Reference - Detail
RRC ID | 142 |
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Author | McPhee SW, Francis J, Janson CG, Serikawa T, Hyland K, Ong EO, Raghavan SS, Freese A, Leone P. |
Title | Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. |
Journal | Brain Res Mol Brain Res |
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. |
Volume | 135(1-2) |
Pages | 112-21 |
Published | 2005-4-27 |
DOI | 10.1016/j.molbrainres.2004.12.007 |
PII | S0169-328X(04)00629-1 |
PMID | 15857674 |
MeSH | Amidohydrolases / genetics Amidohydrolases / metabolism* Amidohydrolases / therapeutic use Analysis of Variance Animals Aspartic Acid / analogs & derivatives* Aspartic Acid / metabolism Behavior, Animal 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 Rats, Mutant Strains Recombinant Proteins / therapeutic use Tremor / etiology Tremor / genetics Tremor / therapy* |
Times Cited | 24 |
Resource | |
Rats | TRM/Kyo(strainID=11) |