Cationic PMMA Nanoparticles Bind and Deliver Antisense Oligoribonucleotides Allowing Restoration of Dystrophin Expression in the mdx Mouse
For subsets of Duchenne muscular dystrophy (DMD) mutations, antisense oligoribonucleotide (AON)-mediated exon skipping has proven to be efficacious in restoring the expression of dystrophin protein. In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23,...
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| Veröffentlicht in: | Molecular therapy 2009-05, Vol.17 (5), p.820-827 |
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| creator | Rimessi, Paola Sabatelli, Patrizia Fabris, Marina Braghetta, Paola Bassi, Elena Spitali, Pietro Vattemi, Gaetano Tomelleri, Giuliano Mari, Lara Perrone, Daniela Medici, Alessandro Neri, Marcella Bovolenta, Matteo Martoni, Elena Maraldi, Nadir M. Gualandi, Francesca Merlini, Luciano Ballestri, Marco Tondelli, Luisa Sparnacci, Katia Bonaldo, Paolo Caputo, Antonella Laus, Michele Ferlini, Alessandra |
| description | For subsets of Duchenne muscular dystrophy (DMD) mutations, antisense oligoribonucleotide (AON)-mediated exon skipping has proven to be efficacious in restoring the expression of dystrophin protein. In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23, has shown proof of concept. Here, we show that using cationic polymethylmethacrylate (PMMA) (marked as T1) nanoparticles loaded with a low dose of 2′-O-methyl-phosphorothioate (2′OMePS) AON delivered by weekly intraperitoneal (IP) injection (0.9 mg/kg/week), could restore dystrophin expression in body-wide striated muscles. Delivery of an identical dose of naked AON did not result in detectable dystrophin expression. Transcription, western, and immunohistochemical analysis showed increased levels of dystrophin transcript and protein, and correct localization at the sarcolemma. This study shows that T1 nanoparticles have the capacity to bind and convoy AONs in body-wide muscle tissues and to reduce the dose required for dystrophin rescue. By immunofluorescence and electron microscopy studies, we highlighted the diffusion pathways of this compound. This nonviral approach may valuably improve the therapeutic usage of AONs in DMD as well as the delivery of RNA molecules with many implications in both basic research and medicine. |
| doi_str_mv | 10.1038/mt.2009.8 |
| format | Article |
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In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23, has shown proof of concept. Here, we show that using cationic polymethylmethacrylate (PMMA) (marked as T1) nanoparticles loaded with a low dose of 2′-O-methyl-phosphorothioate (2′OMePS) AON delivered by weekly intraperitoneal (IP) injection (0.9 mg/kg/week), could restore dystrophin expression in body-wide striated muscles. Delivery of an identical dose of naked AON did not result in detectable dystrophin expression. Transcription, western, and immunohistochemical analysis showed increased levels of dystrophin transcript and protein, and correct localization at the sarcolemma. This study shows that T1 nanoparticles have the capacity to bind and convoy AONs in body-wide muscle tissues and to reduce the dose required for dystrophin rescue. By immunofluorescence and electron microscopy studies, we highlighted the diffusion pathways of this compound. This nonviral approach may valuably improve the therapeutic usage of AONs in DMD as well as the delivery of RNA molecules with many implications in both basic research and medicine.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2009.8</identifier><identifier>PMID: 19240694</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Biodistribution ; Blotting, Western ; Cardiomyopathy ; Drug dosages ; Dystrophin - genetics ; Dystrophin - metabolism ; Electrophoresis, Polyacrylamide Gel ; Emulsion polymerization ; Exons - genetics ; Gene therapy ; Genetic Therapy - methods ; Heart ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred mdx ; Mice, Mutant Strains ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Muscular dystrophy ; Muscular Dystrophy, Animal - genetics ; Muscular Dystrophy, Animal - therapy ; Musculoskeletal system ; Mutation ; Nanoparticles ; Nanoparticles - chemistry ; Oligoribonucleotides, Antisense - genetics ; Oligoribonucleotides, Antisense - metabolism ; Oligoribonucleotides, Antisense - physiology ; Original ; Peptides ; Polymethyl Methacrylate - chemical synthesis ; Polymethyl Methacrylate - chemistry ; Proteins</subject><ispartof>Molecular therapy, 2009-05, Vol.17 (5), p.820-827</ispartof><rights>2009 The American Society of Gene Therapy</rights><rights>Copyright Nature Publishing Group May 2009</rights><rights>Copyright 2009, The American Society of Gene Therapy 2009 The American Society of Gene Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-a5996d20628cb54b25eddc136efb2d8cc2d2840244a4d2f7314b180d900519ef3</citedby><cites>FETCH-LOGICAL-c445t-a5996d20628cb54b25eddc136efb2d8cc2d2840244a4d2f7314b180d900519ef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835127/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1792594398?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771,64361,64365,72215</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19240694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rimessi, Paola</creatorcontrib><creatorcontrib>Sabatelli, Patrizia</creatorcontrib><creatorcontrib>Fabris, Marina</creatorcontrib><creatorcontrib>Braghetta, Paola</creatorcontrib><creatorcontrib>Bassi, Elena</creatorcontrib><creatorcontrib>Spitali, Pietro</creatorcontrib><creatorcontrib>Vattemi, Gaetano</creatorcontrib><creatorcontrib>Tomelleri, Giuliano</creatorcontrib><creatorcontrib>Mari, Lara</creatorcontrib><creatorcontrib>Perrone, Daniela</creatorcontrib><creatorcontrib>Medici, Alessandro</creatorcontrib><creatorcontrib>Neri, Marcella</creatorcontrib><creatorcontrib>Bovolenta, Matteo</creatorcontrib><creatorcontrib>Martoni, Elena</creatorcontrib><creatorcontrib>Maraldi, Nadir M.</creatorcontrib><creatorcontrib>Gualandi, Francesca</creatorcontrib><creatorcontrib>Merlini, Luciano</creatorcontrib><creatorcontrib>Ballestri, Marco</creatorcontrib><creatorcontrib>Tondelli, Luisa</creatorcontrib><creatorcontrib>Sparnacci, Katia</creatorcontrib><creatorcontrib>Bonaldo, Paolo</creatorcontrib><creatorcontrib>Caputo, Antonella</creatorcontrib><creatorcontrib>Laus, Michele</creatorcontrib><creatorcontrib>Ferlini, Alessandra</creatorcontrib><title>Cationic PMMA Nanoparticles Bind and Deliver Antisense Oligoribonucleotides Allowing Restoration of Dystrophin Expression in the mdx Mouse</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>For subsets of Duchenne muscular dystrophy (DMD) mutations, antisense oligoribonucleotide (AON)-mediated exon skipping has proven to be efficacious in restoring the expression of dystrophin protein. In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23, has shown proof of concept. Here, we show that using cationic polymethylmethacrylate (PMMA) (marked as T1) nanoparticles loaded with a low dose of 2′-O-methyl-phosphorothioate (2′OMePS) AON delivered by weekly intraperitoneal (IP) injection (0.9 mg/kg/week), could restore dystrophin expression in body-wide striated muscles. Delivery of an identical dose of naked AON did not result in detectable dystrophin expression. Transcription, western, and immunohistochemical analysis showed increased levels of dystrophin transcript and protein, and correct localization at the sarcolemma. This study shows that T1 nanoparticles have the capacity to bind and convoy AONs in body-wide muscle tissues and to reduce the dose required for dystrophin rescue. By immunofluorescence and electron microscopy studies, we highlighted the diffusion pathways of this compound. This nonviral approach may valuably improve the therapeutic usage of AONs in DMD as well as the delivery of RNA molecules with many implications in both basic research and medicine.</description><subject>Animals</subject><subject>Biodistribution</subject><subject>Blotting, Western</subject><subject>Cardiomyopathy</subject><subject>Drug dosages</subject><subject>Dystrophin - genetics</subject><subject>Dystrophin - metabolism</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Emulsion polymerization</subject><subject>Exons - genetics</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Heart</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred mdx</subject><subject>Mice, Mutant Strains</subject><subject>Microscopy, Electron, Transmission</subject><subject>Microscopy, Fluorescence</subject><subject>Muscular dystrophy</subject><subject>Muscular Dystrophy, Animal - genetics</subject><subject>Muscular Dystrophy, Animal - therapy</subject><subject>Musculoskeletal system</subject><subject>Mutation</subject><subject>Nanoparticles</subject><subject>Nanoparticles - chemistry</subject><subject>Oligoribonucleotides, Antisense - genetics</subject><subject>Oligoribonucleotides, Antisense - metabolism</subject><subject>Oligoribonucleotides, Antisense - physiology</subject><subject>Original</subject><subject>Peptides</subject><subject>Polymethyl Methacrylate - chemical synthesis</subject><subject>Polymethyl Methacrylate - chemistry</subject><subject>Proteins</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkcFuEzEQhi0EoqVw4AWQJU4cEmyvvVlfkELaAlJDEYKz5bVnE1e79mJ7Q_sKPHUdEhWQOIxmrPn0z3h-hF5SMqekat4Oec4IkfPmETqlgokZIYw_fqhpfYKepXRTKipk_RSdUMk4qSU_Rb9WOrvgncFf1usl_qx9GHXMzvSQ8HvnLdYlzqF3O4h46bNL4BPg695tQnRt8FNBQ3a28Mu-Dz-d3-CvkHKIv5Vx6PD5XcoxjFvn8cXtGCGlfaO88hbwYG_xOkwJnqMnne4TvDjmM_T98uLb6uPs6vrDp9XyamY4F3mmhZS1ZaRmjWkFb5kAaw2tauhaZhtjmGUNLwfgmlvWLSrKW9oQKwkRVEJXnaF3B91xagewBnyOuldjdIOOdypop_7teLdVm7BTrKkEZYsi8PooEMOPqXxV3YQp-rKzogvJhOSVbAr15kCZGFKK0D1MoETtbVNDVnvb1J599fdKf8ijTwWoDgCUw-wcRJWMA2_AuggmKxvcf2TvAVibp7g</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>Rimessi, Paola</creator><creator>Sabatelli, Patrizia</creator><creator>Fabris, Marina</creator><creator>Braghetta, Paola</creator><creator>Bassi, Elena</creator><creator>Spitali, Pietro</creator><creator>Vattemi, Gaetano</creator><creator>Tomelleri, Giuliano</creator><creator>Mari, Lara</creator><creator>Perrone, Daniela</creator><creator>Medici, Alessandro</creator><creator>Neri, Marcella</creator><creator>Bovolenta, Matteo</creator><creator>Martoni, Elena</creator><creator>Maraldi, Nadir M.