Bioactivity of AAV2‐neurturin gene therapy (CERE‐120): Differences between Parkinson's disease and nonhuman primate brains
Identifieur interne : 001786 ( Main/Exploration ); précédent : 001785; suivant : 001787Bioactivity of AAV2‐neurturin gene therapy (CERE‐120): Differences between Parkinson's disease and nonhuman primate brains
Auteurs : Raymond T. Bartus [États-Unis] ; Christopher D. Herzog [États-Unis] ; Yaping Chu [États-Unis] ; Alistair Wilson [États-Unis] ; Lamar Brown [États-Unis] ; Joao Siffert [États-Unis] ; Eugene M. Johnson Jr. [États-Unis] ; C. Warren Olanow [États-Unis] ; Elliott J. Mufson [États-Unis] ; Jeffrey H. Kordower [États-Unis]Source :
- Movement Disorders [ 0885-3185 ] ; 2011-01.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
- Aged, Animals, Biological transport, Corpus Striatum (metabolism), Dependovirus (genetics), Dependovirus (metabolism), Disease Models, Animal, Encephalon, Functional Laterality, Gene Expression Regulation (drug effects), Gene therapy, Genetic Therapy (methods), Humans, MPTP Poisoning (chemically induced), MPTP Poisoning (metabolism), MPTP Poisoning (pathology), MPTP Poisoning (therapy), Macaca mulatta, Male, Middle Aged, Nervous system diseases, Neurotrophic factor, Neurturin (genetics), Neurturin (metabolism), Neurturin (therapeutic use), Parkinson Disease (metabolism), Parkinson Disease (pathology), Parkinson Disease (therapy), Parkinson disease, Primates, Repair, Tyrosine 3-Monooxygenase (metabolism), axonal transport, neural repair, neurodegeneration, neurotrophic factors, translational research.
- MESH :
- chemical , genetics : Neurturin.
- chemically induced : MPTP Poisoning.
- drug effects : Gene Expression Regulation.
- genetics : Dependovirus.
- metabolism : Corpus Striatum, Dependovirus, MPTP Poisoning, Neurturin, Parkinson Disease, Tyrosine 3-Monooxygenase.
- methods : Genetic Therapy.
- pathology : MPTP Poisoning, Parkinson Disease.
- chemical , therapeutic use : Neurturin.
- therapy : MPTP Poisoning, Parkinson Disease.
- Aged, Animals, Disease Models, Animal, Functional Laterality, Humans, Macaca mulatta, Male, Middle Aged.
Abstract
Background: AAV2‐neurturin (CERE‐120) is designed to deliver the neurotrophic‐factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic‐factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). Methods: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2‐neurturin in brains of PD patients versus those of nonhuman primates similarly treated. Results: NRTN‐immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral‐NRTN was observed in all monkeys. NRTN‐expression was associated with occasional, sparse TH‐induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH‐induction throughout the nigrostriatal neurons. Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic‐factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon‐transport deficits reduced the bioactivity of AAV2‐NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic‐factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. © 2010 Movement Disorder Society
Url:
DOI: 10.1002/mds.23442
Affiliations:
- États-Unis
- Californie, Illinois, Missouri (État), État de New York
- Saint-Louis (Missouri)
- École de médecine (Université Washington de Saint-Louis)
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Le document en format XML
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<term>Animals</term>
<term>Biological transport</term>
<term>Corpus Striatum (metabolism)</term>
<term>Dependovirus (genetics)</term>
<term>Dependovirus (metabolism)</term>
<term>Disease Models, Animal</term>
<term>Encephalon</term>
<term>Functional Laterality</term>
<term>Gene Expression Regulation (drug effects)</term>
<term>Gene therapy</term>
<term>Genetic Therapy (methods)</term>
<term>Humans</term>
<term>MPTP Poisoning (chemically induced)</term>
<term>MPTP Poisoning (metabolism)</term>
<term>MPTP Poisoning (pathology)</term>
<term>MPTP Poisoning (therapy)</term>
<term>Macaca mulatta</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Nervous system diseases</term>
<term>Neurotrophic factor</term>
<term>Neurturin (genetics)</term>
<term>Neurturin (metabolism)</term>
<term>Neurturin (therapeutic use)</term>
<term>Parkinson Disease (metabolism)</term>
<term>Parkinson Disease (pathology)</term>
<term>Parkinson Disease (therapy)</term>
<term>Parkinson disease</term>
<term>Primates</term>
<term>Repair</term>
<term>Tyrosine 3-Monooxygenase (metabolism)</term>
<term>axonal transport</term>
<term>neural repair</term>
<term>neurodegeneration</term>
<term>neurotrophic factors</term>
<term>translational research</term>
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<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Corpus Striatum</term>
<term>Dependovirus</term>
<term>MPTP Poisoning</term>
<term>Neurturin</term>
<term>Parkinson Disease</term>
<term>Tyrosine 3-Monooxygenase</term>
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<keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Genetic Therapy</term>
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<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>MPTP Poisoning</term>
<term>Parkinson Disease</term>
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<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Neurturin</term>
</keywords>
<keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>MPTP Poisoning</term>
<term>Parkinson Disease</term>
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<term>Animals</term>
<term>Disease Models, Animal</term>
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<term>Macaca mulatta</term>
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<term>Maladie de Parkinson</term>
<term>Pathologie du système nerveux</term>
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<term>Réparation</term>
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<front><div type="abstract" xml:lang="en">Background: AAV2‐neurturin (CERE‐120) is designed to deliver the neurotrophic‐factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic‐factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). Methods: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2‐neurturin in brains of PD patients versus those of nonhuman primates similarly treated. Results: NRTN‐immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral‐NRTN was observed in all monkeys. NRTN‐expression was associated with occasional, sparse TH‐induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH‐induction throughout the nigrostriatal neurons. Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic‐factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon‐transport deficits reduced the bioactivity of AAV2‐NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic‐factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. © 2010 Movement Disorder Society</div>
</front>
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<tree><country name="États-Unis"><region name="Californie"><name sortKey="Bartus, Raymond T" sort="Bartus, Raymond T" uniqKey="Bartus R" first="Raymond T." last="Bartus">Raymond T. Bartus</name>
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<name sortKey="Chu, Yaping" sort="Chu, Yaping" uniqKey="Chu Y" first="Yaping" last="Chu">Yaping Chu</name>
<name sortKey="Herzog, Christopher D" sort="Herzog, Christopher D" uniqKey="Herzog C" first="Christopher D." last="Herzog">Christopher D. Herzog</name>
<name sortKey="Johnson Jr, Eugene M" sort="Johnson Jr, Eugene M" uniqKey="Johnson Jr E" first="Eugene M." last="Johnson Jr.">Eugene M. Johnson Jr.</name>
<name sortKey="Kordower, Jeffrey H" sort="Kordower, Jeffrey H" uniqKey="Kordower J" first="Jeffrey H." last="Kordower">Jeffrey H. Kordower</name>
<name sortKey="Mufson, Elliott J" sort="Mufson, Elliott J" uniqKey="Mufson E" first="Elliott J." last="Mufson">Elliott J. Mufson</name>
<name sortKey="Olanow, C Warren" sort="Olanow, C Warren" uniqKey="Olanow C" first="C. Warren" last="Olanow">C. Warren Olanow</name>
<name sortKey="Siffert, Joao" sort="Siffert, Joao" uniqKey="Siffert J" first="Joao" last="Siffert">Joao Siffert</name>
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