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<title xml:lang="en">Neuroglobin Gene Therapy Prevents Optic Atrophy and Preserves Durably Visual Function in
<italic>Harlequin</italic>
Mice</title>
<author>
<name sortKey="Lechauve, Christophe" sort="Lechauve, Christophe" uniqKey="Lechauve C" first="Christophe" last="Lechauve">Christophe Lechauve</name>
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<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
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<name sortKey="Augustin, Sebastien" sort="Augustin, Sebastien" uniqKey="Augustin S" first="Sébastien" last="Augustin">Sébastien Augustin</name>
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<name sortKey="Lai Kuen, Rene" sort="Lai Kuen, Rene" uniqKey="Lai Kuen R" first="René" last="Lai-Kuen">René Lai-Kuen</name>
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<name sortKey="Corral Debrinski, Marisol" sort="Corral Debrinski, Marisol" uniqKey="Corral Debrinski M" first="Marisol" last="Corral-Debrinski">Marisol Corral-Debrinski</name>
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, Paris,
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<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
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<title xml:lang="en" level="a" type="main">Neuroglobin Gene Therapy Prevents Optic Atrophy and Preserves Durably Visual Function in
<italic>Harlequin</italic>
Mice</title>
<author>
<name sortKey="Lechauve, Christophe" sort="Lechauve, Christophe" uniqKey="Lechauve C" first="Christophe" last="Lechauve">Christophe Lechauve</name>
<affiliation>
<nlm:aff id="aff1">
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
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</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
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</nlm:aff>
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<name sortKey="Augustin, Sebastien" sort="Augustin, Sebastien" uniqKey="Augustin S" first="Sébastien" last="Augustin">Sébastien Augustin</name>
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<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<author>
<name sortKey="Cwerman Thibault, Helene" sort="Cwerman Thibault, Helene" uniqKey="Cwerman Thibault H" first="Hélène" last="Cwerman-Thibault">Hélène Cwerman-Thibault</name>
<affiliation>
<nlm:aff id="aff1">
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Reboussin, Elodie" sort="Reboussin, Elodie" uniqKey="Reboussin E" first="Élodie" last="Reboussin">Élodie Reboussin</name>
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<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Roussel, Delphine" sort="Roussel, Delphine" uniqKey="Roussel D" first="Delphine" last="Roussel">Delphine Roussel</name>
<affiliation>
<nlm:aff id="aff1">
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Lai Kuen, Rene" sort="Lai Kuen, Rene" uniqKey="Lai Kuen R" first="René" last="Lai-Kuen">René Lai-Kuen</name>
<affiliation>
<nlm:aff id="aff4">
<institution>INSERM U705, CNRS UMR 8206, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Faculté de Pharmacie</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Saubamea, Bruno" sort="Saubamea, Bruno" uniqKey="Saubamea B" first="Bruno" last="Saubamea">Bruno Saubamea</name>
<affiliation>
<nlm:aff id="aff4">
<institution>INSERM U705, CNRS UMR 8206, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Faculté de Pharmacie</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Sahel, Jose Alain" sort="Sahel, Jose Alain" uniqKey="Sahel J" first="José-Alain" last="Sahel">José-Alain Sahel</name>
<affiliation>
<nlm:aff id="aff1">
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<author>
<name sortKey="Debeir, Thomas" sort="Debeir, Thomas" uniqKey="Debeir T" first="Thomas" last="Debeir">Thomas Debeir</name>
<affiliation>
<nlm:aff id="aff5">
<institution>Sanofi Fovea – Ophthalmology</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Corral Debrinski, Marisol" sort="Corral Debrinski, Marisol" uniqKey="Corral Debrinski M" first="Marisol" last="Corral-Debrinski">Marisol Corral-Debrinski</name>
<affiliation>
<nlm:aff id="aff1">
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff2">
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="aff3">
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</nlm:aff>
</affiliation>
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<series>
<title level="j">Molecular Therapy</title>
<idno type="ISSN">1525-0016</idno>
<idno type="eISSN">1525-0024</idno>
<imprint>
<date when="2014">2014</date>
</imprint>
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<div type="abstract" xml:lang="en">
<p>Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the
<italic>Harlequin</italic>
(
<italic>Hq</italic>
) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in
<italic>Hq</italic>
retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5′ and 3′UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to
<italic>Hq</italic>
mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure.</p>
</div>
</front>
