Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase
Identifieur interne : 001A13 ( Istex/Corpus ); précédent : 001A12; suivant : 001A14Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase
Auteurs : M. Barkats ; N. Nakao ; E. M Grasbon-Frodl ; A. Bilang-Bleuel ; F. Revah ; J. Mallet ; P. BrundinSource :
- Neuroscience [ 0306-4522 ] ; 1996.
Abstract
Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and β-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.
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DOI: 10.1016/S0306-4522(96)00526-X
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title><author><name sortKey="Barkats, M" sort="Barkats, M" uniqKey="Barkats M" first="M" last="Barkats">M. Barkats</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Nakao, N" sort="Nakao, N" uniqKey="Nakao N" first="N" last="Nakao">N. Nakao</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Grasbon Frodl, E M" sort="Grasbon Frodl, E M" uniqKey="Grasbon Frodl E" first="E. M" last="Grasbon-Frodl">E. M Grasbon-Frodl</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Bilang Bleuel, A" sort="Bilang Bleuel, A" uniqKey="Bilang Bleuel A" first="A" last="Bilang-Bleuel">A. Bilang-Bleuel</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Revah, F" sort="Revah, F" uniqKey="Revah F" first="F" last="Revah">F. Revah</name><affiliation><mods:affiliation>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</mods:affiliation></affiliation></author><author><name sortKey="Mallet, J" sort="Mallet, J" uniqKey="Mallet J" first="J" last="Mallet">J. Mallet</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>To whom correspondence should be addressed.</mods:affiliation></affiliation></author><author><name sortKey="Brundin, P" sort="Brundin, P" uniqKey="Brundin P" first="P" last="Brundin">P. Brundin</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:83295F5D577C3F62AF7483F38439148F967F87D4</idno><date when="1996" year="1996">1996</date><idno type="doi">10.1016/S0306-4522(96)00526-X</idno><idno type="url">https://api.istex.fr/document/83295F5D577C3F62AF7483F38439148F967F87D4/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001A13</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001A13</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title><author><name sortKey="Barkats, M" sort="Barkats, M" uniqKey="Barkats M" first="M" last="Barkats">M. Barkats</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Nakao, N" sort="Nakao, N" uniqKey="Nakao N" first="N" last="Nakao">N. Nakao</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Grasbon Frodl, E M" sort="Grasbon Frodl, E M" uniqKey="Grasbon Frodl E" first="E. M" last="Grasbon-Frodl">E. M Grasbon-Frodl</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Bilang Bleuel, A" sort="Bilang Bleuel, A" uniqKey="Bilang Bleuel A" first="A" last="Bilang-Bleuel">A. Bilang-Bleuel</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Revah, F" sort="Revah, F" uniqKey="Revah F" first="F" last="Revah">F. Revah</name><affiliation><mods:affiliation>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</mods:affiliation></affiliation></author><author><name sortKey="Mallet, J" sort="Mallet, J" uniqKey="Mallet J" first="J" last="Mallet">J. Mallet</name><affiliation><mods:affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</mods:affiliation></affiliation><affiliation><mods:affiliation>To whom correspondence should be addressed.</mods:affiliation></affiliation></author><author><name sortKey="Brundin, P" sort="Brundin, P" uniqKey="Brundin P" first="P" last="Brundin">P. Brundin</name><affiliation><mods:affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Neuroscience</title><title level="j" type="abbrev">NSC</title><idno type="ISSN">0306-4522</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1996">1996</date><biblScope unit="volume">78</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="703">703</biblScope><biblScope unit="page" to="713">713</biblScope></imprint><idno type="ISSN">0306-4522</idno></series><idno type="istex">83295F5D577C3F62AF7483F38439148F967F87D4</idno><idno type="DOI">10.1016/S0306-4522(96)00526-X</idno><idno type="PII">S0306-4522(96)00526-X</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0306-4522</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and β-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>M Barkats</name><affiliations><json:string>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</json:string></affiliations></json:item><json:item><name>N