MRUMRS of a Mouse Model for Canavan Disease

Introduction Canavan disease (CD) is an autosomal recessive leukodystrophy associated with spongy degeneration of the white matter of the brain, leading to mental retardation, megalencephaly and early death {I). Brain histology in CD shows characteristic spongy degeneration of the white matter and astrocytic swelling, while neurons are spared. Aspartoacylase (ASPA) deficiency is the basic defect in CD. This enzyme hydrolyzes N-acetylaspartic acid (NAA) to aspartate and acetate. N-Acetylaspartic acid is abundantly synthesized in brain cells in human and other mammals. How a deficiency in the hydrolysis of NAA leads to spongy degeneration and the phenotypic characteristics of Canavan disease is not known. Here, we characterize a mouse model for human Canavan disease generated by inactivating the murine ASPA gene by homologous recombination in embryonic stem cells. This model can be used for two main purposes: 1) to study the role of NAA in brain, and whether levels of this compound can be modulated. 2) to test gene therapy approaches, direct enzyme delivery and other therapeutic modalities so that a similar therapy could be developed for Canavan disease in children.