Intracoronary delivery of an adenovirus encoding fibroblast growth factor-4 in myocardial ischemia: effect of serum antibodies and previous exposure to adenovirus.
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.
Roth
David A
DA
Collateral Therapeutics Inc., San Diego, CA 92130, USA. droth@genetherapysystems.com
McKirnan
M Dan
MD
Canestrelli
Ilona
I
Gao
Mei Hua
MH
Dalton
Nancy
N
Lai
N Chin
NC
Roth
David M
DM
Hammond
H Kirk
HK
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D051519:Fibroblast Growth Factor 4 / Q000008:administration & dosage* / Q000235:genetics; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007106:Immune Sera; D015552:Injections, Intralesional; D017202:Myocardial Ischemia / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013552:Swine
D000906:Antibodies; D051519:Fibroblast Growth Factor 4; D007106:Immune Sera