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JCI Insight. 2017 Feb 9;2(3):e90807. doi: 10.1172/jci.insight.90807.

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

Author information

1
Department of Microbiology and Physiological Systems.
2
Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
3
University Hospital Heidelberg, Centre for Child and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine.
4
Ruprecht-Karls University, Medical School, Heidelberg, Germany.
5
University of Science and Technology of Kunming, China.
6
Heinrich Heine University, Medical School, Duesseldorf, Germany.
7
Center for Comparative Neuroimaging, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
8
University of Texas Medical Branch, Galveston, USA.
9
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

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.

Conflict of interest statement

G. Gao is a co-founder of Voyager Therapeutics, a biopharmaceutical company, and holds equity in the company. G. Gao and D.J. Gessler are inventors on a patent pending (PCT/US2016/058197) that is relevant to the content of this manuscript, which may result in potential royalties if granted and licensed.

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