title: rAAV Gene Therapy in a Canavan's Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System.
abstract: Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Seemin Seher
authors.initials: SS
authors.lastname: Ahmed
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Schattgen
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Frakes
authors.affiliation: The Center for Comparative Neuroimaging, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Elif M
authors.initials: EM
authors.lastname: Sikoglu
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Mouse Specifics, Inc., Framingham, Massachusetts, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.affiliation: Biology Department, Boston College, Chestnut Hill, Massachusetts, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Denninger
authors.affiliation: Biology Department, Boston College, Chestnut Hill, Massachusetts, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kaspar
authors.affiliation: Department of Pediatrics, Biochemical and Molecular Genetics, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA. Electronic address: Guangping.Gao@umassmed.edu.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
mesh_terms: D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D017825:Canavan Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D009928:Organ Specificity; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000581:Amidohydrolases; C019751:aspartoacylase