Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells
MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs...
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Veröffentlicht in: | Molecular therapy 2020-04, Vol.28 (4), p.1190-1199 |
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creator | De Santi, Chiara Fernández Fernández, Elena Gaul, Rachel Vencken, Sebastian Glasgow, Arlene Oglesby, Irene K. Hurley, Killian Hawkins, Finn Mitash, Nilay Mu, Fangping Raoof, Rana Henshall, David C. Cutrona, Meritxell B. Simpson, Jeremy C. Harvey, Brian J. Linnane, Barry McNally, Paul Cryan, Sally Ann MacLoughlin, Ronan Swiatecka-Urban, Agnieszka Greene, Catherine M. |
description | MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3′ untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3′ UTR 298–305:miR-145-5p or 166–173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.
Precise targeting of specific miR-145-5p or miR-223-3p binding sites with target site blockers encapsulated in biocompatible nanoparticles restores CFTR activity and enhances CFTR modulator action in p.Phe508del/p.Phe508del CF bronchial epithelial cells. |
doi_str_mv | 10.1016/j.ymthe.2020.02.001 |
format | Article |
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Precise targeting of specific miR-145-5p or miR-223-3p binding sites with target site blockers encapsulated in biocompatible nanoparticles restores CFTR activity and enhances CFTR modulator action in p.Phe508del/p.Phe508del CF bronchial epithelial cells.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2020.02.001</identifier><identifier>PMID: 32059764</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; ALI culture ; Aminophenols - pharmacology ; Aminopyridines - pharmacology ; Benzodioxoles - pharmacology ; Bronchi - cytology ; Bronchi - drug effects ; Bronchi - metabolism ; Cells, Cultured ; CFTR ; CFTR modulators ; Child ; Child, Preschool ; Cystic Fibrosis - genetics ; Cystic Fibrosis - metabolism ; Cystic Fibrosis - therapy ; Cystic Fibrosis Transmembrane Conductance Regulator - genetics ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Drug Combinations ; Drug Synergism ; Epithelial Cells - cytology ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Female ; High content screening ; Humans ; Indoles - pharmacology ; Infant ; iPSC-derived CF and CFTR gene-corrected bronchosperes ; Male ; microRNA ; MicroRNAs - genetics ; Middle Aged ; Models, Biological ; Nanoparticles ; nebulised PLGA nanoparticles ; Oligonucleotides - genetics ; Oligonucleotides - pharmacology ; Original ; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry ; Primary bronchial epithelial cells ; Quinolones - pharmacology ; RNA sequencing ; target site blocker</subject><ispartof>Molecular therapy, 2020-04, Vol.28 (4), p.1190-1199</ispartof><rights>2020 The American Society of Gene and Cell Therapy</rights><rights>Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.</rights><rights>2020 The American Society of Gene and Cell Therapy. 2020 The American Society of Gene and Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-4e8ba05e6fd9e77b5824d900c732ef98ba2b5200e56fc9dd9729eae5ecbddb3e3</citedby><cites>FETCH-LOGICAL-c509t-4e8ba05e6fd9e77b5824d900c732ef98ba2b5200e56fc9dd9729eae5ecbddb3e3</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/PMC7132615/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132615/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32059764$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Santi, Chiara</creatorcontrib><creatorcontrib>Fernández Fernández, Elena</creatorcontrib><creatorcontrib>Gaul, Rachel</creatorcontrib><creatorcontrib>Vencken, Sebastian</creatorcontrib><creatorcontrib>Glasgow, Arlene</creatorcontrib><creatorcontrib>Oglesby, Irene K.</creatorcontrib><creatorcontrib>Hurley, Killian</creatorcontrib><creatorcontrib>Hawkins, Finn</creatorcontrib><creatorcontrib>Mitash, Nilay</creatorcontrib><creatorcontrib>Mu, Fangping</creatorcontrib><creatorcontrib>Raoof, Rana</creatorcontrib><creatorcontrib>Henshall, David C.</creatorcontrib><creatorcontrib>Cutrona, Meritxell B.</creatorcontrib><creatorcontrib>Simpson, Jeremy C.</creatorcontrib><creatorcontrib>Harvey, Brian J.</creatorcontrib><creatorcontrib>Linnane, Barry</creatorcontrib><creatorcontrib>McNally, Paul</creatorcontrib><creatorcontrib>Cryan, Sally Ann</creatorcontrib><creatorcontrib>MacLoughlin, Ronan</creatorcontrib><creatorcontrib>Swiatecka-Urban, Agnieszka</creatorcontrib><creatorcontrib>Greene, Catherine M.</creatorcontrib><title>Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3′ untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3′ UTR 298–305:miR-145-5p or 166–173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.
