KNOCKOUT MODEL FOR CANAVAN DISEASE

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DESCRIPTION (from Abstract): The deficiency of aspartoacylase (ASPA) and the accumulation of N-acetylaspartic acid (NAA) in Canavan disease (CD), was discovered in our laboratory in 1988. Since then we have diagnosed more than 170 patients with Canavan disease, of whom 2/3 are of Ashkenazi Jewish extraction. The carrier rate among Ashkenazi Jewish individuals as determined in our laboratory is 1/36, suggesting that Canavan disease is much more common, even in non-Jewish populations, than expected. Aspartoacylase was purified, and full length human, bovine and mouse ASPA cDNA have been isolated and the human ASPA gene has been localized to the short arm of chromosome 17. The purpose of this proposal is: 1) Create a mouse model for Canavan disease. The mouse ASPA gene has been characterized. Disruption in the coding sequence will be introduced for the purpose of the creation of a knock-out mouse. 2) Developmental and behavioral studies will be done so the phenotype of the knock-out mouse model will be determined. 2) Biochemical studies will measure urinary, blood and brain NAA. Brain ASPA activity will also be determined. Brain NAA will also be determined in vivo without sacrificing the animals, which would be important for possible future therapies. 4) Neuropathological parameter will be determined, in an attempt to define the onset of histopathological changes in the mouse brain. The exact cellular localization of aspartoacylase in brain is unknown, although it is in the white matter. The use of the transporter gene will allow for the cellular localization of ASPA. The animal model will be important in establishing the timing of clinical AM histopathological changes in the mouse. 5) The knock-out mouse will be used in future studies for determining the metabolic role of NAA in brain, for experimentation with enzyme therapy and gene therapy.