title: A calcium-sensitive promoter construct for gene therapy.
abstract: Targeting diseased cells is a challenging issue in both pharmacological and biological therapeutics. Gene therapy is emerging as a novel approach for treating rare diseases and for illnesses for which there is no other alternative. An important limitation of gene therapy has been the off-target effects and therefore efforts have been focused on increasing the specificity of gene transfer to the targeted organ. Here, we describe a promoter containing six nuclear factor of activated T cells (NFAT) consensus sequences, which is as efficient as the cytomegalovirus (CMV) promoter to drive expression in vascular smooth muscle cells both in vitro and in vivo. In contrast to the CMV promoter it is activated in a Ca(2+)-dependent manner after endoplasmic reticulum depletion and allows the transgene expression only in proliferative/diseased cells. Overexpression of sarco/endoplasmic reticulum (SR/ER) Ca(2+) ATPase 2a under the control of this NFAT promoter inhibits restenosis after angioplasty in rats. In conclusion, this promoter may be useful for gene therapy in vascular proliferative diseases and other diseases involving upregulation of the NFAT pathway.
authors.affiliation: Transatlantic Cardiovascular Research Center, INSERM UMRS 956, UPMC-Paris 6, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Merlet
authors.forename: L
authors.initials: L
authors.lastname: Lipskaia
authors.forename: A
authors.initials: A
authors.lastname: Marchand
authors.forename: L
authors.initials: L
authors.lastname: Hadri
authors.forename: N
authors.initials: N
authors.lastname: Mougenot
authors.forename: F
authors.initials: F
authors.lastname: Atassi
authors.forename: L
authors.initials: L
authors.lastname: Liang
authors.forename: S N
authors.initials: SN
authors.lastname: Hatem
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: A-M
authors.initials: AM
authors.lastname: Lompré
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000235:genetics / Q000628:therapy; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D003587:Cytomegalovirus / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D044967:Serum
chemical_list: D003470:Culture Media; D050778:NFATC Transcription Factors; D008156:Luciferases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium