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

S. W.J. McPhee, J. Francis, C. G. Janson, T. Serikawa, K. Hyland, E. O. Ong, S. S. Raghavan, A. Freese, P. Leone

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35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalMolecular Brain Research
Issue number1-2
StatePublished - Apr 27 2005

Bibliographical note

Funding Information:
This research was supported by the Neurological Foundation of New Zealand, The University of Auckland, and Hunter's Hope Foundation, with additional support from The Canavan Foundation, Canavan Research Illinois, Canavan Research Fund, and Jacob's Cure. The authors thank R. Horst, R. Bland, H. Fitzsimons, T. Lawlor, and Y. Shifman for technical support. The polyclonal ASPA antibody preparation was a gift from Dr. M.A.A. Namboodiri (USUHS, Bethesda, MD), which was produced under RO1 grant support from NINDS (NS39387).


  • Aspartoacylase
  • Canavan
  • Gene therapy
  • Leukodystrophy
  • NAA
  • Tremor rat


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