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 7

High-field imaging noninvasively evaluates therapy outcomes.

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High-field imaging noninvasively evaluates therapy outcomes. Male mice w...
Male mice were treated at P1 and imaged at P25, comparing untreated Canavan disease knockout (CD KO) mice, WT mice, and treated (Tx) CD KO mice (n = 8–10 each). (A) Representative images are shown for tractography of the corpus callosum. (B) Shown are the fractional anisotropy (FA) values for left and right external capsule (EC) and corpus callosum (CC). KO, untreated CD KO mice. (C) Nineteen brain regions were selected to analyze resting state-functional MRI (rs-fMRI) results and mapped on a sagittal brain map. Green and black dots indicate cortical and subcortical brain regions, respectively. Green lines display all connections that involve cortical regions and red lines show subcortical connections only. (D) T-score statistics of rs-fMRI are shown that indicate differences between corresponding brain regions and overall brain activity (displayed in C). (E) Total N-acetylaspartate (tNAA) normalized against total creatine (tCr) was measured in all mice that underwent diffusion tensor imaging and rs-fMRI imaging. (F) Overall functional connectivity (untreated 31, WT 21, treated 19) was correlated to the average accelerated rotarod performance in seconds (Figure 3A, P27) and analyzed via linear regression analysis (R2 = 0.89). PL, prelimbic area; MC, motor cortex; NAc, nucleus accumbens; SSC, somatosensory cortex; CPu, caudoputamen; SeN, septal nuclei; AgIA, agranular insular area; Amy, amygdalar nuclei; Hpc, hippocampus; Th, thalamus; Hyp, hypothalamus; VC, visual cortex; CA1, cornu ammonis; MMN, medial mammillary nucleus; DG, dentate gyrus; TAC, temporal association cortex; Sub, subiculum; PNc, pontine nuclei. Statistical analysis was performed using 1-way ANOVA with multiple comparison correction for B and E and correlation analysis for F. Data are presented as the mean ± SD, n = 8–10. *P < 0.05, ***P < 0.001, ****P < 0.0001. ns, not significant.