Safety of direct cardiac administration of AdVEGF-All6A+, a replication-deficient adenovirus vector cDNA/genomic hybrid expressing all three major isoforms of human vascular endothelial growth factor, to the ischemic myocardium of rats. Academic Article uri icon

Overview

MeSH

  • Animals
  • Blood Chemical Analysis
  • DNA, Complementary
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Humans
  • Male
  • Myocardium
  • Protein Isoforms
  • Rats
  • Troponin I

MeSH Major

  • Adenoviridae
  • Genetic Vectors
  • Myocardial Ischemia
  • Vascular Endothelial Growth Factor A

abstract

  • Abstract Coronary artery disease (CAD), a leading cause of mortality, is a chronic disease in which blood flow to the myocardium is obstructed, leading to ischemia. Although coronary artery stenting and surgical bypass are successful with localized coronary lesions, patients with diffuse CAD have only pharmacologic options. In a mouse ischemic hind-limb model, AdVEGF-All6A+, an Ad5 vector expressing the cDNA/genomic hybrid of the vascular endothelial growth factor (VEGF) gene (expressing isoforms, 121, 165, and 189) mediated recovery of blood flow at a dose of two logs less than that required with a single isoform. The objective of the current study was to ascertain the safety profile of good manufacturing practice (GMP)-grade AdVEGF-All6A+ in the adult rat ischemic heart model in support of a clinical study to treat humans with diffuse CAD. AdVEGF-All6A+ (10(5), 10(6), or 10(7) particle units), a control vector (AdNull, 10(7) particle units) with no translatable expression cassette and a vehicle sham control (phosphate buffered saline [PBS]) were administered separately to the left ventricle of rats immediately following acute coronary artery ligation to initiate myocardial infarction (MI), designed to evoke an extreme ischemic myocardium in cohorts (n=5 males; n=5 females), with sacrifice at 5, 14, or 30 days. Six cohorts received no ligation but were administered AdVEGF-All6A+ vector or PBS with sacrifice at 30 or 365 days. Although there were surgical-related abnormalities among the groups, blinded evaluation of gross and histopathology, complete blood count, and serum chemistry found no significant differences between control- and vector-treated groups and no adverse effects could be attributed to AdVEGF-All6A+. No changes in serum troponin-I levels persisted beyond those associated with the MI. Gross pathology and histopathology of all major organs showed no AdVEGF-All6A+-related changes. Overall, this safety profile suggests that AdVEGF-All6A+ or AdNull administration to the myocardium meets the criteria to proceed to clinical trial.

publication date

  • March 2013

has subject area

  • Adenoviridae
  • Animals
  • Blood Chemical Analysis
  • DNA, Complementary
  • Disease Models, Animal
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Male
  • Myocardial Ischemia
  • Myocardium
  • Protein Isoforms
  • Rats
  • Troponin I
  • Vascular Endothelial Growth Factor A

Research

keywords

  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1089/humc.2013.054

PubMed ID

  • 23692382

Additional Document Info

start page

  • 38

end page

  • 46

volume

  • 24

number

  • 1