Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains
Identifieur interne : 001C84 ( Main/Merge ); précédent : 001C83; suivant : 001C85Bioactivity 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.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
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.
Links toward previous steps (curation, corpus...)
- to stream PascalFrancis, to step Corpus: 000742
- to stream PascalFrancis, to step Curation: 002576
- to stream PascalFrancis, to step Checkpoint: 000694
Links to Exploration step
Pascal:11-0143215Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains</title><author><name sortKey="Bartus, Raymond T" sort="Bartus, Raymond T" uniqKey="Bartus R" first="Raymond T." last="Bartus">Raymond T. Bartus</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Herzog, Christopher D" sort="Herzog, Christopher D" uniqKey="Herzog C" first="Christopher D." last="Herzog">Christopher D. Herzog</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Yaping Chu" sort="Yaping Chu" uniqKey="Yaping Chu" last="Yaping Chu">YAPING CHU</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Wilson, Alistair" sort="Wilson, Alistair" uniqKey="Wilson A" first="Alistair" last="Wilson">Alistair Wilson</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Brown, Lamar" sort="Brown, Lamar" uniqKey="Brown L" first="Lamar" last="Brown">Lamar Brown</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Siffert, Joao" sort="Siffert, Joao" uniqKey="Siffert J" first="Joao" last="Siffert">Joao Siffert</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Johnson, Eugene M Jr" sort="Johnson, Eugene M Jr" uniqKey="Johnson E" first="Eugene M. Jr" last="Johnson">Eugene M. Jr Johnson</name><affiliation wicri:level="4"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Olanow, C Warren" sort="Olanow, C Warren" uniqKey="Olanow C" first="C. Warren" last="Olanow">C. Warren Olanow</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Mufson, Elliott J" sort="Mufson, Elliott J" uniqKey="Mufson E" first="Elliott J." last="Mufson">Elliott J. Mufson</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Kordower, Jeffrey H" sort="Kordower, Jeffrey H" uniqKey="Kordower J" first="Jeffrey H." last="Kordower">Jeffrey H. Kordower</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0143215</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0143215 INIST</idno><idno type="RBID">Pascal:11-0143215</idno><idno type="wicri:Area/PascalFrancis/Corpus">000742</idno><idno type="wicri:Area/PascalFrancis/Curation">002576</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000694</idno><idno type="wicri:doubleKey">0885-3185:2011:Bartus R:bioactivity:of:aav</idno><idno type="wicri:Area/Main/Merge">001C84</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains</title><author><name sortKey="Bartus, Raymond T" sort="Bartus, Raymond T" uniqKey="Bartus R" first="Raymond T." last="Bartus">Raymond T. Bartus</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Herzog, Christopher D" sort="Herzog, Christopher D" uniqKey="Herzog C" first="Christopher D." last="Herzog">Christopher D. Herzog</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Yaping Chu" sort="Yaping Chu" uniqKey="Yaping Chu" last="Yaping Chu">YAPING CHU</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Wilson, Alistair" sort="Wilson, Alistair" uniqKey="Wilson A" first="Alistair" last="Wilson">Alistair Wilson</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Brown, Lamar" sort="Brown, Lamar" uniqKey="Brown L" first="Lamar" last="Brown">Lamar Brown</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Siffert, Joao" sort="Siffert, Joao" uniqKey="Siffert J" first="Joao" last="Siffert">Joao Siffert</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Ceregene Inc.</s1><s2>San Diego, California</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Johnson, Eugene M Jr" sort="Johnson, Eugene M Jr" uniqKey="Johnson E" first="Eugene M. Jr" last="Johnson">Eugene M. Jr Johnson</name><affiliation wicri:level="4"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Missouri (État)</region><settlement type="city">Saint-Louis (Missouri)</settlement></placeName><orgName type="university">École de médecine (Université Washington de Saint-Louis)</orgName></affiliation></author><author><name sortKey="Olanow, C Warren" sort="Olanow, C Warren" uniqKey="Olanow C" first="C. Warren" last="Olanow">C. Warren Olanow</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Mufson, Elliott J" sort="Mufson, Elliott J" uniqKey="Mufson E" first="Elliott J." last="Mufson">Elliott J. Mufson</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Kordower, Jeffrey H" sort="Kordower, Jeffrey H" uniqKey="Kordower J" first="Jeffrey H." last="Kordower">Jeffrey H. Kordower</name><affiliation wicri:level="2"><inist: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></inist:fA14><country>États-Unis</country><placeName><region type="state">Illinois</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Movement disorders</title><title level="j" type="abbreviated">Mov. disord.</title><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Biological transport</term><term>Encephalon</term><term>Gene therapy</term><term>Nervous system diseases</term><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><term>Thérapie génique</term><term>Primates</term><term>Encéphale</term><term>Facteur neurotrophique</term><term>Transport biologique</term><term>Réparation</term></keywords></textClass></profileDesc></teiHeader><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></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Illinois</li><li>Missouri (État)</li><li>État de New York</li></region><settlement><li>Saint-Louis (Missouri)</li></settlement><orgName><li>École de médecine (Université Washington de Saint-Louis)</li></orgName></list><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></region><name sortKey="Brown, Lamar" sort="Brown, Lamar" uniqKey="Brown L" first="Lamar" last="Brown">Lamar Brown</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, Eugene M Jr" sort="Johnson, Eugene M Jr" uniqKey="Johnson E" first="Eugene M. Jr" last="Johnson">Eugene M. Jr Johnson</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><name sortKey="Wilson, Alistair" sort="Wilson, Alistair" uniqKey="Wilson A" first="Alistair" last="Wilson">Alistair Wilson</name><name sortKey="Yaping Chu" sort="Yaping Chu" uniqKey="Yaping Chu" last="Yaping Chu">YAPING CHU</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Santé/explor/MovDisordV3/Data/Main/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001C84 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Merge/biblio.hfd -nk 001C84 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Santé
|area= MovDisordV3
|flux= Main
|étape= Merge
|type= RBID
|clé= Pascal:11-0143215
|texte= Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains
}}
| This area was generated with Dilib version V0.6.23. |  |