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Article: Evaluation of β-globin gene therapy constructs in single copy transgenic mice

TitleEvaluation of β-globin gene therapy constructs in single copy transgenic mice
Authors
Issue Date1997
PublisherOxford University Press. The Journal's web site is located at http://nar.oxfordjournals.org/
Citation
Nucleic Acids Research, 1997, v. 25 n. 6, p. 1296-1302 How to Cite?
AbstractEffective gene therapy constructs based on retrovirus or adeno-associated virus vectors will require regulatory elements that direct expression of genes transduced at single copy. Most β-globin constructs designed for therapy of β-thalassemias are regulated by the 5'HS2 component of the locus control region (LCR). Here we show that a human β-globin gene flanked by two small 5'HS2 core elements or flanked by a 5'HS3 (footprints 1-3) core and a 5'HS2 core are not reproducibly expressed in single copy transgenic mice. In addition, low copy transgene concatamers that contain only dimer 5'HS2 cores fail to express, whereas those that contain monomer 5'HS2 cores express at 14% per copy. These beta suggest that spacing between HS cores is crucial for LCR activity. We therefore constructed a novel 3.0 kb LCR cassette in which the 5'HS2, 5'HS3 and 5'HS4 cores are each separated by ≃700 bp. When linked to the 815 bp β-globin promoter this LCR directs 45% levels of expression from four independent single copy transgenes. However, the 3.0 kb LCR linked to the 265 bp promoter expresses variable levels, averaging 18%, from three single copy transgenes. Our findings suggest that sequences in the distal promoter play a role in single copy transgene activation and that larger LCR and promoter elements are most suitable for gene therapy applications.
Persistent Identifierhttp://hdl.handle.net/10722/49362
ISSN
2015 Impact Factor: 9.202
2015 SCImago Journal Rankings: 7.458
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorEllis, Jen_HK
dc.contributor.authorPasceri, Pen_HK
dc.contributor.authorTanUn, KCen_HK
dc.contributor.authorWu, Xen_HK
dc.contributor.authorHarper, Aen_HK
dc.contributor.authorFraser, Pen_HK
dc.contributor.authorGrosveld, Fen_HK
dc.date.accessioned2008-06-12T06:40:24Z-
dc.date.available2008-06-12T06:40:24Z-
dc.date.issued1997en_HK
dc.identifier.citationNucleic Acids Research, 1997, v. 25 n. 6, p. 1296-1302en_HK
dc.identifier.issn0305-1048en_HK
dc.identifier.urihttp://hdl.handle.net/10722/49362-
dc.description.abstractEffective gene therapy constructs based on retrovirus or adeno-associated virus vectors will require regulatory elements that direct expression of genes transduced at single copy. Most β-globin constructs designed for therapy of β-thalassemias are regulated by the 5'HS2 component of the locus control region (LCR). Here we show that a human β-globin gene flanked by two small 5'HS2 core elements or flanked by a 5'HS3 (footprints 1-3) core and a 5'HS2 core are not reproducibly expressed in single copy transgenic mice. In addition, low copy transgene concatamers that contain only dimer 5'HS2 cores fail to express, whereas those that contain monomer 5'HS2 cores express at 14% per copy. These beta suggest that spacing between HS cores is crucial for LCR activity. We therefore constructed a novel 3.0 kb LCR cassette in which the 5'HS2, 5'HS3 and 5'HS4 cores are each separated by ≃700 bp. When linked to the 815 bp β-globin promoter this LCR directs 45% levels of expression from four independent single copy transgenes. However, the 3.0 kb LCR linked to the 265 bp promoter expresses variable levels, averaging 18%, from three single copy transgenes. Our findings suggest that sequences in the distal promoter play a role in single copy transgene activation and that larger LCR and promoter elements are most suitable for gene therapy applications.en_HK
dc.format.extent386 bytes-
dc.format.mimetypetext/html-
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://nar.oxfordjournals.org/en_HK
dc.relation.ispartofNucleic Acids Researchen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshGene Therapyen_HK
dc.subject.meshGlobins - biosynthesis - geneticsen_HK
dc.subject.meshMice, Transgenicen_HK
dc.subject.meshDNA Primersen_HK
dc.subject.meshDNA Transposable Elementsen_HK
dc.titleEvaluation of β-globin gene therapy constructs in single copy transgenic miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0305-1048&volume=25&issue=6&spage=1296&epage=1302&date=1997&atitle=Evaluation+of+β-globin+gene+therapy+constructs+in+single+copy+transgenic+miceen_HK
dc.identifier.emailTanUn, KC: kctanun@hkucc.hku.hken_HK
dc.identifier.authorityTanUn, KC=rp00787en_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.doi10.1093/nar/25.6.1296en_HK
dc.identifier.pmid9092642-
dc.identifier.pmcidPMC146564en_HK
dc.identifier.scopuseid_2-s2.0-0030819839en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030819839&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume25en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1296en_HK
dc.identifier.epage1302en_HK
dc.identifier.isiWOS:A1997WP58300029-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridEllis, J=7402715027en_HK
dc.identifier.scopusauthoridPasceri, P=6602276648en_HK
dc.identifier.scopusauthoridTanUn, KC=6602914262en_HK
dc.identifier.scopusauthoridWu, X=7407061146en_HK
dc.identifier.scopusauthoridHarper, A=7201947771en_HK
dc.identifier.scopusauthoridFraser, P=16143421200en_HK
dc.identifier.scopusauthoridGrosveld, F=7101858903en_HK

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