title: RedirectingN-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 inN-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.affiliation: Department of Microbiology and Physiological Systems.|Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.|University Hospital Heidelberg, Centre for Child and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine.|Ruprecht-Karls University, Medical School, Heidelberg, Germany.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Gessler
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
authors.forename: Danning
authors.initials: D
authors.lastname: Li
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.|University of Science and Technology of Kunming, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Xu
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Sanmiguel
authors.affiliation: Heinrich Heine University, Medical School, Duesseldorf, Germany.
authors.forename: Serafettin
authors.initials: S
authors.lastname: Tuncer
authors.affiliation: Center for Comparative Neuroimaging, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Moore
authors.affiliation: Center for Comparative Neuroimaging, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: King
authors.affiliation: University of Texas Medical Branch, Galveston, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.affiliation: Department of Microbiology and Physiological Systems.|Horae Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.|State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
mesh_terms: D000581:Amidohydrolases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives; D001812:Blood-Brain Barrier / Q000378:metabolism; D017825:Canavan Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D002490:Central Nervous System; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D009836:Oligodendroglia / Q000378:metabolism
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase