Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes
Identifieur interne : 000722 ( Pmc/Checkpoint ); précédent : 000721; suivant : 000723Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes
Auteurs : Vanessa Borges Pires [Portugal] ; Ricardo Sim Es [Portugal] ; Kamel Mamchaoui [France] ; Célia Carvalho [Portugal] ; Maria Carmo-Fonseca [Portugal]Source :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.
Url:
DOI: 10.1371/journal.pone.0181065
PubMed: 28742140
PubMed Central: 5524367
Affiliations:
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wicri:step="Checkpoint">000722</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes</title><author><name sortKey="Pires, Vanessa Borges" sort="Pires, Vanessa Borges" uniqKey="Pires V" first="Vanessa Borges" last="Pires">Vanessa Borges Pires</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal</addr-line></nlm:aff><country xml:lang="fr">Portugal</country><wicri:regionArea>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa</wicri:regionArea><wicri:noRegion>Lisboa</wicri:noRegion></affiliation></author><author><name sortKey="Sim Es, Ricardo" sort="Sim Es, Ricardo" uniqKey="Sim Es R" first="Ricardo" last="Sim Es">Ricardo Sim Es</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal</addr-line></nlm:aff><country xml:lang="fr">Portugal</country><wicri:regionArea>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa</wicri:regionArea><wicri:noRegion>Lisboa</wicri:noRegion></affiliation></author><author><name sortKey="Mamchaoui, Kamel" sort="Mamchaoui, Kamel" uniqKey="Mamchaoui K" first="Kamel" last="Mamchaoui">Kamel Mamchaoui</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>Center for Research in Myology, INSERM UMRS974, CNRS FRE3617, Sorbonne Universités, UPMC Univ Paris 06, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Center for Research in Myology, INSERM UMRS974, CNRS FRE3617, Sorbonne Universités, UPMC Univ Paris 06, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Carvalho, Celia" sort="Carvalho, Celia" uniqKey="Carvalho C" first="Célia" last="Carvalho">Célia Carvalho</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal</addr-line></nlm:aff><country xml:lang="fr">Portugal</country><wicri:regionArea>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa</wicri:regionArea><wicri:noRegion>Lisboa</wicri:noRegion></affiliation></author><author><name sortKey="Carmo Fonseca, Maria" sort="Carmo Fonseca, Maria" uniqKey="Carmo Fonseca M" first="Maria" last="Carmo-Fonseca">Maria Carmo-Fonseca</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal</addr-line></nlm:aff><country xml:lang="fr">Portugal</country><wicri:regionArea>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa</wicri:regionArea><wicri:noRegion>Lisboa</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28742140</article-id><article-id pub-id-type="pmc">5524367</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0181065</article-id><article-id pub-id-type="publisher-id">PONE-D-16-49790</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Cytoskeletal Proteins</subject><subj-group><subject>Dystrophin</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Nucleotides</subject><subj-group><subject>Oligonucleotides</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Molecular Biology</subject><subj-group><subject>Molecular Biology Techniques</subject><subj-group><subject>Transfection</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Molecular Biology Techniques</subject><subj-group><subject>Transfection</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Cell Biology</subject><subj-group><subject>Cellular Types</subject><subj-group><subject>Animal Cells</subject><subj-group><subject>Stem Cells</subject><subj-group><subject>Myoblasts</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Cell Differentiation</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Nucleotides</subject><subj-group><subject>Oligonucleotides</subject><subj-group><subject>Antisense Oligonucleotides</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Database and Informatics Methods</subject><subj-group><subject>Bioinformatics</subject><subj-group><subject>Sequence Analysis</subject><subj-group><subject>Sequence Motif Analysis</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Neurology</subject><subj-group><subject>Muscular Dystrophies</subject><subj-group><subject>Duchenne Muscular Dystrophy</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Clinical Genetics</subject><subj-group><subject>X-Linked Traits</subject><subj-group><subject>Duchenne Muscular Dystrophy</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Heredity</subject><subj-group><subject>Genetic Linkage</subject><subj-group><subject>Sex Linkage</subject><subj-group><subject>X-Linked Traits</subject><subj-group><subject>Duchenne Muscular Dystrophy</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes</article-title><alt-title alt-title-type="running-head">Short LNA SSOs restore dystrophin production in DMD myotubes</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Pires</surname><given-names>Vanessa Borges</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Simões</surname><given-names>Ricardo</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mamchaoui</surname><given-names>Kamel</given-names></name><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-5980-595X</contrib-id><name><surname>Carvalho</surname><given-names>Célia</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Carmo-Fonseca</surname><given-names>Maria</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Center for Research in Myology, INSERM UMRS974, CNRS FRE3617, Sorbonne Universités, UPMC Univ Paris 06, Paris, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Buratti</surname><given-names>Emanuele</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>International Centre for Genetic Engineering and Biotechnology, ITALY</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>carmo.fonseca@medicina.ulisboa.pt</email> (MCF); <email>hcelia@medicina.ulisboa.pt</email> (CC)</corresp></author-notes><pub-date pub-type="epub"><day>24</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>7</issue><elocation-id>e0181065</elocation-id><history><date date-type="received"><day>16</day><month>12</month><year>2016</year></date><date date-type="accepted"><day>26</day><month>6</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Pires et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Pires et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0181065.pdf"></self-uri><abstract><p>Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.</p></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001871</institution-id><institution>Fundação para a Ciência e a Tecnologia</institution></institution-wrap></funding-source><award-id>FCT-ANR/BIM-ONC/0009/2013</award-id></award-group><award-group id="award002"><funding-source><institution>Faculdade de Medicina da Universidade de Lisboa (PT)</institution></funding-source><award-id>GAPIC 2012009 GAPIC 20130041</award-id><principal-award-recipient><name><surname>Simões</surname><given-names>Ricardo</given-names></name></principal-award-recipient></award-group><funding-statement>This work was supported by Fundação para a Ciência e Tecnologia, Portugal (FCT-ANR/BIM-ONC/0009/2013), <ext-link ext-link-type="uri" xlink:href="http://www.fct.pt/">http://www.fct.pt/</ext-link>; Faculdade de Medicina da Universidade de Lisboa, Gabinete de Apoio à Investigação Científica, Tecnológica e Inovação, Portugal (GAPIC 2012009 GAPIC 20130041 (RS)), <ext-link ext-link-type="uri" xlink:href="http://www.medicina.ulisboa.pt/investigacao/gapic/">http://www.medicina.ulisboa.pt/investigacao/gapic/</ext-link>. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="5"></fig-count><table-count count="0"></table-count><page-count count="13"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the paper and its Supporting Information files.</p></notes></front></pmc><affiliations><list><country><li>France</li><li>Portugal</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="Portugal"><noRegion><name sortKey="Pires, Vanessa Borges" sort="Pires, Vanessa Borges" uniqKey="Pires V" first="Vanessa Borges" last="Pires">Vanessa Borges Pires</name></noRegion><name sortKey="Carmo Fonseca, Maria" sort="Carmo Fonseca, Maria" uniqKey="Carmo Fonseca M" first="Maria" last="Carmo-Fonseca">Maria Carmo-Fonseca</name><name sortKey="Carvalho, Celia" sort="Carvalho, Celia" uniqKey="Carvalho C" first="Célia" last="Carvalho">Célia Carvalho</name><name sortKey="Sim Es, Ricardo" sort="Sim Es, Ricardo" uniqKey="Sim Es R" first="Ricardo" last="Sim Es">Ricardo Sim Es</name></country><country name="France"><region name="Île-de-France"><name sortKey="Mamchaoui, Kamel" sort="Mamchaoui, Kamel" uniqKey="Mamchaoui K" first="Kamel" last="Mamchaoui">Kamel Mamchaoui</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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