Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs
Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal e...
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| Veröffentlicht in: | Molecular pharmaceutics 2018-02, Vol.15 (2), p.377-384 |
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| creator | Leyman, Bregje Huysmans, Hanne Mc Cafferty, Séan Combes, Francis Cox, Eric Devriendt, Bert Sanders, Niek N |
| description | Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA. The self-replicating mRNA tended to induce the highest protein expression, followed by pDNA, modified mRNA, and unmodified mRNA. Interestingly, the self-replicating mRNA was able to maintain its high expression levels during at least 12 days. In contrast, the expression of pDNA and the nonreplicating mRNAs dropped after respectively one and two days. Six days after intradermal electroporation a dose-dependent expression was observed for all vectors. Again, also at lower doses, the self-replicating mRNA tended to show the highest expression. All the mRNA vectors, including the modified mRNA, induced elevated levels of mRNA encoding cytokines and chemokines in the porcine skin after intradermal electroporation, while no such response was noticed after intradermal electroporation of the pDNA vector. |
| doi_str_mv | 10.1021/acs.molpharmaceut.7b00722 |
| format | Article |
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Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA. The self-replicating mRNA tended to induce the highest protein expression, followed by pDNA, modified mRNA, and unmodified mRNA. Interestingly, the self-replicating mRNA was able to maintain its high expression levels during at least 12 days. In contrast, the expression of pDNA and the nonreplicating mRNAs dropped after respectively one and two days. Six days after intradermal electroporation a dose-dependent expression was observed for all vectors. Again, also at lower doses, the self-replicating mRNA tended to show the highest expression. All the mRNA vectors, including the modified mRNA, induced elevated levels of mRNA encoding cytokines and chemokines in the porcine skin after intradermal electroporation, while no such response was noticed after intradermal electroporation of the pDNA vector.</description><identifier>ISSN: 1543-8384</identifier><identifier>EISSN: 1543-8392</identifier><identifier>DOI: 10.1021/acs.molpharmaceut.7b00722</identifier><identifier>PMID: 29297692</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Chemokines - immunology ; Chemokines - metabolism ; Cytokines - immunology ; Cytokines - metabolism ; DNA, Circular - administration & dosage ; DNA, Circular - genetics ; DNA, Circular - metabolism ; Electroporation - methods ; Female ; Gene Transfer Techniques ; Genetic Therapy - methods ; Genetic Vectors - genetics ; Immunity - genetics ; Kinetics ; Mice, Inbred BALB C ; Models, Animal ; Plasmids - administration & dosage ; Plasmids - genetics ; RNA, Messenger - administration & dosage ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Skin - metabolism ; Sus scrofa</subject><ispartof>Molecular pharmaceutics, 2018-02, Vol.15 (2), p.377-384</ispartof><rights>Copyright © 2018 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a363t-46ae65c91bf3e0a110977543bfb8729b926d00f49b5e2c63661dd907ebc9d3b63</citedby><cites>FETCH-LOGICAL-a363t-46ae65c91bf3e0a110977543bfb8729b926d00f49b5e2c63661dd907ebc9d3b63</cites><orcidid>0000-0003-4585-0343</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.molpharmaceut.7b00722$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.molpharmaceut.7b00722$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27080,27928,27929,56742,56792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29297692$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leyman, Bregje</creatorcontrib><creatorcontrib>Huysmans, Hanne</creatorcontrib><creatorcontrib>Mc Cafferty, Séan</creatorcontrib><creatorcontrib>Combes, Francis</creatorcontrib><creatorcontrib>Cox, Eric</creatorcontrib><creatorcontrib>Devriendt, Bert</creatorcontrib><creatorcontrib>Sanders, Niek N</creatorcontrib><title>Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs</title><title>Molecular pharmaceutics</title><addtitle>Mol. Pharmaceutics</addtitle><description>Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA. The self-replicating mRNA tended to induce the highest protein expression, followed by pDNA, modified mRNA, and unmodified mRNA. Interestingly, the self-replicating mRNA was able to maintain its high expression levels during at least 12 days. In contrast, the expression of pDNA and the nonreplicating mRNAs dropped after respectively one and two days. Six days after intradermal electroporation a dose-dependent expression was observed for all vectors. Again, also at lower doses, the self-replicating mRNA tended to show the highest expression. All the mRNA vectors, including the modified mRNA, induced elevated levels of mRNA encoding cytokines and chemokines in the porcine skin after intradermal electroporation, while no such response was noticed after intradermal electroporation of the pDNA vector.