Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model
Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF s...
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| Veröffentlicht in: | Molecular therapy 2013-05, Vol.21 (5), p.947-953 |
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| creator | Potash, Andrea E Wallen, Tanner J Karp, Philip H Ernst, Sarah Moninger, Thomas O Gansemer, Nicholas D Stoltz, David A Zabner, Joseph Chang, Eugene H |
| description | Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17–28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis. |
| doi_str_mv | 10.1038/mt.2013.49 |
| format | Article |
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The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17–28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2013.49</identifier><identifier>PMID: 23511247</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenoviridae - genetics ; Adenovirus ; Adenoviruses ; Animals ; Animals, Genetically Modified ; Biological Transport ; Cyclic AMP - metabolism ; Cystic Fibrosis - genetics ; Cystic Fibrosis - metabolism ; Cystic Fibrosis - therapy ; Cystic Fibrosis Transmembrane Conductance Regulator - genetics ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Disease Models, Animal ; Drug dosages ; Gene Expression ; Gene therapy ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors - genetics ; Genotype & phenotype ; Green Fluorescent Proteins - genetics ; Hogs ; Humans ; Hypotheses ; Kinases ; Microscopy ; Mutation ; Nasal Mucosa - metabolism ; Nasal Mucosa - ultrastructure ; Original ; Pathogenesis ; Sinuses ; Sinusitis ; Sodium - metabolism ; Swine ; Tissue Culture Techniques ; Transduction, Genetic ; Transgenes</subject><ispartof>Molecular therapy, 2013-05, Vol.21 (5), p.947-953</ispartof><rights>2013 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group May 2013</rights><rights>Copyright © 2013 The American Society of Gene & Cell Therapy 2013 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c484t-dc8d07f5b4aa2fce5d7400e29f9af16b2ff57da14cf0abf6e34ece179a466c6f3</citedby><cites>FETCH-LOGICAL-c484t-dc8d07f5b4aa2fce5d7400e29f9af16b2ff57da14cf0abf6e34ece179a466c6f3</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/PMC3666638/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1792507455?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23511247$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Potash, Andrea E</creatorcontrib><creatorcontrib>Wallen, Tanner J</creatorcontrib><creatorcontrib>Karp, Philip H</creatorcontrib><creatorcontrib>Ernst, Sarah</creatorcontrib><creatorcontrib>Moninger, Thomas O</creatorcontrib><creatorcontrib>Gansemer, Nicholas D</creatorcontrib><creatorcontrib>Stoltz, David A</creatorcontrib><creatorcontrib>Zabner, Joseph</creatorcontrib><creatorcontrib>Chang, Eugene H</creatorcontrib><title>Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17–28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.</description><subject>Adenoviridae - genetics</subject><subject>Adenovirus</subject><subject>Adenoviruses</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Biological Transport</subject><subject>Cyclic AMP - metabolism</subject><subject>Cystic Fibrosis - genetics</subject><subject>Cystic Fibrosis - metabolism</subject><subject>Cystic Fibrosis - therapy</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - genetics</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drug dosages</subject><subject>Gene Expression</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - genetics</subject><subject>Genotype & phenotype</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Hogs</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Kinases</subject><subject>Microscopy</subject><subject>Mutation</subject><subject>Nasal Mucosa - metabolism</subject><subject>Nasal Mucosa - ultrastructure</subject><subject>Original</subject><subject>Pathogenesis</subject><subject>Sinuses</subject><subject>Sinusitis</subject><subject>Sodium - metabolism</subject><subject>Swine</subject><subject>Tissue Culture Techniques</subject><subject>Transduction, Genetic</subject><subject>Transgenes</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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>eNqFkVFLHDEUhUNpqdb2xR8ggb6IsGuSSTKTl4Js1QqKhdrnkE1uNDKTbJOZhf57s127tEVoXnIv5-Nw7z0IHVIyp6TpTodxzght5ly9QvtUMDEjhPHXu5rKPfSulMdaUaHkW7THGkEp4-0-uj9zENM6ZNPjS4iA77KJxUPGi5Qz2LHg8QHwVYpbZZXyiD-DrwoO8Zf2LcSp4PNVqE0fDE4eG_w1ZRuq3eIC3yQH_Xv0xpu-wIfn_wB9vzi_W3yZXd9eXi3OrmeWd3ycOds50nqx5MYwb0G4lhMCTHllPJVL5r1onaHcemKWXkLDwQJtleFSWumbA_Rp67ualgM4C3Gsq-lVDoPJP3UyQf-txPCg79NaN7K-pqsGx88GOf2YoIx6CMVC35sIaSqaStkxKaQi_0ebupNSTMmKfvwHfUxTjvUSug7PBGm5EJU62VI2p1Iy-N3clOhN1HoY9SZqzVWFj_7cdIf-zrYCfAtAvfc6QNbFBogWXNgEq10KL_k-AVgYtqE</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Potash, Andrea E</creator><creator>Wallen, Tanner J</creator><creator>Karp, Philip H</creator><creator>Ernst, Sarah</creator><creator>Moninger, Thomas O</creator><creator>Gansemer, Nicholas D</creator><creator>Stoltz, David A</creator><creator>Zabner, Joseph</creator><creator>Chang, Eugene H</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20130501</creationdate><title>Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model</title><author>Potash, Andrea E ; Wallen, Tanner J ; Karp, Philip H ; Ernst, Sarah ; Moninger, Thomas O ; Gansemer, Nicholas D ; Stoltz, David A ; Zabner, Joseph ; Chang, Eugene H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c484t-dc8d07f5b4aa2fce5d7400e29f9af16b2ff57da14cf0abf6e34ece179a466c6f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adenoviridae - genetics</topic><topic>Adenovirus</topic><topic>Adenoviruses</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Biological Transport</topic><topic>Cyclic AMP - metabolism</topic><topic>Cystic Fibrosis - genetics</topic><topic>Cystic Fibrosis - metabolism</topic><topic>Cystic Fibrosis - therapy</topic><topic>Cystic Fibrosis Transmembrane Conductance Regulator - genetics</topic><topic>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</topic><topic>Disease Models, Animal</topic><topic>Drug dosages</topic><topic>Gene Expression</topic><topic>Gene therapy</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - genetics</topic><topic>Genotype & phenotype</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Hogs</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Kinases</topic><topic>Microscopy</topic><topic>Mutation</topic><topic>Nasal Mucosa - metabolism</topic><topic>Nasal Mucosa - ultrastructure</topic><topic>Original</topic><topic>Pathogenesis</topic><topic>Sinuses</topic><topic>Sinusitis</topic><topic>Sodium - metabolism</topic><topic>Swine</topic><topic>Tissue Culture Techniques</topic><topic>Transduction, Genetic</topic><topic>Transgenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Potash, Andrea E</creatorcontrib><creatorcontrib>Wallen, Tanner J</creatorcontrib><creatorcontrib>Karp, Philip H</creatorcontrib><creatorcontrib>Ernst, Sarah</creatorcontrib><creatorcontrib>Moninger, Thomas O</creatorcontrib><creatorcontrib>Gansemer, Nicholas D</creatorcontrib><creatorcontrib>Stoltz, David A</creatorcontrib><creatorcontrib>Zabner, Joseph</creatorcontrib><creatorcontrib>Chang, Eugene H</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Potash, Andrea E</au><au>Wallen, Tanner J</au><au>Karp, Philip H</au><au>Ernst, Sarah</au><au>Moninger, Thomas O</au><au>Gansemer, Nicholas D</au><au>Stoltz, David A</au><au>Zabner, Joseph</au><au>Chang, Eugene H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>21</volume><issue>5</issue><spage>947</spage><epage>953</epage><pages>947-953</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Cystic fibrosis (CF) pigs spontaneously develop sinus and lung disease resembling human CF. The CF pig presents a unique opportunity to use gene transfer to test hypotheses to further understand the pathogenesis of CF sinus disease. In this study, we investigated the ion transport defect in the CF sinus and found that CF porcine sinus epithelia lack cyclic AMP (cAMP)-stimulated anion transport. We asked whether we could restore CF transmembrane conductance regulator gene (CFTR) current in the porcine CF sinus epithelia by gene transfer. We quantified CFTR transduction using an adenovirus expressing CFTR and green fluorescent protein (GFP). We found that as little as 7% of transduced cells restored 6% of CFTR current with 17–28% of transduced cells increasing CFTR current to 50% of non-CF levels. We also found that we could overcorrect cAMP-mediated current in non-CF epithelia. Our findings indicate that CF porcine sinus epithelia lack anion transport, and a relatively small number of cells expressing CFTR are required to rescue the ion transport phenotype. These studies support the use of the CF pig as a preclinical model for future gene therapy trials in CF sinusitis.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23511247</pmid><doi>10.1038/mt.2013.49</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenoviridae - genetics Adenovirus Adenoviruses Animals Animals, Genetically Modified Biological Transport Cyclic AMP - metabolism Cystic Fibrosis - genetics Cystic Fibrosis - metabolism Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Disease Models, Animal Drug dosages Gene Expression Gene therapy Gene Transfer Techniques Genetic Therapy Genetic Vectors - genetics Genotype & phenotype Green Fluorescent Proteins - genetics Hogs Humans Hypotheses Kinases Microscopy Mutation Nasal Mucosa - metabolism Nasal Mucosa - ultrastructure Original Pathogenesis Sinuses Sinusitis Sodium - metabolism Swine Tissue Culture Techniques Transduction, Genetic Transgenes |
| title | Adenoviral Gene Transfer Corrects the Ion Transport Defect in the Sinus Epithelia of a Porcine CF Model |
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