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<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Mol Ther</journal-id>
<journal-id journal-id-type="iso-abbrev">Mol. Ther</journal-id>
<journal-title-group>
<journal-title>Molecular Therapy</journal-title>
</journal-title-group>
<issn pub-type="ppub">1525-0016</issn>
<issn pub-type="epub">1525-0024</issn>
<publisher>
<publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">24622090</article-id>
<article-id pub-id-type="pmc">4048897</article-id>
<article-id pub-id-type="pii">mt201444</article-id>
<article-id pub-id-type="doi">10.1038/mt.2014.44</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Original Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Neuroglobin Gene Therapy Prevents Optic Atrophy and Preserves Durably Visual Function in
<italic>Harlequin</italic>
Mice</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Lechauve</surname>
<given-names>Christophe</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Augustin</surname>
<given-names>Sébastien</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cwerman-Thibault</surname>
<given-names>Hélène</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Reboussin</surname>
<given-names>Élodie</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Roussel</surname>
<given-names>Delphine</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lai-Kuen</surname>
<given-names>René</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Saubamea</surname>
<given-names>Bruno</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Sahel</surname>
<given-names>José-Alain</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Debeir</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Corral-Debrinski</surname>
<given-names>Marisol</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="aff" rid="aff3">3</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<aff id="aff1">
<label>1</label>
<institution>INSERM, U968</institution>
, Paris,
<country>France</country>
</aff>
<aff id="aff2">
<label>2</label>
<institution>Sorbonne Universités, UPMC Univ Paris, Institut de la Vision</institution>
, Paris,
<country>France</country>
</aff>
<aff id="aff3">
<label>3</label>
<institution>Centre national de la recherche scientifique</institution>
, Paris,
<country>France</country>
</aff>
<aff id="aff4">
<label>4</label>
<institution>INSERM U705, CNRS UMR 8206, Université Paris Descartes, Sorbonne Paris Cité, Université Paris Diderot, Faculté de Pharmacie</institution>
, Paris,
<country>France</country>
</aff>
<aff id="aff5">
<label>5</label>
<institution>Sanofi Fovea – Ophthalmology</institution>
, Paris,
<country>France</country>
</aff>
</contrib-group>
<author-notes>
<corresp id="caf1">
<label>*</label>
INSERM, U968, Paris, F-75012, France. E-mail:
<email>marisol.corral@inserm.fr</email>
</corresp>
<fn fn-type="present-address" id="aunote">
<label></label>
<p>H.C-T. and E.R. contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub">
<month>06</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epreprint">
<day>13</day>
<month>03</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub">
<day>08</day>
<month>04</month>
<year>2014</year>
</pub-date>
<volume>22</volume>
<issue>6</issue>
<fpage>1096</fpage>
<lpage>1109</lpage>
<history>
<date date-type="received">
<day>23</day>
<month>01</month>
<year>2014</year>
</date>
<date date-type="accepted">
<day>06</day>
<month>03</month>
<year>2014</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright © 2014 The American Society of Gene & Cell Therapy</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>The American Society of Gene & Cell Therapy</copyright-holder>
</permissions>
<abstract>
<p>Neuroglobin (NGB) is considered as an endogenous neuroprotective molecule against stroke, since the protein alleviates the adverse effects of hypoxic and ischemic insults. We previously demonstrated the functional link between NGB and mitochondria since it is required for respiratory chain function. Thus, here, we evaluated the relevance of this effect in the
<italic>Harlequin</italic>
(
<italic>Hq</italic>
) mouse strain, which exhibits retinal ganglion cell (RGC) loss and optic atrophy due to a respiratory chain complex I (CI) defect. A twofold decrease of NGB amounts was observed in
<italic>Hq</italic>
retinas. We constructed a recombinant adeno-associated virus which combines to the mouse NGB open reading frame, its 5′ and 3′UTR, for guarantying mRNA stability and translation capacity. The vector was administrated intravitreally to
<italic>Hq</italic>
mice and NGB expression was stable for up to 7 months without negative effect on retinal architecture or function. On the contrary, RGCs and their axons were substantially preserved from degeneration; consequently, CI activity in optic nerves was protected conferring improvements in vision. Hence, we established that NGB prevents respiratory chain impairment, therefore, protecting visual function otherwise compromised by mitochondrial energetic failure.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>

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