Therapeutic strategies for inherited neurodegerative disorders using gene transfer and stem-cell transplantation technologies

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 14370253
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School
• Principal Investigator: SHIMADA Takashi Nippon Medical School, Professor, 大学院・医学研究科, 教授 (20125074)
• Co-Investigator(Kenkyū-buntansha): MIGITA Makoto Nippon Medical School, Associate professor, 医学部, 助教授 (50256963) ; MIYAKE Koichi Nippon Medical School, Assistant professor, 医学部, 講師 (90267211) ; MODHIZUKI Hideki Juntendo University, Associate professor, 医学部, 講師 (90230044) ; NISHI Katsunori Tokyo Metropolitan Inst for Neuroscience, Dept Neurology, Director, 副参事研究員 (00138257)
• Project Period (FY): 2002 – 2004
• Keywords: gene therapy / cell therapy / lysosomal disorders / stem cells / neural stem cells / AAV vector

Research Abstract

1.Gene therapy : We examined the utility of recently identified sulfatase activating enzyme (FGE) for expression of arylsulfatase A(ASA) in gene therapy of metachromatic leukodustrophy(MLD). Our data demonstrated that FGE co-expression is essential for synthesis and secretion of functional ASA both in vitro and in vivo. In a therapeutic model experiment, we generated AAV1 vector carrying either ASA or FGE cDNA. Simultaneous injection of these vectors into the hippocampus of MLD mice significantly increased ASA activity and decreased sulfatide accumulation in the wide areas of the brain. Significant improvement of behavior was confirmed by the rotarod test and the walking pattern. These result support that FGE co-expression is essential for efficient synthesis of functional ASA and have significant implications for the development of MLD gene therapy.
2.Stem cell therapy : Using chimeric mice stably reconstituted with bone marrow cells from GFP transgenic mice, we demonstrated that mesenchymal stem cells derived from bone marrow (BSC) could differentiate various cell lineages. We also succeeded in preparing pluripotent stem cells from adipose tissues(ASC). The feasibility of cell therapy of MLD was demonstrate by direct inoculation of neural progenitor cells stably tranduced with lentiviral vector carrying ASA cDNA. Genetically engineered stem cells may be useful for therapy for neurodegenerative disorders.

