Canavan disease (CD) is an autosom al-recessive neurodegenerative disorder caused by mutations in the gene coding for the enzyme aspartoacylase (ASPA). ASPA catalyzes deacetylation of N-acetylaspartate (NAA), an abundant (~ 10 mM) and nervous system-specific amino acid derivative. CD is characterized by spongiform degeneration of the brain resulting in severe psychomotor retardation, with most affected children dying before the age of 10. The precise pathogenesis of CD remains unclear. The central hypothesis is that ASPA activity is required for myelin synthesis via liberating the NAA-derived acetate for the synthesis of acetyl CoA, which is used in the synthesis of the lipid portion of myelin. In this hypothesis, CD is thought to result from defective myelin synthesis caused by a deficiency in the supply of the NAAderived acetate. A number of studies, including our recent demonstration of the selective localization of ASPA in oligodendrocytes in the CNS, are consistent with the acetate deficiency hypothesis of CD. Furthermore, we have recently tested the acetate deficiency hypothesis in the murine model of CD (ASPA -/- ) directly by 1) determining acetate levels in the brain and 2) studying the myelin-associated lipid synthesis. The results showed that in CD mice brain acetate levels decreased by about 80% and synthesis of a number of myelin related lipids also decreased significantly. These results provided the first direct evidence in support of this hypothesis. A major implication of these findings is that acetate supplementation is likely to provide a simple and inexpensive therapeutic approach for CD. Toward this goal, we have made progress by finding that oral administration of glyceryl triacetate (Triacetin), an acetate precursor, caused acetate levels in the brain to increase by about 10- fold in 1-2 hours, and efforts to test whether or not acetate supplementation using glyceryl triacetate is effective as a treatment of CD is in progress. The Central hypothesis of this competitive renewal application remains the same as that of the previous application. This application involves additional specific aims focused on continuing our efforts toward acetate supplementation therapy for CD and testing additional aspects of CD pathogenesis as a follow up to the current findings. The immediate goals are 1) to continue our ongoing efforts to correct the acetate deficiency of CD using chronic GT A administration and to test its effect on the development of CD, 2) to characterize the acetate pathway of myelin lipid synthesis to further understand the functional roles of NAA and 3) to determine the CNS tissue compartments in which NAA is increased in CD as a first step to understand the role of increased NAA in CD pathology. These studies are likely to lead to a simple and inexpensive method for the treatment of CD and also advance our knowledge on the functional roles of NAA and the relationship of increased NAA to CD pathology.
| Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R et al. (2010) Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease. J Inherit Metab Dis 33:195-210 |
| Madhavarao, C N; Arun, P; Anikster, Y et al. (2009) Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis 32:640 |
