Effective treatment of vascular endothelial growth factor refractory hindlimb ischemia by a mutant endothelial nitric oxide synthase gene

Gene Therapy
H S QianK Kauser

Abstract

Gene delivery of angiogenic growth factors is a promising approach for the treatment of ischemic cardiovascular diseases. However, success of this new therapeutic principle is hindered by the lack of critical understanding as to how disease pathology affects the efficiency of gene delivery and/or the downstream signaling pathways of angiogenesis. Critical limb ischemia occurs in patients with advanced atherosclerosis often exhibiting deficiency in endothelial nitric oxide production. Similar to these patients, segmental femoral artery resection progresses into severe ischemic necrosis in mice deficient in endothelial nitric oxide synthase (ecNOS-KO) as well as in balb/c mice. We used these models to evaluate the influence of severe ischemia on transfection efficiency and duration of transgene expression in the skeletal muscle following plasmid injection in combination with electroporation. Subsequently, we also explored the potential therapeutic effect of the phosphomimetic mutant of ecNOS gene (NOS1177D) using optimized delivery parameters, and found significant benefit both in ecNOS-KO and balb/c mice. Our results indicate that NOS1177D gene delivery to the ischemic skeletal muscle can be efficient to reverse critical limb is...Continue Reading

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Citations

Feb 14, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gabor M Rubanyi
Oct 12, 2011·Journal of Vascular Research·Jennifer S FangJanis M Burt
Aug 29, 2009·The Tohoku Journal of Experimental Medicine·Kenta ItoHiroaki Shimokawa
Aug 19, 2011·American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions·Kenta ItoHiroaki Shimokawa
May 23, 2007·Proceedings of the National Academy of Sciences of the United States of America·Mohammad Mahfuzul HaqueDennis J Stuehr
May 26, 2009·Expert Opinion on Biological Therapy·Deirdre M O'Connor, Timothy O'Brien
Oct 6, 2011·Advanced Drug Delivery Reviews·Hyun-Ji ParkSeung-Woo Cho
Aug 28, 2009·Journal of Cellular Biochemistry·Erica B SneiderLouis M Messina
May 22, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·John P Cooke, Shu Meng
Jun 11, 2021·Circulation Research·Brian H Annex, John P Cooke

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