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

doi:10.1016/j.molbrainres.2004.12.007

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

Neurology

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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.

Original language	English (US)
Pages (from-to)	112-121
Number of pages	10
Journal	Molecular Brain Research
Volume	135
Issue number	1-2
DOIs	https://doi.org/10.1016/j.molbrainres.2004.12.007
State	Published - 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).

Keywords

Aspartoacylase
Canavan
Gene therapy
Leukodystrophy
NAA
Tremor rat

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10.1016/j.molbrainres.2004.12.007

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

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.",

keywords = "Aspartoacylase, Canavan, Gene therapy, Leukodystrophy, NAA, Tremor rat",

author = "McPhee, {S. W.J.} and J. Francis and Janson, {C. G.} and T. Serikawa and K. Hyland and Ong, {E. O.} and Raghavan, {S. S.} and A. Freese and P. Leone",

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).",

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AU - McPhee, S. W.J.

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AU - Janson, C. G.

AU - Serikawa, T.

AU - Hyland, K.

AU - Ong, E. O.

AU - Raghavan, S. S.

AU - Freese, A.

AU - Leone, P.

N1 - 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).

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N2 - 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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Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease

Abstract

Bibliographical note

Keywords

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