Prostaglandin E 2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells
Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34 hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E (PGE ) as a positive mediator of lentiviral transduction of CD34 cells. Supplementation wi...
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| Veröffentlicht in: | Molecular therapy 2018-01, Vol.26 (1), p.320 |
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| creator | Heffner, Garrett C Bonner, Melissa Christiansen, Lauryn Pierciey, Francis J Campbell, Dakota Smurnyy, Yegor Zhang, Wenliang Hamel, Amanda Shaw, Seema Lewis, Gretchen Goss, Kendrick A Garijo, Olivia Torbett, Bruce E Horton, Holly Finer, Mitchell H Gregory, Philip D Veres, Gabor |
| description | Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34
hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E
(PGE
) as a positive mediator of lentiviral transduction of CD34
cells. Supplementation with PGE
increased lentiviral vector (LVV) transduction of CD34
cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34
cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE
increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE
improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE
may be useful in clinical gene therapy applications using lentivirally modified HSPCs. |
| doi_str_mv | 10.1016/j.ymthe.2017.09.025 |
| format | Article |
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hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E
(PGE
) as a positive mediator of lentiviral transduction of CD34
cells. Supplementation with PGE
increased lentiviral vector (LVV) transduction of CD34
cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34
cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE
increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE
improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE
may be useful in clinical gene therapy applications using lentivirally modified HSPCs.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2017.09.025</identifier><identifier>PMID: 29102562</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Anemia, Sickle Cell - genetics ; Anemia, Sickle Cell - metabolism ; Animals ; Antigens, CD34 - metabolism ; beta-Thalassemia - genetics ; beta-Thalassemia - metabolism ; CD34 antigen ; Cell cycle ; Cell Line ; Cell viability ; Copy number ; Cytokines ; Diabetes mellitus ; Dinoprostone - metabolism ; Experiments ; Flow cytometry ; Gene Library ; Gene therapy ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors - genetics ; Globins - genetics ; Hematopoietic stem cells ; Hematopoietic Stem Cells - metabolism ; Humans ; Interleukin 2 ; Lentivirus - genetics ; Leukocyte Common Antigens - metabolism ; Mice ; Progenitor cells ; Prostaglandin E ; Prostaglandin E2 ; Severe combined immunodeficiency ; Sickle cell disease ; Stem cells ; Supplements ; Thalassemia ; Toxicity ; Transduction, Genetic ; Transgenes ; Transplantation, Heterologous ; Transplants & implants ; Virus Internalization ; Xenografts</subject><ispartof>Molecular therapy, 2018-01, Vol.26 (1), p.320</ispartof><rights>Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2017. The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29102562$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heffner, Garrett C</creatorcontrib><creatorcontrib>Bonner, Melissa</creatorcontrib><creatorcontrib>Christiansen, Lauryn</creatorcontrib><creatorcontrib>Pierciey, Francis J</creatorcontrib><creatorcontrib>Campbell, Dakota</creatorcontrib><creatorcontrib>Smurnyy, Yegor</creatorcontrib><creatorcontrib>Zhang, Wenliang</creatorcontrib><creatorcontrib>Hamel, Amanda</creatorcontrib><creatorcontrib>Shaw, Seema</creatorcontrib><creatorcontrib>Lewis, Gretchen</creatorcontrib><creatorcontrib>Goss, Kendrick A</creatorcontrib><creatorcontrib>Garijo, Olivia</creatorcontrib><creatorcontrib>Torbett, Bruce E</creatorcontrib><creatorcontrib>Horton, Holly</creatorcontrib><creatorcontrib>Finer, Mitchell H</creatorcontrib><creatorcontrib>Gregory, Philip D</creatorcontrib><creatorcontrib>Veres, Gabor</creatorcontrib><title>Prostaglandin E 2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34
hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E
(PGE
) as a positive mediator of lentiviral transduction of CD34
cells. Supplementation with PGE
increased lentiviral vector (LVV) transduction of CD34
cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34
cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE
increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE
improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE
may be useful in clinical gene therapy applications using lentivirally modified HSPCs.</description><subject>Anemia, Sickle Cell - genetics</subject><subject>Anemia, Sickle Cell - metabolism</subject><subject>Animals</subject><subject>Antigens, CD34 - metabolism</subject><subject>beta-Thalassemia - genetics</subject><subject>beta-Thalassemia - metabolism</subject><subject>CD34 antigen</subject><subject>Cell cycle</subject><subject>Cell Line</subject><subject>Cell viability</subject><subject>Copy number</subject><subject>Cytokines</subject><subject>Diabetes mellitus</subject><subject>Dinoprostone - metabolism</subject><subject>Experiments</subject><subject>Flow cytometry</subject><subject>Gene Library</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - genetics</subject><subject>Globins - genetics</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Interleukin 2</subject><subject>Lentivirus - genetics</subject><subject>Leukocyte Common Antigens - metabolism</subject><subject>Mice</subject><subject>Progenitor cells</subject><subject>Prostaglandin E</subject><subject>Prostaglandin E2</subject><subject>Severe combined immunodeficiency</subject><subject>Sickle cell disease</subject><subject>Stem cells</subject><subject>Supplements</subject><subject>Thalassemia</subject><subject>Toxicity</subject><subject>Transduction, Genetic</subject><subject>Transgenes</subject><subject>Transplantation, Heterologous</subject><subject>Transplants & implants</subject><subject>Virus Internalization</subject><subject>Xenografts</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LwzAYhYMoTqe_QJCA1635aNPlcozpBgMFp7clTd_MjDatSSoM_PFWnF6dc_HwHDgI3VCSUkLF_T49tPEdUkZokRKZEpafoAuaszwhhGWn_52KCboMYT82mktxjiZM0pEW7AJ9PfsuRLVrlKutw0vM8NppDypAwBtw0X5arxr8Bjp2Hm-9cqEedLTdCBtjtQWnD7gzeF4PTcSroVUOr6BVses7C9Fq_BKhxaMfj1s7cPZHtICmCVfozKgmwPUxp-j1YbldrJLN0-N6Md8kPeUiJrw2M1VxKQknBRe1pAIMY7LQitdcMk6Bg-CQgclAVZrJmSmEKSoKlS4Kxafo7tfb--5jgBDLfTd4N06WjMrZ-B_J5EjdHqmhaqEue29b5Q_l31n8Gz2LbrU</recordid><startdate>20180103</startdate><enddate>20180103</enddate><creator>Heffner, Garrett C</creator><creator>Bonner, Melissa</creator><creator>Christiansen, Lauryn</creator><creator>Pierciey, Francis J</creator><creator>Campbell, Dakota</creator><creator>Smurnyy, Yegor</creator><creator>Zhang, Wenliang</creator><creator>Hamel, Amanda</creator><creator>Shaw, Seema</creator><creator>Lewis, Gretchen</creator><creator>Goss, Kendrick A</creator><creator>Garijo, Olivia</creator><creator>Torbett, Bruce E</creator><creator>Horton, Holly</creator><creator>Finer, Mitchell H</creator><creator>Gregory, Philip D</creator><creator>Veres, Gabor</creator><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>K9.</scope></search><sort><creationdate>20180103</creationdate><title>Prostaglandin E 2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells</title><author>Heffner, Garrett C ; Bonner, Melissa ; Christiansen, Lauryn ; Pierciey, Francis J ; Campbell, Dakota ; Smurnyy, Yegor ; Zhang, Wenliang ; Hamel, Amanda ; Shaw, Seema ; Lewis, Gretchen ; Goss, Kendrick A ; Garijo, Olivia ; Torbett, Bruce E ; Horton, Holly ; Finer, Mitchell H ; Gregory, Philip D ; Veres, Gabor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p136t-3df8ab399030736d916ef2297ca3d39231e3e63e4ef4eabc298f76f7b1ebc77a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Anemia, Sickle Cell - genetics</topic><topic>Anemia, Sickle Cell - metabolism</topic><topic>Animals</topic><topic>Antigens, CD34 - metabolism</topic><topic>beta-Thalassemia - genetics</topic><topic>beta-Thalassemia - metabolism</topic><topic>CD34 antigen</topic><topic>Cell cycle</topic><topic>Cell Line</topic><topic>Cell viability</topic><topic>Copy