title: Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct.
abstract: The development of clinically beneficial myocardial gene therapy has been slowed by reliance on the use of viral carriers and non-physiologic, constitutive gene expression. To specifically address these issues, we have developed a non-viral gene carrier, water-soluble lipopolymer (WSLP), and an ischemia-inducible plasmid construct expressing vascular endothelial growth factor (VEGF), pRTP801-VEGF, to treat myocardial ischemia and infarction. Rabbits underwent ligation of the circumflex artery followed by injection of (a) an ischemia-inducible VEGF gene construct in a WSLP carrier; (b) a constitutively expressed, or unregulated, SV-VEGF gene construct in a WSLP carrier; (c) WSLP carrier alone; or (d) no injection therapy. Following 4 weeks treatment, ligation alone resulted in infarction of 48+/-7% of the left ventricle. With injection of WSLP carrier alone, 49+/-6% of the left ventricle was infarcted (P=NS). The constitutively expressed gene construct, SV-VEGF, reduced the infarct size to 32+/-7% of the left ventricle (P=0.007). The ischemia-inducible gene construct, RTP801-VEGF, further reduced the infarct size to 13+/-4% of the left ventricle (P<0.001). The use of a non-viral carrier to deliver an ischemia-inducible VEGF construct is effective in the treatment of acutely ischemic myocardium.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Yockman
authors.forename: D
authors.initials: D
authors.lastname: Choi
authors.forename: M G
authors.initials: MG
authors.lastname: Whitten
authors.forename: C W
authors.initials: CW
authors.lastname: Chang
authors.forename: A
authors.initials: A
authors.lastname: Kastenmeier
authors.forename: H
authors.initials: H
authors.lastname: Erickson
authors.forename: A
authors.initials: A
authors.lastname: Albanil
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.forename: D A
authors.initials: DA
authors.lastname: Bull
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D007267:Injections; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011108:Polymers; D011817:Rabbits; D014162:Transfection / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics*
chemical_list: D011108:Polymers; D042461:Vascular Endothelial Growth Factor A