An approach for ALS genetic therapy using Herpes Simplex Virus Vector

• Project/Area Number: 15590916
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka Medical College
• Principal Investigator: KIMURA Fumiharu Osaka Medical College, Faculty of Medicine, Assistant Professor, 医学部, 講師 (90204990)
• Co-Investigator(Kenkyū-buntansha): MIYATAKE Shin-Ichi Osaka Medical College, Faculty of Medicine, Associate professor, 医学部, 助教授 (90209916) ; FURUTAMA Daisuke Osaka Medical College, Faculty of Medicine, Research associate, 医学部, 助手 (70291987) ; 上原 秀明 大阪医科大学, 医学部, 専攻医
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,100,000 (Direct Cost: ¥3,100,000); Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: ALS / FGF2 / MCAO / one marrow stromal cell / HSV-1 vector / 遺伝子治療 / HGF / 骨髄間葉系幹細胞 / 脳虚血 / 筋萎縮性側策硬化症 / 単純ヘルペス / 肝細胞増殖因子 / 線維芽細胞増殖因子 / 血管内皮細胞増殖因子 / ウイルスベクター / Herpes Vector / Motor Neuron disease

Research Abstract

Background and Purpose : Fibroblast growth factor-2 (FGF-2) administration and bone marrow stromal cell (MSC) transplantation could improve neurological deficits after occlusive cerebrovascular disease. In the present study, we examined the effects of neurological improvement after transient middle cerebral artery occlusion (MCAO) in rats by a novel therapeutic strategy with FGF-2 gene transferred MSCs by the herpes simplex virus type 1 (HSV-1) vector. Methods Adult Wistar rats were anesthetized. Nonmodified MSCs, FGF-2 modified MSCs with HSV-1 1764/-4/pR19/ ssIL2-FGF-2, or PBS was administered intracerebrally 24 hours after transient right MCAO. All animals underwent behavioral tests for 21 days, and the infarction volume with 2-3-5-triphenylterazolium was detected 3 days and 14 days after the MCAO. Three days and 7 days after the MCAO, the FGF-2 production in the ipsilateral hemisphere of the MCAO was measured with ELISA. Seven and 14 days after the MCAO, immunohistochemical staining for FGF-2 was applied. Results The stroke animals receiving FGF-2 modified MSCs demonstrated significant functional recovery compared with the other groups. Fourteen days after the MCAO, there was a significant reduction in infarction volume only in FGF-2 modified MSC-treated group. FGF-2 production in the FGF-2 modified MSC-treated brain was significantly higher compared with the other groups at 3 and 7 days after MCAO. Administrated FGF-2 modified MSCs strongly expressed the FGF-2 protein, which was proven by ELISA. Conclusions Our data suggest that the FGF-2 gene modified MSCs with the HSV-1 vector can contribute to remarkable functional recovery after stroke compared with MSCs transplantation alone.

Research Products

• [Journal Article] Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS (2006)
  • Author(s): F.Kimura, et al.
  • Journal Title: NEUROLOGY 66 Pages: 265-267
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS (2006)
  • Author(s): F.Kimura, C.Fujimura, S.Ishida, H.Nakajima, D.Furutama, H.Uehara, K.Shinoda, M.Sugino, T.Hanafusa
  • Journal Title: Neurology 66 Pages: 265-267
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS (2006)
  • Author(s): Kimura F et al.
  • Journal Title: Neurology 66(2) Pages: 265-267
• [Journal Article] Wheelchair Economy Class Syndrome in Amyotrophic Lateral Sclerosis. (2006)
  • Author(s): Kimuea F et al.
  • Journal Title: Neuromuscular disorders 16(3) Pages: 204-207
• [Journal Article] Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and Ex Vivo HGF Gene Transfer with HSV-1 Vector. (2006)
  • Author(s): Zhao MZ et al.
  • Journal Title: J Cereb Blood Flow Metab (In press)
• [Journal Article] Bone Marrow Stromal Cells That Enhanced Fibroblast Growth Factor-2 Secretion by Herpes Simplex Virus Vector Improve Neurological Outcome After Transient Focal Cerebral Ischemia in Rats (2005)
  • Author(s): Naokado Ikeda, et al.
  • Journal Title: Stroke. 36 Pages: 2725-2730
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bone Marrow Stromal Cells That Enhanced Fibroblast Growth Factor-2 Secretion by Herpes Simplex Virus Vector Improve Neurological Outcome After Transient Focal Cerebral Ischemia in Rats (2005)
  • Author(s): Naokado Ikeda, MD, Naosuke Nonoguchi, MD, Ming Zhu Zhao, MD, Takuji Watanabe, MD, PhD, Yoshinaga Kajimoto, MD, PhD, Daisuke Furutama, MD, PhD, Fumiharu Kimura, MD, PhD, Mari Dezawa, MD, PhD, Robert S.Coffin, MD, PhD, Yoshinori Otsuki, MD, PhD, Toshihiko Kuroiwa, MD, PhD, Shin-Ichi Miyatake, MD, Ph
  • Journal Title: Stroke. 36 Pages: 2725-2730
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bone marrow stromal cells that enhanced FGF-2 secretion by Herpes Simplex virus vector improve neurological outcome after transient focal ischemia in rats (2005)
  • Author(s): Ikeda N et al.
  • Journal Title: Stroke 36(12) Pages: 2725-2730
• [Journal Article] Post-Ischemic Intraventricular Administration of FGF-2 Expressing Adenoviral Vectors Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Cerebral Ischemia in Rats. (2004)
  • Author(s): Watanabe T et al.
  • Journal Title: J Cerebral Blood Flow and Metabolism 24 Pages: 1205-13
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Postischemic- intraventricular administration of FGF-2 expressing adenobiral bettors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats. (2004)
  • Author(s): Watanabe T, Okuda Y, Nonoguchi N, Zhao MZ, Kajimoto Y, Furutama D, Yukawa H, Shibata MA, Otsuki Y, Kuroiwa T, Miyatake
  • Journal Title: J Cereb Blood Flow Metab 24(11) Pages: 1205-1213
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Post-lschemic Intraventricular Administration of FGF-2 Expressing Adenoviral Vectors Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Cerebral Ischemia in Rats. (2004)
  • Author(s): Watanabe-T et al.
  • Journal Title: J Cerebral Blood Flow and Metabolism 24 Pages: 1205-1213
• [Publications] 木村 文治: "筋萎縮性側索硬化症100例の変遷"臨床神経. 43. 385-391 (2003)
• [Publications] 中嶋秀人, 古玉大介, 木村文治: "球脊髄性筋萎縮症病態の解明と治療へ向けた単純ヘルペスウィルスベクター遺伝子導入システム"公益信託「生命の彩」ALS研究助成基金研究報告書. 11. 1-5 (2003)