 9 AAV vector. (2010)
  • 著者名/発表者名: Miyake N, Miyake K, Asakawa N, Okabe M, Yamamoto M, Shimada T.
  • 学会等名: European Human Genetics Conference 2010.
  • 発表場所: Gothenburg, Sweden
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• [学会発表] Long term correction of biochemical and neurological abnormalities of MLD model mice by systemic neonatal injection of serotype 9. (2010)
  • 著者名/発表者名: Miyake N, Miyake K, Asakawa N, Yamamoto M, Shimada T.
  • 学会等名: 13th Annual Meeting of the American Society of Gene & Cell Therapy.
  • 発表場所: Washington, DC
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• [学会発表] AAV Vector Mediated Enzyme Replacement Therapy of Hypophosphatasia (HPP) Model Mice. (2010)
  • 著者名/発表者名: Matsumoto T, Yamamoto S, Orimo H, Miyake K, Miyake N, Narisawa S, Millan JL, Fukunaga Y, Shimada T.
  • 学会等名: 13th Annual Meeting of the AmericanSociety of Gene & Cell Therapy.
  • 発表場所: Washington, DC
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• [学会発表] Genotype frequency of 1559T deletion (1559delT) in the TNSALP gene and clinical significance of hypophoshatasia in Japan. (2010)
  • 著者名/発表者名: Watanabe A, Naing BT, Sawai H, Karasugi T, Kondo H, Ikegawa S, Orimo H, Shimada T.
  • 学会等名: 2010 ACMG Annual Clinical Genetics Meeting.
  • 発表場所: Albuquerque, NM
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• [図書] Development of muscle directed systemic cancer gene therapy. (2013)
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• [図書] Prenatal diagnosis of severe perinatal (lethal) hypophosphatasia. (2012)
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