Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease
Dominic J. Gessler, Danning Li, Hongxia Xu, Qin Su, Julio Sanmiguel, Serafettin Tuncer, Constance Moore, Jean King, Reuben Matalon, Guangping Gao
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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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 5

Dose reduction of 3rd generation therapy achieves efficacious disease rescue in Canavan disease knockout (CD KO) mice.

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Dose reduction of 3rd generation therapy achieves efficacious disease re...
CD KO mice were treated at P1 via facial vein with either 4 × 1010 (0.1X), 1.33 × 1011 (0.3X), or 4 × 1011 (1X) genome copies of 3rd generation gene replacement therapy. (A) MRI T2 sequences of different brain regions are shown with WT and untreated (KO) control mice. All mice were imaged at P25 (n = 3). (B) Total N-acetylaspartate (tNAA) levels of the same mice as in A were quantified by magnetic resonance spectrometry at P25 and normalized against total creatine (tCr) (n = 3). (C) Dose-dependent neuropathology assessed by H&E staining of brain regions of mice at P25 treated with 3rd generation or full-dose 1st generation vectors. WT and KO were used as controls (n = 3; original magnification, ×10). (D) Dose-dependent motor function was assessed on rotarod, balance beam, and inverted screen at P27 and P90 (n = 6–8). Cx/St, cortex/striatum; Hpc/Th, hippocampus/thalamus; Mb, midbrain; Cbl/Po, cerebellum/pons; Cx, cortex; DG, dentate gyrus; Th, thalamus; Po, pons. Statistical analysis was performed using 1-way ANOVA with multiple comparison correction. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. ns, not significant.