McPhee SW, Francis J, Janson CG, Serikawa T, Hyland K, Ong EO, Raghavan SS, Freese A, Leone P.
Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease.
Brain Res. Mol. Brain Res.
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.
Amidohydrolases / genetics
Amidohydrolases / metabolism*
Amidohydrolases / therapeutic use
Analysis of Variance
Aspartic Acid / analogs & derivatives*
Aspartic Acid / metabolism
Brain / drug effects
Brain / virology
Canavan Disease / complications
Canavan Disease / virology
Dependovirus / genetics
Dependovirus / physiology
Disease Models, Animal
Gene Transfer Techniques
Genetic Vectors / physiology
Glial Fibrillary Acidic Protein / metabolism
Green Fluorescent Proteins / metabolism
Immunohistochemistry / methods
Locomotion / physiology
Phosphopyruvate Hydratase / metabolism
Psychomotor Performance / physiology
Rats, Mutant Strains
Recombinant Proteins / therapeutic use
Tremor / etiology
Tremor / genetics
Tremor / therapy*