</creator><creator>Gualandi, Francesca</creator><creator>Merlini, Luciano</creator><creator>Ballestri, Marco</creator><creator>Tondelli, Luisa</creator><creator>Sparnacci, Katia</creator><creator>Bonaldo, Paolo</creator><creator>Caputo, Antonella</creator><creator>Laus, Michele</creator><creator>Ferlini, Alessandra</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20090501</creationdate><title>Cationic PMMA Nanoparticles Bind and Deliver Antisense Oligoribonucleotides Allowing Restoration of Dystrophin Expression in the mdx Mouse</title><author>Rimessi, Paola ; Sabatelli, Patrizia ; Fabris, Marina ; Braghetta, Paola ; Bassi, Elena ; Spitali, Pietro ; Vattemi, Gaetano ; Tomelleri, Giuliano ; Mari, Lara ; Perrone, Daniela ; Medici, Alessandro ; Neri, Marcella ; Bovolenta, Matteo ; Martoni, Elena ; Maraldi, Nadir M. ; Gualandi, Francesca ; Merlini, Luciano ; Ballestri, Marco ; Tondelli, Luisa ; Sparnacci, Katia ; Bonaldo, Paolo ; Caputo, Antonella ; Laus, Michele ; Ferlini, Alessandra</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-a5996d20628cb54b25eddc136efb2d8cc2d2840244a4d2f7314b180d900519ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Biodistribution</topic><topic>Blotting, Western</topic><topic>Cardiomyopathy</topic><topic>Drug dosages</topic><topic>Dystrophin - 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In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23, has shown proof of concept. Here, we show that using cationic polymethylmethacrylate (PMMA) (marked as T1) nanoparticles loaded with a low dose of 2′-O-methyl-phosphorothioate (2′OMePS) AON delivered by weekly intraperitoneal (IP) injection (0.9 mg/kg/week), could restore dystrophin expression in body-wide striated muscles. Delivery of an identical dose of naked AON did not result in detectable dystrophin expression. Transcription, western, and immunohistochemical analysis showed increased levels of dystrophin transcript and protein, and correct localization at the sarcolemma. This study shows that T1 nanoparticles have the capacity to bind and convoy AONs in body-wide muscle tissues and to reduce the dose required for dystrophin rescue. By immunofluorescence and electron microscopy studies, we highlighted the diffusion pathways of this compound. This nonviral approach may valuably improve the therapeutic usage of AONs in DMD as well as the delivery of RNA molecules with many implications in both basic research and medicine.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19240694</pmid><doi>10.1038/mt.2009.8</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1525-0016 |
| ispartof | Molecular therapy, 2009-05, Vol.17 (5), p.820-827 |
| issn | 1525-0016 1525-0024 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2835127 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ProQuest Central UK/Ireland; PubMed Central; Alma/SFX Local Collection |
| subjects | Animals Biodistribution Blotting, Western Cardiomyopathy Drug dosages Dystrophin - genetics Dystrophin - metabolism Electrophoresis, Polyacrylamide Gel Emulsion polymerization Exons - genetics Gene therapy Genetic Therapy - methods Heart Immunohistochemistry Male Mice Mice, Inbred mdx Mice, Mutant Strains Microscopy, Electron, Transmission Microscopy, Fluorescence Muscular dystrophy Muscular Dystrophy, Animal - genetics Muscular Dystrophy, Animal - therapy Musculoskeletal system Mutation Nanoparticles Nanoparticles - chemistry Oligoribonucleotides, Antisense - genetics Oligoribonucleotides, Antisense - metabolism Oligoribonucleotides, Antisense - physiology Original Peptides Polymethyl Methacrylate - chemical synthesis Polymethyl Methacrylate - chemistry Proteins |
| title | Cationic PMMA Nanoparticles Bind and Deliver Antisense Oligoribonucleotides Allowing Restoration of Dystrophin Expression in the mdx Mouse |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-25T09%3A07%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cationic%20PMMA%20Nanoparticles%20Bind%20and%20Deliver%20Antisense%20Oligoribonucleotides%20Allowing%20Restoration%20of%20Dystrophin%20Expression%20in%20the%20mdx%20Mouse&rft.jtitle=Molecular%20therapy&rft.au=Rimessi,%20Paola&rft.date=2009-05-01&rft.volume=17&rft.issue=5&rft.spage=820&rft.epage=827&rft.pages=820-827&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1038/mt.2009.8&rft_dat=%3Cproquest_pubme%3E4072893951%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1792594398&rft_id=info:pmid/19240694&rft_els_id=S1525001616317804&rfr_iscdi=true |