Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease
Open accessAbstract
Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.
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AAV-mediated transgene expression has peaked to stable levels by 3 weeks after vector injection.
“At 3 weeks following vector injection, when AAV-mediated transgene expression has peaked to stable levels (Klugmann et al., 2005a), animals were killed and the brains assessed by immunohistochemistry to detect GFP in immuno-identified neurons, oligodendrocytes, and astrocytes.”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as Klugmann et al., 2005a
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Long-term follow-up after gene therapy for canavan disease
Leone, P., Shera, D., McPhee, S. W. J., Francis, J. S., Kolodny, E. H., Bilaniuk, L. T., Wang, D.-J., Assadi, M., Goldfarb, O., Goldman, H. W., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003454 · Cited by 307 · see citing works
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Self-citationGlial promoter selectivity following AAV-delivery to the immature brain
von Jonquieres, G., Mersmann, N., Klugmann, C. B., Harasta, A. E., Lutz, B., Teahan, O., Housley, G. D., Fröhlich, D., Krämer-Albers, E.-M., & Klugmann, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065646 · Cited by 133 · see citing works
Self-citationGessler, D. J., Li, D., Xu, H., Su, Q., Sanmiguel, J., Tuncer, S., Moore, C., King, J., Matalon, R., & Gao, G. (2017) · JCI Insight · doi:10.1172/jci.insight.90807 · Cited by 70 · see citing works
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- Authors
- Klugmann, M., Leichtlein, C. B., Symes, C. W., Serikawa, T., Young, D., & During, M. J.
- Affiliations
- University of Auckland (NZ)
- Kyoto University (JP)
- Corresponding author
- Klugmann, Matthias
- During, Matthew J.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 11
- Issue
- 5
- Pages
- 745-753
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2040779106
- Cited by
- 55
- References
- 1
- Citations by year
- 2026: 1 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 3 · 2012: 1
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Canavan disease, aspartoacylase, N-acetylaspartate, AAV gene delivery, demyelination, hypomyelination, motor impairment, seizures, neuronal hyperexcitation, oligodendrocyte dysfunction, central nervous system neurons, leukodystrophy
- MeSH terms
- Dependovirus, Amidohydrolases, Animals, Aspartic Acid, Central Nervous System, Disease Models, Animal, Female, Male, Motor Neurons, Myelin Sheath, Seizures, Gene Expression, Canavan Disease, Rats
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