Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data.
This paper reports the preclinical data that were used to support clinical trials of intracoronary delivery of a replication-incompetent human adenovirus-5 vector encoding human fibroblast growth factor 4 (Ad5FGF4). Using stress-induced myocardial ischemia in pigs, intracoronary injection of Ad5FGF4 resulted in mRNA and protein expression of the transferred gene. Two weeks after gene transfer, regional stress-induced dysfunction and perfusion were ameliorated and improved function persisted for at least 12 weeks. Transgene protein was present in hearts of all animals that received gene transfer but was not found in extracardiac sites. FGF4 was undetectable in samples of plasma obtained at multiple time points after intracoronary delivery of Ad5FGF4. Adenovirus vector DNA was detected in some extracardiac tissues by polymerase chain reaction (PCR) and was dose dependent, occurring primarily after the highest dose delivered (10(12) virus particles [vp]) with much less incidence at 10(11) vp. Histologic evaluation indicated that intracoronary administration of Ad5FGF4 was not associated with abnormal findings in any organ examined. These data provide a rationale for intracoronary delivery of Ad5FGF4 to increase regional cardiac perfusion and function in patients with myocardial ischemia. Based on these preclinical studies, the method does not appear to be associated with major toxic effects.
Gao
Mei Hua
MH
VA San Diego Healthcare System (111-A), 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Lai
N Chin
NC
McKirnan
M Dan
MD
Roth
David A
DA
Rubanyi
Gabor M
GM
Dalton
Nancy
N
Roth
David M
DM
Hammond
H Kirk
HK
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004279:DNA, Viral / Q000032:analysis; D003673:Defective Viruses; D004195:Disease Models, Animal; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D016513:Mice, SCID; D017202:Myocardial Ischemia / Q000209:etiology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D013312:Stress, Physiological; D034421:Sus scrofa; D019076:Transgenes / Q000502:physiology
D004279:DNA, Viral; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors