Molecular Pathogenesis of Brain Damage and Gene Therapy in Genetic Leukodystrophy

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1. Pathogenesis of Leukodystrophy in Globoide Cell Leukodystrophy and Other1) Using animal model of Krabbe globoid cell leukodystrophy(GLD), we tried to identified the cause of leukodytrophy in twitcher mice. The cause of neural cell damage might be caused by the influx of intracellular calcium in such mice which was demonstrated by patch cramp method. The increased intracellular calcium resulted in the activation of cellular protease and hense damage the neural cells.2) We studied the clinical phnotype and genotype in metachromatic leukodystrophy and also identified novel genotype in two cases with MLD. Furthermore, we demonstrated that the G99D mutation was neruological severe type and consisted of 50% of all genotype of Japanese MLD.3) Japanese patients with Sjogren Larrson syndrome shows particular genotype in Japanese.4) We studied the genotype identifications in Fabry disease which were L16H, A37V, W209X, 342QIVS-1-1 etc.2. Cell therapy and gene therapy in genetic leukodystrophyGene therapy and cell therapy were carried out using Twitcher mice and Sly Mice.1) Twitcher mice were treated with adenovirus vector which was administered into intraventricle, during fetal period. The number of globoid cells were decreased in treated animals after the administration of viral vetor. Simultaneously, the amount of psychosine was decreased in treated animals.2) Neural stem cells obtained fromhuman fetal brains were injected into Sly mice brain and the accumulated compounds in Sly mice were decreased. The data suggest that neural stem cells were effective for the treatment of The CNS involvement in these neurological mutants.3) Injection of mesenchymal stem cells into Sly mice showed decreased storage Materials and effective for neurological mice.