Precise targeting of specific miR-145-5p or miR-223-3p binding sites with target site blockers encapsulated in biocompatible nanoparticles restores CFTR activity and enhances CFTR modulator action in p.Phe508del/p.Phe508del CF bronchial epithelial cells.</description><subject>Adult</subject><subject>ALI culture</subject><subject>Aminophenols - pharmacology</subject><subject>Aminopyridines - pharmacology</subject><subject>Benzodioxoles - pharmacology</subject><subject>Bronchi - cytology</subject><subject>Bronchi - drug effects</subject><subject>Bronchi - metabolism</subject><subject>Cells, Cultured</subject><subject>CFTR</subject><subject>CFTR modulators</subject><subject>Child</subject><subject>Child, Preschool</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>Drug Combinations</subject><subject>Drug Synergism</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Female</subject><subject>High content screening</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Infant</subject><subject>iPSC-derived CF and CFTR gene-corrected bronchosperes</subject><subject>Male</subject><subject>microRNA</subject><subject>MicroRNAs - genetics</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Nanoparticles</subject><subject>nebulised PLGA nanoparticles</subject><subject>Oligonucleotides - genetics</subject><subject>Oligonucleotides - pharmacology</subject><subject>Original</subject><subject>Polylactic Acid-Polyglycolic Acid Copolymer - chemistry</subject><subject>Primary bronchial epithelial cells</subject><subject>Quinolones - pharmacology</subject><subject>RNA sequencing</subject><subject>target site blocker</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1KAzEQhYMo1r8nECQv0HWSbXabC4Va6g-ISq3gXdhNZtuU7W5JYqFvb2q16I1XOWTmnJn5CDlnkDBg2eU8WS_CDBMOHBLgCQDbI0dMcNEF4L39nWZZhxx7P4-KCZkdkk7KQcg86x2R9xeH2nqkk8JNMdhmStuKLuz4aUBfbUBPx-hD66IY3k7GdKCDXdmwpraJH_TGtY2e2aKmo6WNy9QbOcS69qfkoCpqj2ff7wl5ux1Nhvfdx-e7h-HgsasFyNDtYb8sQGBWGYl5Xoo-7xkJoPOUYyVjkZeCA6DIKi2NkTmXWKBAXRpTppiekOtt7vKjXKDR2ARX1Grp7KJwa9UWVv2tNHampu1K5SzlGRMxIN0GaNd677DaeRmoDWg1V1-g1Qa0Aq4ix-i6-D125_khGxuutg0Yj19ZdMpri41GYyPxoExr_x3wCd6Okf0</recordid><startdate>20200408</startdate><enddate>20200408</enddate><creator>De Santi, Chiara</creator><creator>Fernández Fernández, Elena</creator><creator>Gaul, Rachel</creator><creator>Vencken, Sebastian</creator><creator>Glasgow, Arlene</creator><creator>Oglesby, Irene K.</creator><creator>Hurley, Killian</creator><creator>Hawkins, Finn</creator><creator>Mitash, Nilay</creator><creator>Mu, Fangping</creator><creator>Raoof, Rana</creator><creator>Henshall, David C.</creator><creator>Cutrona, Meritxell B.</creator><creator>Simpson, Jeremy C.</creator><creator>Harvey, Brian J.</creator><creator>Linnane, Barry</creator><creator>McNally, Paul</creator><creator>Cryan, Sally Ann</creator><creator>MacLoughlin, Ronan</creator><creator>Swiatecka-Urban, Agnieszka</creator><creator>Greene, Catherine M.</creator><general>Elsevier Inc</general><general>American Society of Gene & Cell Therapy</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>5PM</scope></search><sort><creationdate>20200408</creationdate><title>Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells</title><author>De Santi, Chiara ; Fernández Fernández, Elena ; Gaul, Rachel ; Vencken, Sebastian ; Glasgow, Arlene ; Oglesby, Irene K. ; Hurley, Killian ; Hawkins, Finn ; Mitash, Nilay ; Mu, Fangping ; Raoof, Rana ; Henshall, David C. ; Cutrona, Meritxell B. ; Simpson, Jeremy C. ; Harvey, Brian J. ; Linnane, Barry ; McNally, Paul ; Cryan, Sally Ann ; MacLoughlin, Ronan ; Swiatecka-Urban, Agnieszka ; Greene, Catherine M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-4e8ba05e6fd9e77b5824d900c732ef98ba2b5200e56fc9dd9729eae5ecbddb3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>ALI culture</topic><topic>Aminophenols - pharmacology</topic><topic>Aminopyridines - pharmacology</topic><topic>Benzodioxoles - pharmacology</topic><topic>Bronchi - cytology</topic><topic>Bronchi - drug effects</topic><topic>Bronchi - metabolism</topic><topic>Cells, Cultured</topic><topic>CFTR</topic><topic>CFTR modulators</topic><topic>Child</topic><topic>Child, Preschool</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>Drug Combinations</topic><topic>Drug