</description><subject>Animals</subject><subject>Chemokines - immunology</subject><subject>Chemokines - metabolism</subject><subject>Cytokines - immunology</subject><subject>Cytokines - metabolism</subject><subject>DNA, Circular - administration & dosage</subject><subject>DNA, Circular - genetics</subject><subject>DNA, Circular - metabolism</subject><subject>Electroporation - methods</subject><subject>Female</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - genetics</subject><subject>Immunity - genetics</subject><subject>Kinetics</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Animal</subject><subject>Plasmids - administration & dosage</subject><subject>Plasmids - genetics</subject><subject>RNA, Messenger - administration & dosage</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Skin - metabolism</subject><subject>Sus scrofa</subject><issn>1543-8384</issn><issn>1543-8392</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1uEzEUhS1ERUvhFZDZsSDBPzOe8TIKASKqtKpgPbI9d1pXY3uwPYg8Dm-Ko4RKiE1X9-rqnHN19CH0lpIlJYx-UCYtXRinexWdMjDnZaMJaRh7hi5oXfFFyyV7_ri31Tl6mdIDIayqGX-BzplkshGSXaDf6-AmFW0KHocB53vAm19ThJRsuXy1HrI1CSvf461zsw8pWzePKoe4xyuT7U-b9wfnLUyjNSpbf4fd7W71Hu-Cj_8dD0HTx90KqyFDxFufo-qh1BjxZgSTY5hCLIby3Hp8Y-_SK3Q2qDHB69O8RN8_bb6tvyyurj9v16urheKC50UlFIjaSKoHDkRRSmTTlP560G3DpJZM9IQMldQ1MCO4ELTvJWlAG9lzLfglenfMnWL4MUPKnbPJwDgqD2FOHZVtxSpRtU2RyqPUxJBShKGbonUq7jtKugOhrhDq_iHUnQgV75vTm1k76B-df5EUQX0UHDIewhx9af2E4D_JoKgA</recordid><startdate>20180205</startdate><enddate>20180205</enddate><creator>Leyman, Bregje</creator><creator>Huysmans, Hanne</creator><creator>Mc Cafferty, Séan</creator><creator>Combes, Francis</creator><creator>Cox, Eric</creator><creator>Devriendt, Bert</creator><creator>Sanders, Niek N</creator><general>American Chemical Society</general><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>7X8</scope><orcidid>https://orcid.org/0000-0003-4585-0343</orcidid></search><sort><creationdate>20180205</creationdate><title>Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs</title><author>Leyman, Bregje ; Huysmans, Hanne ; Mc Cafferty, Séan ; Combes, Francis ; Cox, Eric ; Devriendt, Bert ; Sanders, Niek N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a363t-46ae65c91bf3e0a110977543bfb8729b926d00f49b5e2c63661dd907ebc9d3b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Chemokines - immunology</topic><topic>Chemokines - metabolism</topic><topic>Cytokines - immunology</topic><topic>Cytokines - metabolism</topic><topic>DNA, Circular - administration & dosage</topic><topic>DNA, Circular - genetics</topic><topic>DNA, Circular - metabolism</topic><topic>Electroporation - methods</topic><topic>Female</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - genetics</topic><topic>Immunity - genetics</topic><topic>Kinetics</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Animal</topic><topic>Plasmids - administration & dosage</topic><topic>Plasmids - genetics</topic><topic>RNA, Messenger - administration & dosage</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Skin - metabolism</topic><topic>Sus scrofa</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leyman, Bregje</creatorcontrib><creatorcontrib>Huysmans, Hanne</creatorcontrib><creatorcontrib>Mc Cafferty, Séan</creatorcontrib><creatorcontrib>Combes, Francis</creatorcontrib><creatorcontrib>Cox, Eric</creatorcontrib><creatorcontrib>Devriendt, Bert</creatorcontrib><creatorcontrib>Sanders, Niek N</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmaceutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leyman, Bregje</au><au>Huysmans, Hanne</au><au>Mc Cafferty, Séan</au><au>Combes, Francis</au><au>Cox, Eric</au><au>Devriendt, Bert</au><au>Sanders, Niek N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs</atitle><jtitle>Molecular pharmaceutics</jtitle><addtitle>Mol. Pharmaceutics</addtitle><date>2018-02-05</date><risdate>2018</risdate><volume>15</volume><issue>2</issue><spage>377</spage><epage>384</epage><pages>377-384</pages><issn>1543-8384</issn><eissn>1543-8392</eissn><abstract>Synthetic mRNA is becoming increasingly popular as an alternative to pDNA-based gene therapy. Currently, multiple synthetic mRNA platforms have been developed. In this study we investigated the expression kinetics and the changes in mRNA encoding cytokine and chemokine levels following intradermal electroporation in pigs of pDNA, self-replicating mRNA, and modified and unmodified mRNA. The self-replicating mRNA tended to induce the highest protein expression, followed by pDNA, modified mRNA, and unmodified mRNA. Interestingly, the self-replicating mRNA was able to maintain its high expression levels during at least 12 days. In contrast, the expression of pDNA and the nonreplicating mRNAs dropped after respectively one and two days. 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| subjects | Animals Chemokines - immunology Chemokines - metabolism Cytokines - immunology Cytokines - metabolism DNA, Circular - administration & dosage DNA, Circular - genetics DNA, Circular - metabolism Electroporation - methods Female Gene Transfer Techniques Genetic Therapy - methods Genetic Vectors - genetics Immunity - genetics Kinetics Mice, Inbred BALB C Models, Animal Plasmids - administration & dosage Plasmids - genetics RNA, Messenger - administration & dosage RNA, Messenger - genetics RNA, Messenger - metabolism Skin - metabolism Sus scrofa |
| title | Comparison of the Expression Kinetics and Immunostimulatory Activity of Replicating mRNA, Nonreplicating mRNA, and pDNA after Intradermal Electroporation in Pigs |
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