Canavan disease (CD) is an incurable, progressive leukodystrophy that develops in infancy as the result of Aspa mutations which disrupt the functionality of aspartoacylase (ASPA). ASPA is an oligodendroglial-enriched enzyme responsible for cleaving the abundant brain amino acid, N-acetyl-L-aspartate (NAA). As a result, infants and children with CD are unable to metabolize NAA and have extremely elevated levels of brain NAA accompanied by spongiform white matter degeneration, motor and cognitive delays, ataxia, and progressive neuronal atrophy. Attempts at ASPA gene replacement have proven largely ineffective, resulting in an urgent need to define new therapeutic targets for this fatal disease.We hypothesize that the primary mechanism of Canavan disease pathophysiology is brain toxicity resulting from elevated NAA. Indeed, constitutive knockout of the NAA-synthesizing enzyme NAT8L (N-acetyltransferase-8-like) is protective against development of vacuolar leukodystrophy and ataxia in the well characterized CD model mouse (Aspanur7/nur7, “CD mouse”). The current body of work is based upon this “NAA toxicity” hypothesis, with an emphasis on developing and testing translational therapies for CD. In the first study, I treated adult, symptomatic CD mice with an antisense oligonucleotide (ASO) targeting the knockdown of NAT8L. Intracisternal delivery of this NAT8L ASO lowers NAA levels and improves motor function and brain vacuolation within 2 weeks. In the second study, we identified a sodium-coupled dicarboxylate plasma membrane transporter (NaDC3) with a high affinity for NAA that is exclusively expressed by astrocytes in the parenchyma. Operating under the hypothesis that vacuolar degeneration and fluid retention in CD is the result of sodium/NAA overloading specifically in astrocytes, I generated CD mice with constitutive ablation of NaDC3. Indeed, NaDC3 knockout prevents the development of leukodystrophy and ataxia in CD mice. Ongoing studies seek to determine the benefit of astroglial-specific conditional NaDC3 knockout, given that NaDC3 is also highly expressed in the meninges and kidney. The strong astroglial phenotypes observed in CD, coupled with Purkinje cell dendritic abnormalities that I was the first to report in CD mice, led me to the radial astrocytes of the cerebellum, the Bergmann glia. I hypothesize that Bergmann glia exert a non-cell autonomous mechanism for Purkinje cell dysfunction in CD. In the third and final study, I report profound Bergmann glia structural damage in CD mice in concert with prolonged, less frequent calcium signals in Bergmann glial processes. Importantly, NAT8L ASO therapy improves the structural integrity of both Bergmann glia and Purkinje cells. Overall, I demonstrate that lowering NAA, either by blocking its synthesis or cellular uptake, is therapeutic for CD mice. I also present a novel, astroglial-centric perspective on CD pathogenesis. We are encouraged by the translatability of these findings, and as such, I conclude with a summary of remaining questions in the field of CD research as well as future directions for CD therapy.