Intracoronary delivery of an adenovirus encoding fibroblast growth factor-4 in myocardial ischemia: effect of serum antibodies and previous exposure to adenovirus

Hum Gene Ther. 2006 Feb;17(2):230-8. doi: 10.1089/hum.2006.17.230.

Abstract

The presence of anti-adenoviral serotype 5 (Ad5) antibodies may limit the efficacy of Ad5-mediated gene transfer. We therefore tested the hypothesis that intracoronary delivery of an adenovirus encoding human fibroblast growth factor type 4 (Ad5.FGF4) would improve regional myocardial function in an animal model of ischemia when high antibody levels preexist or after a prior intracoronary dose of Ad5. High anti-Ad5 antibody levels were generated in pigs by subcutaneous immunization with an adenovirus encoding LacZ (Ad5.lacZ). Neutralizing antibody levels increased 648-fold (range, 82- to 2108-fold) above preimmunization levels, and persisted for the duration of the study. Myocardial function during pacing-induced ischemia was improved in the ischemic region (p<0.001) at both 2 and 4 weeks after Ad5.FGF4 administration despite the presence of preexisting antibodies to Ad5. In a second set of experiments, the efficacy of a second intracoronary administration of Ad5 was determined by exposing the animals first to an intracoronary dose of Ad5.lacZ, followed 7 weeks later by the therapeutic dose of Ad5.FGF4. After delivery of Ad5.lacZ, anti-Ad5 antibody levels increased 8-fold (range, 1- to 18-fold), but this prior exposure to Ad5 did not prevent the therapeutic effects after subsequent intracoronary dosing with Ad5.FGF4 (p<0.001). In the porcine Ameroid constrictor model of myocardial ischemia the presence of anti-Ad5 antibodies or prior intracoronary dosing with adenovirus does not prevent the ability of Ad5.FGF4, delivered by intracoronary injection, from normalizing regional myocardial function.

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology*
  • Animals
  • Antibodies / immunology
  • Fibroblast Growth Factor 4 / administration & dosage*
  • Fibroblast Growth Factor 4 / genetics
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology*
  • Humans
  • Immune Sera
  • Injections, Intralesional
  • Myocardial Ischemia / immunology
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / therapy*
  • Swine

Substances

  • Antibodies
  • Fibroblast Growth Factor 4
  • Immune Sera