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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

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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 3

Optimized gene replacement therapy leads to sustained rescue of neuropathology and biomarker expression.

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Optimized gene replacement therapy leads to sustained rescue of neuropat...
Mice were treated at P1 intravenously with 4 × 1011 genome copies of 1st, 2nd, or 3rd generation vector. Data from 1 year after treatment are shown in comparison to WT. (A) MRI imaging comparing WT and all 3 vector generations. (B) H&E staining shows degree of neuropathologic changes (original magnification, ×10; insets, ×40). (C) Magnetic resonance spectrometry (MRS) analysis of brain total N-acetylaspartate (tNAA) levels normalized against total creatine (tCr) at 1 year of age. (D) NAA levels of urine normalized against creatinine at 1 year of age as quantified by MRS. Statistical analysis was performed using 1-way ANOVA with multiple comparison correction. Data are presented as the mean ± SD, n = 3. ****P < 0.0001. ns, not significant.

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