Nakao</name><affiliations><json:string>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</json:string></affiliations></json:item><json:item><name>E.M Grasbon-Frodl</name><affiliations><json:string>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</json:string></affiliations></json:item><json:item><name>A Bilang-Bleuel</name><affiliations><json:string>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</json:string></affiliations></json:item><json:item><name>F Revah</name><affiliations><json:string>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</json:string></affiliations></json:item><json:item><name>J Mallet</name><affiliations><json:string>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</json:string><json:string>To whom correspondence should be addressed.</json:string></affiliations></json:item><json:item><name>P Brundin</name><affiliations><json:string>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>neural graft</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mesencephalic cells</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>superoxide dismutase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>adenovirus</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ex vivo gene transfer</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Ad-hCuZnSOD, recombinant adenovirus encoding the human Cu/Zn SOD</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Ad-RSVβgal, recombinant adenovirus encoding the E. coli β-galactosidase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>βgal, β-galactosidase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CR3, complement receptor 3</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>DA, dopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HBSS, Hank's balanced salt solution</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MOI, multiplicity of infection</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>6-OHDA, 6-hydroxydopamine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PBS, phosphate-buffered saline</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PD, Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pfu, plaque forming unit</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>RSV, Rous sarcoma virus</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SOD, superoxide dismutase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TH, tyrosine hydroxylase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>VM, ventral mesencephalon</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and β-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.</abstract><qualityIndicators><score>7.628</score><pdfVersion>1.2</pdfVersion><pdfPageSize>598 x 776 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>22</keywordCount><abstractCharCount>1601</abstractCharCount><pdfWordCount>6674</pdfWordCount><pdfCharCount>43548</pdfCharCount><pdfPageCount>11</pdfPageCount><abstractWordCount>219</abstractWordCount></qualityIndicators><title>Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title><pii><json:string>S0306-4522(96)00526-X</json:string></pii><refBibs><json:item><author><json:item><name>M Abercrombie</name></json:item></author><host><volume>94</volume><pages><last>247</last><first>239</first></pages><author></author><title>Anat. 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An example of cavity (cav) is illustrated in d. c, f) high magnification of βgal-positive cells (scale bar=100μm). Specific blue staining of βgal-positive nuclei (nu) and non-specific blue staining (ns) are illustrated in c.</note><note type="content">Fig. 2: Human CuZnSOD immunostaining of the neural grafts infected with the hCuZnSOD adenovirus analysed at four days (a, c) and five weeks (b, d) post-transplantation. a, b) low magnification of hCuZnSOD-positive cells inside the graft (scale bar=100μm). c) high magnification of hCuZnSOD-positive cells with a “neuron-like” (n) or “glia-like” (g) morphology (scale bar=30μm). d) high magnification of hCuZnSOD-positive cells (scale bar=30μm) showing a non-neuronal cell (arrow).</note><note type="content">Fig. 3: Microglia/macrophage (CR3) immunostaining of coronal sections through the neural grafts at four days (a,b,c) and five weeks (d,e,f) after transplantation. a, d) control; b, e) βgal; and c, f) SOD representative neural grafts (scale bar=250μm).</note><note type="content">Fig. 4: TH-immunostaining of coronal sections through the neural grafts at five weeks after transplantation in one representative rat from each group. a) control; b) βgal; and c) SOD groups are illustrated (scale bar=250μm).