Research Products

• [Journal Article] An asymptomatic heterozygous female with Fabry disease : implications for enzyme replacement therapy. (2005)
  • Author(s): Inagaki, S., et al.
  • Journal Title: J. Nippon Med. Sch. 72 Pages: 387-390
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Co-expression of FGE is essential for synthesis and secretion of functional arylsulfatase A in a mouse model of metachromatic leukodystrophy. (2005)
  • Author(s): Takakusaki, Y., et al.
  • Journal Title: Hum. Gene Ther. 16 Pages: 1-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of bone marrow cells in the healing process of mouse experimental glomerulonephritis. (2005)
  • Author(s): Hayakawa, M., et al.
  • Journal Title: Ped. Research 58 Pages: 323-328
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An asymptomatic heterozygous female with Fabry disease : implications for enzyme replacement therapy. (2005)
  • Author(s): Inagaki, S., Migita, M., Hayakawa, M., Yoshida, J., Ishizaki, M., Kotani, M., Sakuraba, H., Shimada, T., Murakami, M., Fukunaga, Y.
  • Journal Title: J.Nippon Med.Sch. 72 Pages: 387-390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Co-expression of FGE is essential for synthesis and secretion of functional arylsulfatase A in a mouse model of metachromatic leukodystrophy. (2005)
  • Author(s): Takakusaki, Y., Hisayasu, S., Hirai, Y., Shimada, T.
  • Journal Title: Hum.Gene Ther. 16 Pages: 1-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of bone marrow cells in the healing process of mouse experimental glomerulonephritis. (2005)
  • Author(s): Hayakawa, M., Ishizaki, M., Hayakawa, J., Migita, M., Nurakami, M., Shimada, T., Fukunaga, Y.
  • Journal Title: Ped.Research 58 Pages: 323-328
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adipogenic defferentiation by adipose-derived stem cells harvested from GFP transgenic mice - including relationship of sex differences-. (2004)
  • Author(s): Ogawa, R., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 23 Pages: 871-877
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] HGF receptor is a coreceptor for adeno-associatedvirus type 2 (AAV2) infection. (2004)
  • Author(s): Kashiwakura, Y., et al.
  • Journal Title: J. Viol. 79 Pages: 609-614
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Chondrogenic and osteogenic differentiation of adipose-derived stem cells isolated from GFP transgenic mice. (2004)
  • Author(s): Ogawa, R., et al.
  • Journal Title: J. Nippon Med. Sch. 71 Pages: 240-241
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Recipient non-hematopoietic bone marrow cells in the intestinal graft after fetal small intestinal transplantation. (2004)
  • Author(s): Kato, Y., et al.
  • Journal Title: Pediatr. Surg. Int. 20 Pages: 1-4
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Osteogenic and Chondrogenic Differentiation by Adipose-derived Stem Cells Harvested from GFP Transgenic Mice. (2004)
  • Author(s): Ogawa, R., Mizuno, H., Watanabe, A., Migita, A., Shimada, T., Hyakusoku, H.
  • Journal Title: Biochem.Biophys.Res.Commun. 23 Pages: 871-877
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adipogenic defferentiation by adipose-derived stem cells harvested from GEP transgenic mice -including relationship of sex differences-. (2004)
  • Author(s): Ogawa, R., Mizuno, H., Watanabe, A., Migita, M., Hyakusoku, H., Shimada, T.
  • Journal Title: Biochem.Biophys.Res.Commun. 319 Pages: 511-517
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] HGF receptor is a coreceptor for adeno-associated virus type 2 (AAV2) infection. (2004)
  • Author(s): Kashiwakura, Y., Tamayose, K., Iwabuti, K., Hirai, Y., Shimada, T., Matsumoto, K., Nakamura, T., Oshimi, K., Daiwa, H.
  • Journal Title: J.Viol. 79 Pages: 609-614
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chondrogenic and osteogenic differentiation of adipose-derived stem cells isolated from GFP transgenic mice. (2004)
  • Author(s): Ogawa, R., Mizuno, H., Hyakusoku, H.Watanabe, A., Migita, M., Shimada, T.
  • Journal Title: J.Nippon Med.Sch. 71 Pages: 240-241
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Recipient non-hematopoietic bone marrow cells in the intestinal graft after fetal small intestinal transplantation. (2004)
  • Author(s): Kato, Y., Yamataka, A., Miyahara, K., Sueyoshi, N., Hayakawa, J., Hayashida, M., Migita, M., Shimada, T., Kobayashi, H., Lane, G.J., Miyano, T.
  • Journal Title: Pediatr.Surg.Int. 20 Pages: 1-4
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Glucocerebrosidase level in the cerebrospinal fluid during enzymereplacement therapy -unsuccessful treatment to the neurological abnormality of type 2 Gaucher disease. (2003)
  • Author(s): Migita M., et al.
  • Journal Title: Eur. J. Paed. 162 Pages: 524-525
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a murine proliferative retinopathy model. (2003)
  • Author(s): Igarashi, T., et al.
  • Journal Title: Gene Ther. 10 Pages: 219-226
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Migration of EGFP expressing bone marrow-derived microglia/macrophage into the mice brain following permanent focal ischemia. (2003)
  • Author(s): Tanaka, R., et al.
  • Journal Title: Neuroscience 117 Pages: 531-539
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Home treatment with enzyme replacement therapy for Gaucher disease. (2003)
  • Author(s): Migita, M., et al.
  • Journal Title: Pediatr. Int. 45 Pages: 363-365
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bone formation following transplantation of genetically modified primary bone marrow stromal cells. (2003)
  • Author(s): Sugiyama, O., et al.
  • Journal Title: J. Orthop. Res. 21 Pages: 630-637
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders. (2003)
  • Author(s): Furuya, T., et al.
  • Journal Title: NeuroReport 14 Pages: 629-631
