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.
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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.)
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Chemical References |
- Glial Fibrillary Acidic Protein
- Recombinant Proteins
- Green Fluorescent Proteins
- Aspartic Acid
- N-acetylaspartate
- Amidohydrolases
- aspartoacylase
- Phosphopyruvate Hydratase
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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)
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