</note><note type="content">Table 1: Amphetamine-induced rotation asymmetry</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title><author xml:id="author-1"><persName><forename type="first">M</forename><surname>Barkats</surname></persName><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">N</forename><surname>Nakao</surname></persName><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation></author><author xml:id="author-3"><persName><forename type="first">E.M</forename><surname>Grasbon-Frodl</surname></persName><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation></author><author xml:id="author-4"><persName><forename type="first">A</forename><surname>Bilang-Bleuel</surname></persName><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">F</forename><surname>Revah</surname></persName><affiliation>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">J</forename><surname>Mallet</surname></persName><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation><affiliation>To whom correspondence should be addressed.</affiliation></author><author xml:id="author-7"><persName><forename type="first">P</forename><surname>Brundin</surname></persName><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation></author></analytic><monogr><title level="j">Neuroscience</title><title level="j" type="abbrev">NSC</title><idno type="pISSN">0306-4522</idno><idno type="PII">S0306-4522(00)X0049-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1996"></date><biblScope unit="volume">78</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="703">703</biblScope><biblScope unit="page" to="713">713</biblScope></imprint></monogr><idno type="istex">83295F5D577C3F62AF7483F38439148F967F87D4</idno><idno type="DOI">10.1016/S0306-4522(96)00526-X</idno><idno type="PII">S0306-4522(96)00526-X</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1996</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and β-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>neural graft</term></item><item><term>dopamine</term></item><item><term>mesencephalic cells</term></item><item><term>superoxide dismutase</term></item><item><term>adenovirus</term></item><item><term>ex vivo gene transfer</term></item><item><term>Parkinson's disease</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>Ad-hCuZnSOD, recombinant adenovirus encoding the human Cu/Zn SOD</term></item><item><term>Ad-RSVβgal, recombinant adenovirus encoding the E. coli β-galactosidase</term></item><item><term>βgal, β-galactosidase</term></item><item><term>CR3, complement receptor 3</term></item><item><term>DA, dopamine</term></item><item><term>HBSS, Hank's balanced salt solution</term></item><item><term>MOI, multiplicity of infection</term></item><item><term>6-OHDA, 6-hydroxydopamine</term></item><item><term>PBS, phosphate-buffered saline</term></item><item><term>PD, Parkinson's disease</term></item><item><term>pfu, plaque forming unit</term></item><item><term>RSV, Rous sarcoma virus</term></item><item><term>SOD, superoxide dismutase</term></item><item><term>TH, tyrosine hydroxylase</term></item><item><term>VM, ventral mesencephalon</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1996">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/83295F5D577C3F62AF7483F38439148F967F87D4/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="gr4"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla"><item-info><jid>NSC</jid><aid>2048</aid><ce:pii>S0306-4522(96)00526-X</ce:pii><ce:doi>10.1016/S0306-4522(96)00526-X</ce:doi><ce:copyright year="1996" type="other">IBRO</ce:copyright></item-info><head><ce:title>Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</ce:title><ce:author-group><ce:author><ce:given-name>M</ce:given-name><ce:surname>Barkats</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>N</ce:given-name><ce:surname>Nakao</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:author><ce:given-name>E.M</ce:given-name><ce:surname>Grasbon-Frodl</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:author><ce:given-name>A</ce:given-name><ce:surname>Bilang-Bleuel</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref></ce:author><ce:author><ce:given-name>F</ce:given-name><ce:surname>Revah</ce:surname><ce:cross-ref refid="AFF3">c</ce:cross-ref></ce:author><ce:author><ce:given-name>J</ce:given-name><ce:surname>Mallet</ce:surname><ce:cross-ref refid="AFF1">a</ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref></ce:author><ce:author><ce:given-name>P</ce:given-name><ce:surname>Brundin</ce:surname><ce:cross-ref refid="AFF2">b</ce:cross-ref></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</ce:textfn></ce:affiliation><ce:affiliation id="AFF3"><ce:label>c</ce:label><ce:textfn>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>To whom correspondence should be addressed.