MovDisordV3, PascalFrancis, Curation, bibRecord, 002576

Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains

Identifieur interne : 002576 ( PascalFrancis/Curation ); précédent : 002575; suivant : 002577

Bioactivity 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. Jr Johnson [États-Unis] ; C. Warren Olanow [États-Unis] ; Elliott J. Mufson [États-Unis] ; Jeffrey H. Kordower [États-Unis]

Source :

Movement disorders [ 0885-3185 ] ; 2011.

RBID : Pascal:11-0143215

Descripteurs français

Pascal (Inist)
- Maladie de Parkinson, Pathologie du système nerveux, Thérapie génique, Primates, Encéphale, Facteur neurotrophique, Transport biologique, Réparation.

English descriptors

KwdEn :
- Biological transport, Encephalon, Gene therapy, Nervous system diseases, Neurotrophic factor, Parkinson disease, Primates, Repair.

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.

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A11	`02`	`1`		`@1 HERZOG (Christopher D.)`
A11	`03`	`1`		`@1 YAPING CHU`
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A14	`01`			`@1 Ceregene Inc. @2 San Diego, California @3 USA @Z 1 aut. @Z 2 aut. @Z 4 aut. @Z 5 aut. @Z 6 aut.`
A14	`02`			`@1 Department of Neurological Sciences, Rush University Medical Center @2 Chicago, Illinois @3 USA @Z 3 aut. @Z 9 aut. @Z 10 aut.`
A14	`03`			`@1 Department of Neurology, Washington University School of Medicine @2 St. Louis, Missouri @3 USA @Z 7 aut.`
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C01	`01`		`ENG`	@0 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.
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C03	`05`	`X`	`FRE`	`@0 Encéphale @5 11`
C03	`05`	`X`	`ENG`	`@0 Encephalon @5 11`
C03	`05`	`X`	`SPA`	`@0 Encéfalo @5 11`
C03	`06`	`X`	`FRE`	`@0 Facteur neurotrophique @5 12`
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C03	`07`	`X`	`FRE`	`@0 Transport biologique @5 13`
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C03	`08`	`X`	`SPA`	`@0 Reparación @5 14`
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C07	`02`	`X`	`ENG`	`@0 Vertebrata @2 NS`
C07	`02`	`X`	`SPA`	`@0 Vertebrata @2 NS`
C07	`03`	`X`	`FRE`	`@0 Pathologie de l'encéphale @5 37`
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C07	`03`	`X`	`SPA`	`@0 Encéfalo patología @5 37`
C07	`04`	`X`	`FRE`	`@0 Syndrome extrapyramidal @5 38`
C07	`04`	`X`	`ENG`	`@0 Extrapyramidal syndrome @5 38`
C07	`04`	`X`	`SPA`	`@0 Extrapiramidal síndrome @5 38`
C07	`05`	`X`	`FRE`	`@0 Maladie dégénérative @5 39`
C07	`05`	`X`	`ENG`	`@0 Degenerative disease @5 39`
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C07	`06`	`X`	`FRE`	`@0 Pathologie du système nerveux central @5 40`
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C07	`07`	`X`	`SPA`	`@0 Sistema nervioso central @5 42`
N21				`@1 094`
N44	`01`			`@1 OTO`
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Pascal:11-0143215

Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Biological transport</term>
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<term>Neurotrophic factor</term>
<term>Parkinson disease</term>
<term>Primates</term>
<term>Repair</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Maladie de Parkinson</term>
<term>Pathologie du   système nerveux</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.</div>
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<fA08 i1="01" i2="1" l="ENG"><s1>Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains</s1>
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<fA11 i1="01" i2="1"><s1>BARTUS (Raymond T.)</s1>
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<fA11 i1="02" i2="1"><s1>HERZOG (Christopher D.)</s1>
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<fA11 i1="07" i2="1"><s1>JOHNSON (Eugene M. JR)</s1>
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<fA11 i1="08" i2="1"><s1>OLANOW (C. Warren)</s1>
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<fA11 i1="09" i2="1"><s1>MUFSON (Elliott J.)</s1>
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<fA11 i1="10" i2="1"><s1>KORDOWER (Jeffrey H.)</s1>
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<fA14 i1="01"><s1>Ceregene Inc.</s1>
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<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
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<fA14 i1="02"><s1>Department of Neurological Sciences, Rush University Medical Center</s1>
<s2>Chicago, Illinois</s2>
<s3>USA</s3>
<sZ>3 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
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<fA14 i1="03"><s1>Department of Neurology, Washington University School of Medicine</s1>
<s2>St. Louis, Missouri</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
</fA14>
<fA14 i1="04"><s1>Department of Neurology, Mt. Sinai School of Medicine</s1>
<s2>New York, New York</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
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<fA20><s1>27-36</s1>
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<fC01 i1="01" l="ENG"><s0>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.</s0>
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	Movement Disorders (revue)
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Movement Disorders (revue)

Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains

Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains

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