Abstract

Angiogenesis is a physiologic process in which new blood vessels are formed to meet the oxygen demands of local tissues. With the identification of specific biologic mediators of angiogenesis, it is now possible to consider """"""""therapeutic angiogenesis"""""""" where angiogenic molecules could be administered to develop new vascular networks to circumvent the ischemic consequences of atherosclerosis occluding the arterial system. The focus of this application is to evaluate the hypothesis related to the biology of the in vivo delivery of the potent angiogenesis-mediator, vascular endothelial growth factor (VEGF) in the form of a cDNA using replication deficient recombinant adenovirus (Ad) vectors. The VEGF gene is naturally expressed through alternative splicing as four mRNA transcripts, coding for secreted proteins of 206, 189, 165 and 121 residues, each with different bio availability secondary to different associations with the extracellular matrix. The VEGF proteins exert their function almost exclusively on endothelial cells through two specific receptors, flt-1 and KDR/flk-1. In order to develop a gene therapy study using Ad vector-mediated transfer of the VEGF-related genes for the treatment of diffuse atherosclerosis, the specific aims of this application are focused upon: (i) the characterization of the angiogenic response of the different VEGF isoforms delivered with Ad vectors, (ii) the evaluation of the consequences of providing VEGF to tissues after Ad vectors have been used to transfer the cDNAs for the VEGF receptors to the endothelium and (iii) to examine whether modification of the genotype of the Ad capsid, deletion of the E4 gene or the addition of the E3 gene will escape anti-Ad vector recognition by neutralizing antibodies and/or cellular immunity, thus permitting repetitive Ad vector-mediated VEGF or VEGF receptor gene transfer and expression in order to evoke localized angiogenesis as needed. The results of these studies should help define gene therapy strategies for therapeutic angiogenesis for the treatment of atherosclerosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057318-03
Application #
6184254
Study Section
Pathology A Study Section (PTHA)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
2000-05-22
Budget End
2001-03-31
Support Year
3
Fiscal Year
2000
Total Cost
$278,134
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Retuerto, Mauricio A; Beckmann, James T; Carbray, JoAnn et al. (2007) Angiogenic pretreatment to enhance myocardial function after cellular cardiomyoplasty with skeletal myoblasts. J Thorac Cardiovasc Surg 133:478-484.e2
Sarateanu, Cristian Sorin; Retuerto, Mauricio A; Beckmann, James T et al. (2006) An Egr-1 master switch for arteriogenesis: studies in Egr-1 homozygous negative and wild-type animals. J Thorac Cardiovasc Surg 131:138-45
Schalch, Paul; Patejunas, Gerald; Retuerto, Mauricio et al. (2004) Homozygous deletion of early growth response 1 gene and critical limb ischemia after vascular ligation in mice: evidence for a central role in vascular homeostasis. J Thorac Cardiovasc Surg 128:595-601
Schalch, Paul; Rahman, G Farah; Patejunas, Gerald et al. (2004) Adenoviral-mediated transfer of vascular endothelial growth factor 121 cDNA enhances myocardial perfusion and exercise performance in the nonischemic state. J Thorac Cardiovasc Surg 127:535-40
Whitlock, Paul R; Hackett, Neil R; Leopold, Philip L et al. (2004) Adenovirus-mediated transfer of a minigene expressing multiple isoforms of VEGF is more effective at inducing angiogenesis than comparable vectors expressing individual VEGF cDNAs. Mol Ther 9:67-75
Retuerto, Mauricio A; Schalch, Paul; Patejunas, Gerald et al. (2004) Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation. J Thorac Cardiovasc Surg 127:1041-9; discussion 1049-51
Harvey, Ben-Gary; Maroni, Jaman; O'Donoghue, Kelley A et al. (2002) Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther 13:15-63
Leotta, Eros; Patejunas, Gerald; Murphy, Glenn et al. (2002) Gene therapy with adenovirus-mediated myocardial transfer of vascular endothelial growth factor 121 improves cardiac performance in a pacing model of congestive heart failure. J Thorac Cardiovasc Surg 123:1101-13
Hidaka, Chisa; Ibarra, Clemente; Hannafin, Jo A et al. (2002) Formation of vascularized meniscal tissue by combining gene therapy with tissue engineering. Tissue Eng 8:93-105
Crystal, Ronald G; Harvey, Ben-Gary; Wisnivesky, Juan P et al. (2002) Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum Gene Ther 13:65-100

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