2004 Fiscal Year Final Research Report Summary
Development of novel therapy and elucidation of pathophysiology for genetic leukodystrophy
| Project/Area Number |
14370252
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
ETO Yoshikatsu Jikei University School of Medicine, Professor, 医学部, 教授 (50056909)
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| Co-Investigator(Kenkyū-buntansha) |
OHASHI Toya Jikei University School of Medicine, Assistant Professor, 医学部, 助教授 (60160595)
IDA Hiroyuki Jikei University School of Medicine, Assistant Professor, 医学部, 助教授 (90167255)
TSUDA Takashi Jikei University School of Medicine, Assistant Lecture, 医学部, 講師 (50188554)
MIYATA Ichiro Jikei University School of Medicine, Assistant Lecture, 医学部, 講師 (10200180)
SUZUKI Hideaki Jikei University School of Medicine, Assistant, 医学部, 助手 (20206519)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Gene Therapy / Leucodystrophy / Pre-natal Gene therapy / Krabbe disease / Retrovirus vector |
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| Research Abstract |
We are developing gene and cell therapy for genetic leukodystrophies. The main disease, which we focused on, was Krabbe disease. This disease is caused by a genetic deficiency of galactocerebrosidase and the authentic murine model of Krabbe disease is available. Using this murine model, we tried several gene therapy approaches. First, we injected adenoviral vector, which carries bacterial LacZ gene into lateral ventricles of normal mouse embryo. LacZ expression was observed throughout the brain and this expression was persisted more than 100 days after birth. Main cell type, which expressed LacZ gene was neuron and astorocytes. However, no oligodendrocytes expressed LacZ. Although this approach was very effective for mucopolysaccharidosis type VII mice, mouse model of Krabbe disease failed to be cured by this method. This failure may be due that the main affected cell in Krabbe disease is oligodendrocyte. So we tested retroviral vector instead of adenovirus vector. As a result, not only neurons and astrocytes, but also olingodendrocytes expressed LacZ, and the expression period was more than 100 days without significant decrement of expression. This observation strongly indicated that retrovirus vector transdused neural stem cell. So we injected retorovirus vector into subventricular zone of newborn mouse brain, which is known that many neural stem cells exist. In this case, mainly, astorcyte and oligidendrocyte expressed LacZ. From this observation, we generated retrovirus vector which expressed galactocerebrosidase and injected subventricular zone of newborn twitcher mouse, which is authentic mouse model of Krabbe disease. The abnormal morphology of twitcher mouse oligodedrocyte was restored by retrovirus transduction. This indicated that neonatal gene therapy may be feasible for treatment of neural involvement of Krabbe disease.
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