Foamy virus vector-mediated gene transfer into long-term HSC in the gene therapy for primary immunodeficiencies.

• Project/Area Number: 25860836
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: UCHIYAMA TORU 独立行政法人国立成育医療研究センター, 成育遺伝研究部, 室長 (10436107)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: FVベクター / X連鎖重症複合免疫不全症 / 遺伝子治療 / X連鎖重症複合免役不全症 / dNLnk

Outline of Final Research Achievements

Using Foamy virus-based (FV) vector, we have established the gene transfer system for X-linked severe combined immunodeficiency (X-SCID). We constructed FV vector containing human γc under the control of A2UCOE for stable gene expression, and transduced the bone marrow cells from X-SCID mice. Gene transduced cells were transplanted into NOD/SCID-γc null mice, which provided high level of engraftment of hematopoietic cells. In transplanted mice, splenic T cells showed the improvement in proliferation and IL-2 production in response to anti-CD3 stimulation, and serum levels of IgM, IgA and IgG were also elevated. These results revealed the functional reconstitution of immune system. Analysis of vector integration demonstrated that FV integration sites were slightly less likely to be located within or near transcriptional start sites than retroviral vector (RV) integration sites. These data suggest that FV vector is a safer system than RV vector in stem cell gene therapy for X-SCID.