</ce:text></ce:correspondence></ce:author-group><ce:date-accepted day="26" month="9" year="1996"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells <ce:italic>in vitro</ce:italic>, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the <ce:italic>E. coli</ce:italic> lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and <ce:italic>β</ce:italic>-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance.</ce:simple-para><ce:simple-para>Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that <ce:italic>ex vivo</ce:italic> gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>neural graft</ce:text></ce:keyword><ce:keyword><ce:text>dopamine</ce:text></ce:keyword><ce:keyword><ce:text>mesencephalic cells</ce:text></ce:keyword><ce:keyword><ce:text>superoxide dismutase</ce:text></ce:keyword><ce:keyword><ce:text>adenovirus</ce:text></ce:keyword><ce:keyword><ce:text><ce:italic>ex vivo</ce:italic> gene transfer</ce:text></ce:keyword><ce:keyword><ce:text>Parkinson's disease</ce:text></ce:keyword></ce:keywords><ce:keywords class="abr"><ce:section-title>Abbreviations</ce:section-title><ce:keyword><ce:text>Ad-hCuZnSOD, recombinant adenovirus encoding the human Cu/Zn SOD</ce:text></ce:keyword><ce:keyword><ce:text>Ad-RSV<ce:italic>β</ce:italic>gal, recombinant adenovirus encoding the <ce:italic>E. coli</ce:italic> <ce:italic>β</ce:italic>-galactosidase</ce:text></ce:keyword><ce:keyword><ce:text><ce:italic>β</ce:italic>gal, <ce:italic>β</ce:italic>-galactosidase</ce:text></ce:keyword><ce:keyword><ce:text>CR3, complement receptor 3</ce:text></ce:keyword><ce:keyword><ce:text>DA, dopamine</ce:text></ce:keyword><ce:keyword><ce:text>HBSS, Hank's balanced salt solution</ce:text></ce:keyword><ce:keyword><ce:text>MOI, multiplicity of infection</ce:text></ce:keyword><ce:keyword><ce:text>6-OHDA, 6-hydroxydopamine</ce:text></ce:keyword><ce:keyword><ce:text>PBS, phosphate-buffered saline</ce:text></ce:keyword><ce:keyword><ce:text>PD, Parkinson's disease</ce:text></ce:keyword><ce:keyword><ce:text>pfu, plaque forming unit</ce:text></ce:keyword><ce:keyword><ce:text>RSV, Rous sarcoma virus</ce:text></ce:keyword><ce:keyword><ce:text>SOD, superoxide dismutase</ce:text></ce:keyword><ce:keyword><ce:text>TH, tyrosine hydroxylase</ce:text></ce:keyword><ce:keyword><ce:text>VM, ventral mesencephalon</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase</title></titleInfo><name type="personal"><namePart type="given">M</namePart><namePart type="family">Barkats</namePart><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">N</namePart><namePart type="family">Nakao</namePart><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E.M</namePart><namePart type="family">Grasbon-Frodl</namePart><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Bilang-Bleuel</namePart><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">F</namePart><namePart type="family">Revah</namePart><affiliation>Gencell Rhône-Poulenc-RORER, Vitry sur Seine, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Mallet</namePart><affiliation>Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR CNRS C9923, Hôpital de la Pitié Salpêtrière, Paris, France</affiliation><affiliation>To whom correspondence should be addressed.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Brundin</namePart><affiliation>Section for Neuronal Survival, Department of Physiology and Neuroscience, University of Lund, Lund, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1996</dateIssued><copyrightDate encoding="w3cdtf">1996</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Intrastriatal grafting of embryonic dopamine-containing neurons is a promising approach for treating clinical and experimental Parkinson's disease. However, neuropathological analyses of grafted patients and transplanted rats have demonstrated that the survival of grafted dopamine neurons is relatively poor. In the present study, we pursued a strategy of transferring a potentially neuroprotective gene into rat embryonic mesencephalic rat cells in vitro, before grafting them into the denervated striatum of 6-hydroxydopamine-lesioned rats. We performed intrastriatal grafts of embryonic day 14 mesencephalic cells infected with replication-defective adenoviruses bearing either the human copper-zinc superoxide dismutase gene or, as