number</topic><topic>Cytokines</topic><topic>Diabetes mellitus</topic><topic>Dinoprostone - metabolism</topic><topic>Experiments</topic><topic>Flow cytometry</topic><topic>Gene Library</topic><topic>Gene therapy</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - genetics</topic><topic>Globins - genetics</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Humans</topic><topic>Interleukin 2</topic><topic>Lentivirus - genetics</topic><topic>Leukocyte Common Antigens - metabolism</topic><topic>Mice</topic><topic>Progenitor cells</topic><topic>Prostaglandin E</topic><topic>Prostaglandin E2</topic><topic>Severe combined immunodeficiency</topic><topic>Sickle cell disease</topic><topic>Stem cells</topic><topic>Supplements</topic><topic>Thalassemia</topic><topic>Toxicity</topic><topic>Transduction, Genetic</topic><topic>Transgenes</topic><topic>Transplantation, Heterologous</topic><topic>Transplants & implants</topic><topic>Virus Internalization</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heffner, Garrett C</creatorcontrib><creatorcontrib>Bonner, Melissa</creatorcontrib><creatorcontrib>Christiansen, Lauryn</creatorcontrib><creatorcontrib>Pierciey, Francis J</creatorcontrib><creatorcontrib>Campbell, Dakota</creatorcontrib><creatorcontrib>Smurnyy, Yegor</creatorcontrib><creatorcontrib>Zhang, Wenliang</creatorcontrib><creatorcontrib>Hamel, Amanda</creatorcontrib><creatorcontrib>Shaw, Seema</creatorcontrib><creatorcontrib>Lewis, Gretchen</creatorcontrib><creatorcontrib>Goss, Kendrick A</creatorcontrib><creatorcontrib>Garijo, Olivia</creatorcontrib><creatorcontrib>Torbett, Bruce E</creatorcontrib><creatorcontrib>Horton, Holly</creatorcontrib><creatorcontrib>Finer, Mitchell H</creatorcontrib><creatorcontrib>Gregory, Philip D</creatorcontrib><creatorcontrib>Veres, Gabor</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heffner, Garrett C</au><au>Bonner, Melissa</au><au>Christiansen, Lauryn</au><au>Pierciey, Francis J</au><au>Campbell, Dakota</au><au>Smurnyy, Yegor</au><au>Zhang, Wenliang</au><au>Hamel, Amanda</au><au>Shaw, Seema</au><au>Lewis, Gretchen</au><au>Goss, Kendrick A</au><au>Garijo, Olivia</au><au>Torbett, Bruce E</au><au>Horton, Holly</au><au>Finer, Mitchell H</au><au>Gregory, Philip D</au><au>Veres, Gabor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prostaglandin E 2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2018-01-03</date><risdate>2018</risdate><volume>26</volume><issue>1</issue><spage>320</spage><pages>320-</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34
hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E
(PGE
) as a positive mediator of lentiviral transduction of CD34
cells. Supplementation with PGE
increased lentiviral vector (LVV) transduction of CD34
cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34
cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE
increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE
improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE
may be useful in clinical gene therapy applications using lentivirally modified HSPCs.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>29102562</pmid><doi>10.1016/j.ymthe.2017.09.025</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Anemia, Sickle Cell - genetics Anemia, Sickle Cell - metabolism Animals Antigens, CD34 - metabolism beta-Thalassemia - genetics beta-Thalassemia - metabolism CD34 antigen Cell cycle Cell Line Cell viability Copy number Cytokines Diabetes mellitus Dinoprostone - metabolism Experiments Flow cytometry Gene Library Gene therapy Gene Transfer Techniques Genetic Therapy Genetic Vectors - genetics Globins - genetics Hematopoietic stem cells Hematopoietic Stem Cells - metabolism Humans Interleukin 2 Lentivirus - genetics Leukocyte Common Antigens - metabolism Mice Progenitor cells Prostaglandin E Prostaglandin E2 Severe combined immunodeficiency Sickle cell disease Stem cells Supplements Thalassemia Toxicity Transduction, Genetic Transgenes Transplantation, Heterologous Transplants & implants Virus Internalization Xenografts |
| title | Prostaglandin E 2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells |
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