CANAVAN DISEASE PATHOGENESIS AND TREATMENT

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DESCRIPTION (adapted from applicant's abstract): Canavan disease (CD) is an autosomal-recessive neurodegenerative disorder that develops after birth and results in death usually before age 10. CD is found worldwide, but the majority of patients so far identified are of Ashkenazi Jewish descent. The CD carrier frequency in this population is estimated to be 1 in 38, which is as high as that of Tay Sachs disease. CD is caused by mutations in the gene coding for the enzyme aspartoacylase (ASPA) that degrades N-acetylaspartate (NAA), a highly abundant (5-10 mM) and nervous system specific metabolite, into acetate and aspartate. However, neither the pathogenesis of CD nor the functions of NAA have been defined. Further, no animal model for exploration of potential treatment for CD is available. The investigators propose to make a mouse model for CD and test the hypothesis that CD pathogenesis involves reduced availability of NAA-derived acetate for fatty acid/lipid synthesis during myelination. Making the animal model for CD involves generating heterozygous and homozygous mice in which the ASPA gene is knocked out. Development of CD will be confirmed using a behavioral test and subsequent light and electron microscopic analysis of the brain. The hypothesis mentioned above will be tested in the animal model by determining whether or not treatment with acetate, a fatty acid precursor which can easily enter brain, prevents development of CD in the animal model. Based on the endogenous and nontoxic nature of acetate, and the urgency for a treatment for CD, acetate administration will be optimized in normal mice with regard to dosage and safety to enable clinical trials of acetate as soon as possible. Toward these goals, they have successfully cloned and expressed mouse ASPA cDNA by a PCR strategy, and have identified an artificial bacterial chromosome containing the complete ASPA gene. Sequencing of the genomic clone is in progress. Successful completion of the proposed study would establish the use of acetate for the treatment of CD. Further, the methodological innovations of the proposed study will have a major impact in the field by stimulating research into the nervous system specific roles of NAA and N-acetylaspartylglutamate, a putative neurotransmitter derived from NAA.