Research Products

• [Journal Article] Interstitial Lung Disease with Multiple Microgranulomas in Chronic Granulomatous Disease. (2014)
  • Author(s): Kawai T, Watanabe N, Yokoyama M, Nakazawa Y, Goto F, Uchiyama T, Higuchi M, Maekawa T, Tamura E, Nagasaka S, Hojo M, Onodera M
  • Journal Title: Journal of Clinical Immunology Volume: 34 Issue: 8 Pages: 933-940
  • DOI: 10.1007/s10875-014-0089-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The open conformation of WASP regulates its nuclear localization and gene transcription in myeloid cells. (2014)
  • Author(s): 2.Looi CY, Sasahara Y, Watanabe Y, Sato M, Hakozaki I, Uchiyama M, Wong WF, Uchiyama T, Kumaki S, Tsuchiya S, Kure S
  • Journal Title: International Immnology Volume: 26 Issue: 6 Pages: 341-352
  • DOI: 10.1093/intimm/dxt072
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 原発性免疫不全－複合免疫不全 (2014)
  • Author(s): 内山徹
  • Journal Title: 小児の治療指針 Volume: 77 Pages: 228-230
• [Journal Article] Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector (2013)
  • Author(s): Horino S, Uchiyama T, So T, Nagashima H, Sun SL, Sato M, Asao A, Haji Y, Sasahara Y, Candotti F, Tsuchiya S, Kure S, Sugamura K, and Ishii N
  • Journal Title: PLoS ONE Volume: 8 Issue: 8 Pages: e71594-e71594
  • DOI: 10.1371/journal.pone.0071594
  • Peer Reviewed
• [Journal Article] Current status and future prospects of stem cell gene therapy for primary immunodeficiency (2013)
  • Author(s): Uchiyama T, Onodera M
  • Journal Title: Nihon Rinsho Meneki Gakkai kaishi Volume: 36 Pages: 148-155
  • NAID: 10031185521
• [Journal Article] A case series of CAEBV of children and young adults treated with reduced-intensity conditioning and allogeneic bone marrow transplantation: a single-center study. (2013)
  • Author(s): Watanabe Y, Sasahara Y, Satoh M, Looi CY, Katayama S, Suzuki T, Suzuki N, Ouchi M, Horino S, Moriya K, Nanjyo Y, Onuma M, Kitazawa H, Irie M, Niizuma H, Uchiyama T, Rikiishi T, Kumaki S, Minegishi M, Wada T, Yachie A, Tsuchiya S, Kure S.
  • Journal Title: Eur J Haematol Volume: 91 Issue: 3 Pages: 242-248
  • DOI: 10.1111/ejh.12151
  • Peer Reviewed
• [Journal Article] Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations (2013)
  • Author(s): Kitazawa H, Moriya K, Niizuma H, Kawano K, Saito-Nanjo Y, Uchiyama T, Rikiishi T, Sasahara Y, Sakamoto O, Setoguchi Y, Kure S
  • Journal Title: Eur J Pediatr Volume: 172(7) Issue: 7 Pages: 953-7
  • DOI: 10.1007/s00431-013-1977-8
  • Peer Reviewed
• [Presentation] 原発性免疫不全症に対する造血幹細胞移植 (2015)
  • Author(s): 内山徹
  • Organizer: 第５回国際遺伝病遺伝子治療フォーラム
  • Place of Presentation: 東京
  • Year and Date: 2015-01-15
  • Invited
• [Presentation] 原発性免疫不全症への造血幹細胞遺伝子治療の現況 (2014)
  • Author(s): 内山 徹
  • Organizer: 第４回関西免疫不全症研究会
  • Place of Presentation: 大阪
  • Year and Date: 2014-07-19
  • Invited
• [Presentation] 慢性肉芽腫症の炎症性肉芽腫に対するサリドマイドの治療効果 (2014)
  • Author(s): 河合利尚、中澤裕美子、後藤文洋、内山徹、新井勝大、久保田雅也、石黒精、布井博幸、小林正夫、小野寺雅史
  • Organizer: 第117回小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] 慢性肉芽腫症42例における肉芽腫性疾患の臨床的検討 (2014)
  • Author(s): 後藤文洋、河合利尚、中澤裕美子、内山徹、原山静子、田村英一郎、亀井宏一、新井勝大、小野寺雅史
  • Organizer: 第117回小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] 酸素補充療法が造血幹細胞遺伝子治療後のADA欠損症患者に与える免疫機能改善効果 (2014)
  • Author(s): 中澤裕美子、河合利尚、後藤文洋、内山徹、渡辺信之、前川貴伸、石黒精、奥山虎之、山田雅文、大津真、有賀正、小野寺雅史
  • Organizer: 第117回小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] Foamy virus vectorを用いたX連鎖重症複合免疫不全症に対する遺伝子治療モデルの作製 (2014)
  • Author(s): 堀野智史、内山徹、宗孝紀、佐藤美季、孫舒嵐、笹原洋二、土屋滋、呉繁夫、菅村和夫、石井直人
  • Organizer: 第117回小児科学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] Gene Therapy models of X-linked severe combined immunodeficiency and Wiskott-Aldrich syndrome using foamy virus vectors. (2013)
  • Author(s): Toru Uchiyama, Satoshi Horino, Tkanori So, G Jayashree Jagadeesh, Naoto Ishii, Fabio Candotti
  • Organizer: European Society of Gene and Cell Therapy Congress 2013
  • Place of Presentation: Madrid, Spain
• [Presentation] 慢性肉芽腫症における肺間質性炎症 (2013)
  • Author(s): 河合利尚、中澤裕美子、渡辺信之、横山みどり、内山徹、田村英一郎、伊藤秀一、放生雅章、小野寺雅史
  • Organizer: 第23回日本小児リウマチ学会
  • Place of Presentation: 埼玉
• [Presentation] 単球の活性酸素産生能低下による肉芽腫性腸炎 (2013)
  • Author(s): 河合利尚、中澤裕美子、田村英一郎、清水泰岳、伊藤玲子、内山徹
  • Organizer: 第45回日本小児感染症学会
  • Place of Presentation: 札幌
• [Presentation] Effects of chronic granulomatous disease-associated bowel inflammation on microbial gut flora. (2013)
  • Author(s): Kawai T, Nakazawa Y, Uchiyama T, Arai K. Onodera M
  • Organizer: 第13回アジア汎太平洋小児栄養消化器肝臓学会
  • Place of Presentation: 東京
• [Presentation] Effect of Thalidomide Therapy on Bowel Inflammation in Chronic Granulomatous Disease. (2013)
  • Author(s): Nakazawa Y, Kawai T, Uchiyama T, Arai K. Onodera M
  • Organizer: 第13回アジア汎太平洋小児栄養消化器肝臓学会
  • Place of Presentation: 東京