Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease

• Published in: Brain research. Molecular brain research. Vol. 135; no. 1; pp. 112 - 121
• Main Authors: McPhee, S.W.J., Francis, J., Janson, C.G., Serikawa, T., Hyland, K., Ong, E.O., Raghavan, S.S., Freese, A., Leone, P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 27.04.2005; Elsevier
• Subjects: Amidohydrolases - genetics; Amidohydrolases - metabolism; Amidohydrolases - therapeutic use; Analysis of Variance; Animals; Aspartic Acid - analogs & derivatives; Aspartic Acid - metabolism; Aspartoacylase; Behavior, Animal; Biological and medical sciences; Brain - drug effects; Brain - virology; Canavan; Canavan Disease - complications; Canavan Disease - virology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dependovirus - genetics; Dependovirus - physiology; Disease Models, Animal; Gene therapy; Gene Transfer Techniques; Genetic Vectors - physiology; Glial Fibrillary Acidic Protein - metabolism; Green Fluorescent Proteins - metabolism; Immunohistochemistry - methods; Leukodystrophy; Locomotion - physiology; Medical sciences; NAA; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Phosphopyruvate Hydratase - metabolism; Psychomotor Performance - physiology; Rats; Rats, Mutant Strains; Recombinant Proteins - therapeutic use; Tremor - etiology; Tremor - genetics; Tremor - therapy; Tremor rat; Disorders of the nervous system; Canavan; Leukodystrophy; Aspartoacylase; Gene therapy; Tremor rat; NAA; Animal model; Gangliosidosis; Rat; Lipids; Sphingolipidosis; Enzymopathy; Involuntary movement; Canavan disease; Degenerative disease; Neurological disorder; Lipoidosis; Nervous system diseases; Tremor; Enzyme; Rodentia; Metabolic diseases; Motor control; Cerebral disorder; Genetic disease; Vertebrata; Mammalia; Animal; Central nervous system disease; Transfer; Hydrolases
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/j.molbrainres.2004.12.007

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.