Efficient gene regulation by PPAR gamma and thiazolidinediones in skeletal muscle and heart.
We have developed a new gene regulation system for gene therapy. This system consists of two expression cassettes; one expresses the human peroxisome proliferator-activated receptor gamma(PPAR gamma), and the other expresses the therapeutic gene under the control of multiple peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) linked to a basal promoter. Using direct injection of plasmid DNA into skeletal muscle or myocardium of rodents and oral administration of clinically approved PPAR gamma activators, we demonstrate that reporter gene expression can be induced more than 25-fold. We show that oral administration of PPAR gamma activator at intervals separated by several months results in repeated pulses of high-level reporter gene expression. We also document a PPAR gamma activator dose-response effect on reporter gene expression. This is the first report of a gene regulation system that makes use of a human transcription factor and that may be safer than chimeric transcription factors for human gene therapy.
Darteil
Raphaël
R
Gencell, 13 quai Jules Guesde, Vitry sur Seine, 94403, France.
Wang
Manping
M
Latta-Mahieu
Martine
M
Caron
Anne
A
Mahfoudi
Abderrahim
A
Staels
Bart
B
Thuillier
Vincent
V
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D006321:Heart / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*
D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D008156:Luciferases