title: Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease.
abstract: The tremor rat is a spontaneous epilepsy model with a seizure phenotype caused by a deletion in the aspartoacylase (ASPA) gene. The absence of ASPA expression in these animals results in undetectable levels of enzyme activity and the accumulation of the substrate N-acetyl-aspartate (NAA) in brain, leading to generalized myelin vacuolation and severe motor and cognitive impairment. In support of human gene therapy for CD, recombinant adeno-associated viral vector (AAV-2) expressing ASPA was stereotactically delivered to the tremor rat brain and effects on the mutant phenotype were measured. AAV-ASPA gene transfer resulted in elevated aspartoacylase bioactivity compared to untreated mutant animals and elicited a significant decrease in the pathologically elevated whole-brain NAA levels. Assessment of motor function via quantitative rotorod testing demonstrated that rats injected with AAV-ASPA significantly improved on tests of balance and coordinated locomotion compared to animals receiving control vectors. This study provides evidence that AAV-2-mediated aspartoacylase gene transfer to the brain improves biochemical and behavioral deficits in tremor rat mutants (tm/tm) and supports the rationale of human gene transfer for Canavan disease.
authors.affiliation: Cell and Gene Therapy Center, UMDNJ-Robert Wood Johnson Medical School, 401 Haddon Avenue, Suite #395, Camden, NJ 08103, USA. scott.mcphee@umdnj.edu
authors.forename: S W J
authors.initials: SW
authors.lastname: McPhee
authors.forename: J
authors.initials: J
authors.lastname: Francis
authors.forename: C G
authors.initials: CG
authors.lastname: Janson
authors.forename: T
authors.initials: T
authors.lastname: Serikawa
authors.forename: K
authors.initials: K
authors.lastname: Hyland
authors.forename: E O
authors.initials: EO
authors.lastname: Ong
authors.forename: S S
authors.initials: SS
authors.lastname: Raghavan
authors.forename: A
authors.initials: A
authors.lastname: Freese
authors.forename: P
authors.initials: P
authors.lastname: Leone
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001522:Behavior, Animal; D001921:Brain / Q000187:drug effects / Q000821:virology; D017825:Canavan Disease / Q000150:complications / Q000821:virology; D000229:Dependovirus / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008124:Locomotion / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D011922:Rats, Mutant Strains; D011994:Recombinant Proteins / Q000627:therapeutic use; D014202:Tremor / Q000209:etiology / Q000235:genetics / Q000628:therapy*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase; D010751:Phosphopyruvate Hydratase