Synergism</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Female</topic><topic>High content screening</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Infant</topic><topic>iPSC-derived CF and CFTR gene-corrected bronchosperes</topic><topic>Male</topic><topic>microRNA</topic><topic>MicroRNAs - genetics</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Nanoparticles</topic><topic>nebulised PLGA nanoparticles</topic><topic>Oligonucleotides - genetics</topic><topic>Oligonucleotides - pharmacology</topic><topic>Original</topic><topic>Polylactic Acid-Polyglycolic Acid Copolymer - chemistry</topic><topic>Primary bronchial epithelial cells</topic><topic>Quinolones - pharmacology</topic><topic>RNA sequencing</topic><topic>target site blocker</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Santi, Chiara</creatorcontrib><creatorcontrib>Fernández Fernández, Elena</creatorcontrib><creatorcontrib>Gaul, Rachel</creatorcontrib><creatorcontrib>Vencken, Sebastian</creatorcontrib><creatorcontrib>Glasgow, Arlene</creatorcontrib><creatorcontrib>Oglesby, Irene K.</creatorcontrib><creatorcontrib>Hurley, Killian</creatorcontrib><creatorcontrib>Hawkins, Finn</creatorcontrib><creatorcontrib>Mitash, Nilay</creatorcontrib><creatorcontrib>Mu, Fangping</creatorcontrib><creatorcontrib>Raoof, Rana</creatorcontrib><creatorcontrib>Henshall, David C.</creatorcontrib><creatorcontrib>Cutrona, Meritxell B.</creatorcontrib><creatorcontrib>Simpson, Jeremy C.</creatorcontrib><creatorcontrib>Harvey, Brian J.</creatorcontrib><creatorcontrib>Linnane, Barry</creatorcontrib><creatorcontrib>McNally, Paul</creatorcontrib><creatorcontrib>Cryan, Sally Ann</creatorcontrib><creatorcontrib>MacLoughlin, Ronan</creatorcontrib><creatorcontrib>Swiatecka-Urban, Agnieszka</creatorcontrib><creatorcontrib>Greene, Catherine M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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>De Santi, Chiara</au><au>Fernández Fernández, Elena</au><au>Gaul, Rachel</au><au>Vencken, Sebastian</au><au>Glasgow, Arlene</au><au>Oglesby, Irene K.</au><au>Hurley, Killian</au><au>Hawkins, Finn</au><au>Mitash, Nilay</au><au>Mu, Fangping</au><au>Raoof, Rana</au><au>Henshall, David C.</au><au>Cutrona, Meritxell B.</au><au>Simpson, Jeremy C.</au><au>Harvey, Brian J.</au><au>Linnane, Barry</au><au>McNally, Paul</au><au>Cryan, Sally Ann</au><au>MacLoughlin, Ronan</au><au>Swiatecka-Urban, Agnieszka</au><au>Greene, Catherine M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2020-04-08</date><risdate>2020</risdate><volume>28</volume><issue>4</issue><spage>1190</spage><epage>1199</epage><pages>1190-1199</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3′ untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3′ UTR 298–305:miR-145-5p or 166–173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.
Precise targeting of specific miR-145-5p or miR-223-3p binding sites with target site blockers encapsulated in biocompatible nanoparticles restores CFTR activity and enhances CFTR modulator action in p.Phe508del/p.Phe508del CF bronchial epithelial cells.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32059764</pmid><doi>10.1016/j.ymthe.2020.02.001</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult ALI culture Aminophenols - pharmacology Aminopyridines - pharmacology Benzodioxoles - pharmacology Bronchi - cytology Bronchi - drug effects Bronchi - metabolism Cells, Cultured CFTR CFTR modulators Child Child, Preschool Cystic Fibrosis - genetics Cystic Fibrosis - metabolism Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Drug Combinations Drug Synergism Epithelial Cells - cytology Epithelial Cells - drug effects Epithelial Cells - metabolism Female High content screening Humans Indoles - pharmacology Infant iPSC-derived CF and CFTR gene-corrected bronchosperes Male microRNA MicroRNAs - genetics Middle Aged Models, Biological Nanoparticles nebulised PLGA nanoparticles Oligonucleotides - genetics Oligonucleotides - pharmacology Original Polylactic Acid-Polyglycolic Acid Copolymer - chemistry Primary bronchial epithelial cells Quinolones - pharmacology RNA sequencing target site blocker |
title | Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells |
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