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta-cells. (2003)
  • Author(s): Choi, J.B., et al.
  • Journal Title: Diabetologia 46 Pages: 1366-1374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells : a useful model for studying the behaviour of bone marrow cells in regeneration in vivo. (2003)
  • Author(s): Hayakawa, J., et al.
  • Journal Title: Int. J. Hematol. 77 Pages: 456-462
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cardiomyocyte regeneration from circulating bone marrow cells in mice. (2003)
  • Author(s): Kuramochi, Y., et al.
  • Journal Title: Pediatr. Res. 77 Pages: 456-462
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Osteogenic and Chondrogenic Differentiation by Adipose-derived Stem Cells Harvested from GFP Transgenic Mice. (2003)
  • Author(s): Ogawa, R., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 54 Pages: 319-325
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Glucocerebrosidase level in the cerebrospinal fluid during enzymereplacement therapy -unsuccessful treatment to the neurological abnormality of type 2 Gaucher disease. (2003)
  • Author(s): Migita M., Hamada, H., Fujimura, J., Watanabe, A., Shimada, T., Fukunaga, Y.
  • Journal Title: Eur.J.Paed. 162 Pages: 524-525
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a murine proliferative retinopathy model. (2003)
  • Author(s): Igarashi, T., Miyake, K., Kato, K., Watanabe, A., Ishizaki, M., Ohara, K., Shimada, T.
  • Journal Title: Gene Ther. 10 Pages: 219-226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Migration of EGFP expressing bone marrow-derived microglia/macrophage into the mice brain following permanent focal ischemia. (2003)
  • Author(s): Tanaka, R., Komine-Kobayashi, M., Mochizuki, H., Yamada, M., Furuya, T., Migita, M., Shimada, T., Mizuno, Y., Urabe, T.
  • Journal Title: Neuroscience 117 Pages: 531-539
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Home treatment with enzyme replacement therapy for Gaucher disease. (2003)
  • Author(s): Migita, M., Shimada, T., Hayakawa, J., Morita, T., Fukunaga, Y.
  • Journal Title: Pediatr.Int. 45 Pages: 363-365
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bone formation following transplantation of genetically modified primary bone marrow stromal cells. (2003)
  • Author(s): Sugiyama, O., Orimo, H., Suzuki, S., Yamashita, K., Ito, H., Shimada, T.
  • Journal Title: J.Orthop.Res. 21 Pages: 630-637
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders. (2003)
  • Author(s): Furuya, T., Tanaka, R., Urabe, T., Hayakawa, J., Migita, M., Shimada, T., Mizuno, Y., Mochizuki, H.
  • Journal Title: NeuroReport 14 Pages: 629-631
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta-cells. (2003)
  • Author(s): Choi, J.B., Uchino, H., Azuma, K., Iwashita, N., Tanaka, Y., Mochizuki, H., Migita, M., Shimada, T., Kawamori, R., Watada, H.
  • Journal Title: Diabetologia 46 Pages: 1366-1374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of a chimeric mouse reconstituted with green fluorescent protein-positive bone marrow cells : a useful model for studying the behavior of bone marrow cells in regeneration in vivo. (2003)
  • Author(s): Hayakawa, J., Migita, M., Ueda, T., Shimada, T., Fukunaga, Y.
  • Journal Title: Int.J.Hematol. 77 Pages: 456-462
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardiomyocyte regeneration from circulating bone marrow cells in mice. (2003)
  • Author(s): Kuramochi, Y., Fukazawa, R., Migita, M., Hayakawa, J., Hayashida, M., Uchikoba, Y., Fukumi, D., Shimada, T., Ogawa, S.
  • Journal Title: Pediatr.Res. 54 Pages: 319-325
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] New strategy for in vivo transgene expression in corneal epithelial progenitor cells. (2002)
  • Author(s): Igarashi T., et al.
  • Journal Title: Current Eye Res. 24 Pages: 46-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer. (2002)
  • Author(s): Takahashi, H., et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA. 99 Pages: 13777-13782
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adeno-associated virus mediated antiapoptotic gene delivery : in vivo gene therapy for neurological disorders. (2002)
  • Author(s): Mochizuki, H., et al.
  • Journal Title: Methods 28 Pages: 248-252
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] New strategy for in vivo transgene expression in corneal epithelial progenitor cells. (2002)
  • Author(s): Igarashi, T., Miyake, K., Suzuki, N., Kato, K., Takahashi, H., Ohara, K., Shimada, T.
  • Journal Title: Current Eye Res. 24 Pages: 46-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer. (2002)
  • Author(s): Takahashi, H., Hirai, Y., Migita, M., Seino, Y., Fukuda, Y., Sakuraba, H., Kase, R., Kobayashi, T., Hashimoto, Y., Shimada, T.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 99 Pages: 13777-13782
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adeno-associated virus mediated antiapoptotic gene delivery : in vivo gene therapy for neurological disorders. (2002)
  • Author(s): Mochizuki, H., Miura, M., Shimada, T., Mizuno, Y.
  • Journal Title: Methods 28 Pages: 248-252
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Anti-apoptotic therapy for Parkinson's disease : overexpression of an apf-1-dominant-gnegative inhibitor can block MPTP toxicity. Mapping the Program of Alzheimer's and Parkinson's Disease. (edited by Mizuno et al.) (2002)
  • Author(s): Mochizuki, H., Hayakawa, H., Nigita, M., Shimada, T., Masyuki, M., Mizuno, Y.
  • Total Pages: 469-472
  • Publisher: Kluwer Academic Publishers
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] 脂肪組織由来幹細胞からの骨髄を形成するための組成物およぴその方法 (2005)
  • Inventor(s): 小川令, 水野博司, 百束比古, 島田隆
  • Industrial Property Rights Holder: 小川令, 水野博司, 百束比古, 島田隆
  • Industrial Property Number: 特願2004-133827
  • Filing Date: 2005-04-28
  • Description: 「研究成果報告書概要(和文)」より