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
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.</title><author><name sortKey="Herzog, Christopher D" sort="Herzog, Christopher D" uniqKey="Herzog C" first="Christopher D" last="Herzog">Christopher D. Herzog</name><affiliation><nlm:affiliation>Ceregene Inc, San Diego, CA 92121, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Dass, Biplob" sort="Dass, Biplob" uniqKey="Dass B" first="Biplob" last="Dass">Biplob Dass</name></author><author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name></author><author><name sortKey="Stansell, James" sort="Stansell, James" uniqKey="Stansell J" first="James" last="Stansell">James Stansell</name></author><author><name sortKey="Gasmi, Mehdi" sort="Gasmi, Mehdi" uniqKey="Gasmi M" first="Mehdi" last="Gasmi">Mehdi Gasmi</name></author><author><name sortKey="Tuszynski, Mark H" sort="Tuszynski, Mark H" uniqKey="Tuszynski M" first="Mark H" last="Tuszynski">Mark H. Tuszynski</name></author><author><name sortKey="Bartus, Raymond T" sort="Bartus, Raymond T" uniqKey="Bartus R" first="Raymond T" last="Bartus">Raymond T. Bartus</name></author><author><name sortKey="Kordower, Jeffrey H" sort="Kordower, Jeffrey H" uniqKey="Kordower J" first="Jeffrey H" last="Kordower">Jeffrey H. Kordower</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2007">2007</date><idno type="doi">10.1002/mds.21503</idno><idno type="RBID">pubmed:17443702</idno><idno type="pmid">17443702</idno><idno type="wicri:Area/PubMed/Corpus">002764</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.</title><author><name sortKey="Herzog, Christopher D" sort="Herzog, Christopher D" uniqKey="Herzog C" first="Christopher D" last="Herzog">Christopher D. Herzog</name><affiliation><nlm:affiliation>Ceregene Inc, San Diego, CA 92121, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Dass, Biplob" sort="Dass, Biplob" uniqKey="Dass B" first="Biplob" last="Dass">Biplob Dass</name></author><author><name sortKey="Holden, James E" sort="Holden, James E" uniqKey="Holden J" first="James E" last="Holden">James E. Holden</name></author><author><name sortKey="Stansell, James" sort="Stansell, James" uniqKey="Stansell J" first="James" last="Stansell">James Stansell</name></author><author><name sortKey="Gasmi, Mehdi" sort="Gasmi, Mehdi" uniqKey="Gasmi M" first="Mehdi" last="Gasmi">Mehdi Gasmi</name></author><author><name sortKey="Tuszynski, Mark H" sort="Tuszynski, Mark H" uniqKey="Tuszynski M" first="Mark H" last="Tuszynski">Mark H. Tuszynski</name></author><author><name sortKey="Bartus, Raymond T" sort="Bartus, Raymond T" uniqKey="Bartus R" first="Raymond T" last="Bartus">Raymond T. Bartus</name></author><author><name sortKey="Kordower, Jeffrey H" sort="Kordower, Jeffrey H" uniqKey="Kordower J" first="Jeffrey H" last="Kordower">Jeffrey H. Kordower</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="ISSN">0885-3185</idno><imprint><date when="2007" type="published">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aging (physiology)</term><term>Animals</term><term>Corpus Striatum (metabolism)</term><term>Corpus Striatum (pathology)</term><term>Corpus Striatum (virology)</term><term>Dependovirus (metabolism)</term><term>Disease Models, Animal</term><term>Dopamine (metabolism)</term><term>Female</term><term>Fluorodeoxyglucose F18 (diagnostic use)</term><term>Fluorodeoxyglucose F18 (pharmacokinetics)</term><term>Macaca mulatta</term><term>Neurturin (therapeutic use)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (pathology)</term><term>Parkinson Disease (virology)</term><term>Positron-Emission Tomography</term><term>Radiopharmaceuticals (diagnostic use)</term><term>Radiopharmaceuticals (pharmacokinetics)</term><term>Substantia Nigra (metabolism)</term><term>Substantia Nigra (pathology)</term><term>Substantia Nigra (virology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="diagnostic use" xml:lang="en"><term>Fluorodeoxyglucose F18</term><term>Radiopharmaceuticals</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Corpus Striatum</term><term>Dependovirus</term><term>Parkinson Disease</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Corpus Striatum</term><term>Parkinson Disease</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Fluorodeoxyglucose F18</term><term>Radiopharmaceuticals</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Aging</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Neurturin</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Corpus Striatum</term><term>Parkinson Disease</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Macaca mulatta</term><term>Positron-Emission Tomography</term></keywords></textClass></profileDesc></teiHeader><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></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">17443702</PMID><DateCreated><Year>2007</Year><Month>07</Month><Day>30</Day></DateCreated><DateCompleted><Year>2007</Year><Month>09</Month><Day>07</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0885-3185</ISSN><JournalIssue CitedMedium="Print"><Volume>22</Volume><Issue>8</Issue><PubDate><Year>2007</Year><Month>Jun</Month><Day>15</Day></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys.</ArticleTitle><Pagination><MedlinePgn>1124-32</MedlinePgn></Pagination><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></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Herzog</LastName><ForeName>Christopher D</ForeName><Initials>CD</Initials><AffiliationInfo><Affiliation>Ceregene Inc, San Diego, CA 92121, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dass</LastName><ForeName>Biplob</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Holden</LastName><ForeName>James E</ForeName><Initials>JE</Initials></Author><Author ValidYN="Y"><LastName>Stansell</LastName><ForeName>James</ForeName><Initials>J</Initials><Suffix>3rd</Suffix></Author><Author ValidYN="Y"><LastName>Gasmi</LastName><ForeName>Mehdi</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Tuszynski</LastName><ForeName>Mark H</ForeName><Initials>MH</Initials></Author><Author ValidYN="Y"><LastName>Bartus</LastName><ForeName>Raymond T</ForeName><Initials>RT</Initials></Author><Author ValidYN="Y"><LastName>Kordower</LastName><ForeName>Jeffrey H</ForeName><Initials>JH</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mov Disord</MedlineTA><NlmUniqueID>8610688</NlmUniqueID><ISSNLinking>0885-3185</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051101">Neurturin</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019275">Radiopharmaceuticals</NameOfSubstance></Chemical><Chemical><RegistryNumber>0Z5B2CJX4D</RegistryNumber><NameOfSubstance UI="D019788">Fluorodeoxyglucose F18</NameOfSubstance></Chemical><Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber><NameOfSubstance UI="D004298">Dopamine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000375">Aging</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000502">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000818">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D003342">Corpus Striatum</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000378">metabolism</QualifierName><QualifierName MajorTopicYN="N" UI="Q000473">pathology</QualifierName><QualifierName MajorTopicYN="N" UI="Q000821">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000229">Dependovirus</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000378">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D004195">Disease Models, Animal</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D004298">Dopamine</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000378">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D005260">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D019788">Fluorodeoxyglucose F18</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000176">diagnostic use</QualifierName><QualifierName MajorTopicYN="N" UI="Q000493">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D008253">Macaca mulatta</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D051101">Neurturin</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D010300">Parkinson Disease</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000378">metabolism</QualifierName><QualifierName MajorTopicYN="N" UI="Q000473">pathology</QualifierName><QualifierName MajorTopicYN="N" UI="Q000821">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D049268">Positron-Emission Tomography</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D019275">Radiopharmaceuticals</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000176">diagnostic use</QualifierName><QualifierName MajorTopicYN="N" UI="Q000493">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D013378">Substantia Nigra</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000378">metabolism</QualifierName><QualifierName MajorTopicYN="N" UI="Q000473">pathology</QualifierName><QualifierName MajorTopicYN="N" UI="Q000821">virology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate 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