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: S W J McPhee, J Francis, C G Janson, T Serikawa, K Hyland, E O Ong, S S Raghavan, A Freese, P Leone
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 135 Issue 1-2 Pg. 112-21 (Apr 27 2005) ISSN: 0169-328X [Print] Netherlands
• PMID: 15857674 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Glial Fibrillary Acidic Protein
• Recombinant Proteins
• Green Fluorescent Proteins
• Aspartic Acid
• N-acetylaspartate
• Amidohydrolases
• aspartoacylase
• Phosphopyruvate Hydratase

Topics

• Amidohydrolases (genetics, metabolism, therapeutic use)
• Analysis of Variance
• Animals
• Aspartic Acid (analogs & derivatives, metabolism)
• Behavior, Animal
• Brain (drug effects, virology)
• Canavan Disease (complications, virology)
• Dependovirus (genetics, 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
• Rats, Mutant Strains
• Recombinant Proteins (therapeutic use)
• Tremor (etiology, genetics, therapy)