RRC ID 142
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
Rats TRM/Kyo(strainID=11)