1993 Fiscal Year Final Research Report Summary
Studies of genetic analysis and gene therapy for myelin-associated disorders.
| Project/Area Number |
04454282
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | The Jikei University School of Medicine |
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Principal Investigator |
MAEKAWA Kihei Jikei Unive.Pediatr., professor, 小児科, 教授 (80056613)
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| Co-Investigator(Kenkyū-buntansha) |
OHASHI T. assistant, 小児科, 助手 (60160595)
TATSUSHIMA H. lecturer, 小児科, 講師 (70190460)
TOKORO T. lecturer, 小児科, 講師 (40112841)
ITO F. assistant professor, 小児科, 助教授 (10057010)
ETO Y. assistant professor, 小児科, 助教授 (50056909)
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| Project Period (FY) |
1992 – 1993
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| Keywords | Gaucher disease / Metachromatic / Krabbe's disease / genotype / gene therapy / demyelination / 脱髄 |
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| Research Abstract |
We investigated the genotype of Japanese Gaucher disease (GD), metachromatic leukodystrophy (MLD) to evaluate the correlation between genotype and phenotype, and to characterize the ethnicity. In 7 patients with type II GD, a new 754A missense mutation was identified in 3 cases heteroallelically.
A new heteroalleic 1070A missense mutation was found in 2 cases of Japanese patients with MLD.These two mutations have not been reported mong Jewish and Caucasian population, which suggests that the genotypes of GD and MLD in Japan is unique.
In order to evaluate the potential gene therapy for MLD, we constructed a retroviral vector for the transfer of the arylsulfatase cDNA, and transfected and expressed the gene in human MLD fibroblasts. As a result of gene transfer, the enzyme activity of MLD fibroblasts was increased about 70% of normal fibroblast level. Those observation demonstrates the feasibility of gene therapy for MLD.
To understand the cause of demyelination in Krabbe's disease (GLD), the neurotoxicity of psychosine in neural cell culture was investigated. By immunofluorescence staining method using an anti-neurofilament antibody, psychosine treated cells showed destruction of cytoskelton and pathy intracellular changes. An electron microscopic study showed swelling of mitochondria, desruption of cristae in mitochondria, and disappearance of microtubules and neuro-filaments. These data suggest that psychosine influences mitochondrial function, possibly through inhibition in the destruction of cellular components.
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