Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease
Dominic J. Gessler, … , Reuben Matalon, Guangping Gao
Dominic J. Gessler, … , Reuben Matalon, Guangping Gao
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e90807. https://doi.org/10.1172/jci.insight.90807.
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Research Article Metabolism Therapeutics

Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

Abstract

Canavan disease (CD) is a debilitating and lethal leukodystrophy caused by mutations in the aspartoacylase (ASPA) gene and the resulting defect in N-acetylaspartate (NAA) metabolism in the CNS and peripheral tissues. Recombinant adeno-associated virus (rAAV) has the ability to cross the blood-brain barrier and widely transduce the CNS. We developed a rAAV-based and optimized gene replacement therapy, which achieves early, complete, and sustained rescue of the lethal disease phenotype in CD mice. Our treatment results in a super-mouse phenotype, increasing motor performance of treated CD mice beyond that of WT control mice. We demonstrate that this rescue is oligodendrocyte independent, and that gene correction in astrocytes is sufficient, suggesting that the establishment of an astrocyte-based alternative metabolic sink for NAA is a key mechanism for efficacious disease rescue and the super-mouse phenotype. Importantly, the use of clinically translatable high-field imaging tools enables the noninvasive monitoring and prediction of therapeutic outcomes for CD and might enable further investigation of NAA-related cognitive function.

Authors

Dominic J. Gessler, Danning Li, Hongxia Xu, Qin Su, Julio Sanmiguel, Serafettin Tuncer, Constance Moore, Jean King, Reuben Matalon, Guangping Gao

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Figure 2

Optimized gene replacement therapy normalizes motor function in Canavan disease knockout (CD KO) mice.

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Optimized gene replacement therapy normalizes motor function in Canavan ...
Each assay was performed with an independent group of CD KO mice. Mice (n = 24) were treated at P1 with 4 × 1011 genome copies into the facial vein using the 2nd or 3rd generation gene therapy and divided into 3 groups (n = 8 each) for each motor function assay. Shown are testing time points at P27 and P365 (see Supplemental Data for additional time points). (A) On accelerated rotarod, mice were trained for 2 consecutive days prior to the testing day. (B) Balance beam tests for deficits in equilibrium sense and for ataxia. Cut-off time point was 300 seconds. (C) Muscle/grip strength was tested on inverted screen for up to 300 seconds. Statistical analysis was performed using 1-way ANOVA with multiple comparison correction. Data are presented as the mean ± SD; for all motor assays, n = 6–8 at P27 and n = 8 at P375. ***P < 0.001, ****P < 0.0001. ns, not significant.