a control, the E. coli lac Z marker gene. The transgenes were expressed in the grafts four days after transplantation and the expression persisted for at least five weeks thereafter. After five weeks postgrafting, there was more extensive functional recovery in the superoxide dismutase group as compared to the control (uninfected cells) and β-galactosidase groups. The functional recovery was significantly correlated with the number of tyrosine hydroxylase-positive cells in the grafts, although the clear trend to increased survival of the dopamine neurons in the superoxide dismutase grafts did not reach statistical significance. Only a moderate inflammatory reaction was revealed by OX-42 immunostaining in all groups, suggesting that ex vivo gene transfer using adenoviral vectors is a promising method for delivering functional proteins into brain grafts.</abstract><note type="content">Fig. 1: X-gal histochemistry (a, b, c) and βgal immunohistochemistry (d, e, f) in the neural grafts at four days (a, c, d) and five weeks (b, e, f) after intra-striatal transplantation of embryonic mesencephalic tissue infected with the βgal adenovirus. a, b, d, e) low magnification of βgal-positive cells (scale bar=100μm). An example of cavity (cav) is illustrated in d. c, f) high magnification of βgal-positive cells (scale bar=100μm). Specific blue staining of βgal-positive nuclei (nu) and non-specific blue staining (ns) are illustrated in c.</note><note type="content">Fig. 2: Human CuZnSOD immunostaining of the neural grafts infected with the hCuZnSOD adenovirus analysed at four days (a, c) and five weeks (b, d) post-transplantation. a, b) low magnification of hCuZnSOD-positive cells inside the graft (scale bar=100μm). c) high magnification of hCuZnSOD-positive cells with a “neuron-like” (n) or “glia-like” (g) morphology (scale bar=30μm). d) high magnification of hCuZnSOD-positive cells (scale bar=30μm) showing a non-neuronal cell (arrow).</note><note type="content">Fig. 3: Microglia/macrophage (CR3) immunostaining of coronal sections through the neural grafts at four days (a,b,c) and five weeks (d,e,f) after transplantation. a, d) control; b, e) βgal; and c, f) SOD representative neural grafts (scale bar=250μm).</note><note type="content">Fig. 4: TH-immunostaining of coronal sections through the neural grafts at five weeks after transplantation in one representative rat from each group. a) control; b) βgal; and c) SOD groups are illustrated (scale bar=250μm).</note><note type="content">Table 1: Amphetamine-induced rotation asymmetry</note><subject><genre>Keywords</genre><topic>neural graft</topic><topic>dopamine</topic><topic>mesencephalic cells</topic><topic>superoxide dismutase</topic><topic>adenovirus</topic><topic>ex vivo gene transfer</topic><topic>Parkinson's disease</topic></subject><subject><genre>Abbreviations</genre><topic>Ad-hCuZnSOD, recombinant adenovirus encoding the human Cu/Zn SOD</topic><topic>Ad-RSVβgal, recombinant adenovirus encoding the E. coli β-galactosidase</topic><topic>βgal, β-galactosidase</topic><topic>CR3, complement receptor 3</topic><topic>DA, dopamine</topic><topic>HBSS, Hank's balanced salt solution</topic><topic>MOI, multiplicity of infection</topic><topic>6-OHDA, 6-hydroxydopamine</topic><topic>PBS, phosphate-buffered saline</topic><topic>PD, Parkinson's disease</topic><topic>pfu, plaque forming unit</topic><topic>RSV, Rous sarcoma virus</topic><topic>SOD, superoxide dismutase</topic><topic>TH, tyrosine hydroxylase</topic><topic>VM, ventral mesencephalon</topic></subject><relatedItem type="host"><titleInfo><title>Neuroscience</title></titleInfo><titleInfo type="abbreviated"><title>NSC</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">19970327</dateIssued></originInfo><identifier type="ISSN">0306-4522</identifier><identifier type="PII">S0306-4522(00)X0049-8</identifier><part><date>19970327</date><detail type="volume"><number>78</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue pages"><start>625</start><end>928</end></extent><extent unit="pages"><start>703</start><end>713</end></extent></part></relatedItem><identifier type="istex">83295F5D577C3F62AF7483F38439148F967F87D4</identifier><identifier type="DOI">10.1016/S0306-4522(96)00526-X</identifier><identifier type="PII">S0306-4522(96)00526-X</identifier><accessCondition type="use and reproduction" contentType="copyright">©1996 IBRO</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>IBRO, ©1996</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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