Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease
Authors
Gessler, Dominic J.Li, Danning
Xu, Hongxia
Su, Qin
Sanmiguel, Julio
Tuncer, Serafettin
Moore, Constance M.
King, Jean A.
Matalon, Reuben
Gao, Guangping
UMass Chan Affiliations
Center for Comparative Neuroimaging, Department of PsychiatryHorae Gene Therapy Center
Department of Microbiology and Physiological Systems
Document Type
Journal ArticlePublication Date
2017-02-09
Metadata
Show full item recordAbstract
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.Source
JCI Insight. 2017 Feb 9;2(3):e90807. doi: 10.1172/jci.insight.90807. Link to article on publisher's siteDOI
10.1172/jci.insight.90807Permanent Link to this Item
http://hdl.handle.net/20.500.14038/46221PubMed ID
28194442Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.90807