Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.
Identifieur interne : 002764 ( PubMed/Corpus ); précédent : 002763; suivant : 002765Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.
Auteurs : Christopher D. Herzog ; Biplob Dass ; James E. Holden ; James Stansell ; Mehdi Gasmi ; Mark H. Tuszynski ; Raymond T. Bartus ; Jeffrey H. KordowerSource :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2007.
English descriptors
- KwdEn :
- Aging (physiology), Animals, Corpus Striatum (metabolism), Corpus Striatum (pathology), Corpus Striatum (virology), Dependovirus (metabolism), Disease Models, Animal, Dopamine (metabolism), Female, Fluorodeoxyglucose F18 (diagnostic use), Fluorodeoxyglucose F18 (pharmacokinetics), Macaca mulatta, Neurturin (therapeutic use), Parkinson Disease (metabolism), Parkinson Disease (pathology), Parkinson Disease (virology), Positron-Emission Tomography, Radiopharmaceuticals (diagnostic use), Radiopharmaceuticals (pharmacokinetics), Substantia Nigra (metabolism), Substantia Nigra (pathology), Substantia Nigra (virology).
- MESH :
- chemical , diagnostic use : Fluorodeoxyglucose F18, Radiopharmaceuticals.
- chemical , metabolism : Dopamine.
- metabolism : Corpus Striatum, Dependovirus, Parkinson Disease, Substantia Nigra.
- pathology : Corpus Striatum, Parkinson Disease, Substantia Nigra.
- chemical , pharmacokinetics : Fluorodeoxyglucose F18, Radiopharmaceuticals.
- physiology : Aging.
- chemical , therapeutic use : Neurturin.
- virology : Corpus Striatum, Parkinson Disease, Substantia Nigra.
- Animals, Disease Models, Animal, Female, Macaca mulatta, Positron-Emission Tomography.
Abstract
Neurturin (NTN) is a potent survival factor for midbrain dopaminergic neurons. CERE-120, an adeno-associated virus type 2 (AAV2) vector encoding human NTN (AAV2-NTN), is currently being developed as a potential therapy for Parkinson's disease. This study examined the bioactivity and safety/tolerability of AAV2-NTN in the aged monkey model of nigrostriatal dopamine insufficiency. Aged rhesus monkeys received unilateral injections of AAV2-NTN into the caudate and putamen, with each animal therefore serving as its own control. Robust expression of NTN within the nigrostriatal system was observed 8 months postadministration. (18)F-fluorodopa imaging using positron emission tomography revealed statistically significant increases in (18)F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. In addition, at 8 months postadministration, a significant enhancement in tyrosine hydroxylase immunoreactive fibers and an increase in the number of tyrosine hydroxylase immunoreactive cells was observed in the AAV2-NTN injected striatum compared with the uninjected side. Robust activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra was also observed. Histopathological analyses revealed no adverse effects of AAV2-NTN in the brain. Collectively, these results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2-NTN may have therapeutic benefit for Parkinson's disease.
DOI: 10.1002/mds.21503
PubMed: 17443702
Links to Exploration step
pubmed:17443702Le document en format XML
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<author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name>
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<author><name sortKey="Stansell, James" sort="Stansell, James" uniqKey="Stansell J" first="James" last="Stansell">James Stansell</name>
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<author><name sortKey="Gasmi, Mehdi" sort="Gasmi, Mehdi" uniqKey="Gasmi M" first="Mehdi" last="Gasmi">Mehdi Gasmi</name>
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<front><div type="abstract" xml:lang="en">Neurturin (NTN) is a potent survival factor for midbrain dopaminergic neurons. CERE-120, an adeno-associated virus type 2 (AAV2) vector encoding human NTN (AAV2-NTN), is currently being developed as a potential therapy for Parkinson's disease. This study examined the bioactivity and safety/tolerability of AAV2-NTN in the aged monkey model of nigrostriatal dopamine insufficiency. Aged rhesus monkeys received unilateral injections of AAV2-NTN into the caudate and putamen, with each animal therefore serving as its own control. Robust expression of NTN within the nigrostriatal system was observed 8 months postadministration. (18)F-fluorodopa imaging using positron emission tomography revealed statistically significant increases in (18)F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. In addition, at 8 months postadministration, a significant enhancement in tyrosine hydroxylase immunoreactive fibers and an increase in the number of tyrosine hydroxylase immunoreactive cells was observed in the AAV2-NTN injected striatum compared with the uninjected side. Robust activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra was also observed. Histopathological analyses revealed no adverse effects of AAV2-NTN in the brain. Collectively, these results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2-NTN may have therapeutic benefit for Parkinson's disease.</div>
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<Abstract><AbstractText>Neurturin (NTN) is a potent survival factor for midbrain dopaminergic neurons. CERE-120, an adeno-associated virus type 2 (AAV2) vector encoding human NTN (AAV2-NTN), is currently being developed as a potential therapy for Parkinson's disease. This study examined the bioactivity and safety/tolerability of AAV2-NTN in the aged monkey model of nigrostriatal dopamine insufficiency. Aged rhesus monkeys received unilateral injections of AAV2-NTN into the caudate and putamen, with each animal therefore serving as its own control. Robust expression of NTN within the nigrostriatal system was observed 8 months postadministration. (18)F-fluorodopa imaging using positron emission tomography revealed statistically significant increases in (18)F-fluorodopa uptake in the injected striatum compared with the uninjected side at 4 and 8 months. In addition, at 8 months postadministration, a significant enhancement in tyrosine hydroxylase immunoreactive fibers and an increase in the number of tyrosine hydroxylase immunoreactive cells was observed in the AAV2-NTN injected striatum compared with the uninjected side. Robust activation of phosphorylated extracellular signal-regulated kinase immunoreactivity in the substantia nigra was also observed. Histopathological analyses revealed no adverse effects of AAV2-NTN in the brain. Collectively, these results are consistent with the neurotrophic effects of NTN on the dopaminergic nigrostriatal system and extend the growing body of evidence supporting the concept that AAV2-NTN may have therapeutic benefit for Parkinson's disease.</AbstractText>
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