High-dose plasmid-mediated VEGF gene transfer is safe in patients with severe ischemic heart disease (Genesis-I). A phase I, open-label, two-year follow-up trial.
OBJECTIVE
We aimed to assess safety and, secondarily, the efficacy of intramyocardial high-dose plasmid-vascular endothelial growth factor (VEGF) 165 (pVEGF165) gene transfer in no-option patients with coronary artery disease (CAD).


BACKGROUND
Controlled trials of pVEGF165 in CAD have shown little benefit. One possible reason is shortness of dosage. We have shown in large mammalian models of chronic myocardial ischemia and acute myocardial infarction that intramyocardial pVEGF165 at doses significantly higher than those used in recent phase II trials is safe and efficacious on myocardial perfusion, left ventricular function, and infarct size limitation.


METHODS
Using an injection catheter, 10 patients with severe CAD not amenable for revascularization received 10 intramyocardial injections of 0.38 mg (total dose, 3.8 mg) pVEGF165 in zones exhibiting myocardial ischemia, as assessed by combined stress 99mTc-sestamibi single-photon emission computed tomography and stress echocardiography.


RESULTS
No serious adverse events related to either VEGF or the injection procedure occurred over the 2-year follow-up. One patient suffered femoral artery thrombosis after a follow-up coronary angiography, successfully resolved with medical treatment. Six patients suffered uncomplicated coronary ischemic events during the second year follow-up. Angina functional class decreased from 2.6 ± 0.2 to 1.2 ± 0.3 (mean ± SEM, P < 0.05), quality of life increased from 56.9 ± 3.2 to 82.6 ± 2.4 (P < 0.05), the summed difference score of myocardial perfusion decreased from 13.4 ± 2 to 7.7 ± 1.8 (P < 0.04), and stress ejection fraction did not change (44.2 ± 3.6% to 47.8 ± 3.1%, P = NS).


CONCLUSIONS
High-dose intramyocardial pVEGF165 is safe at 2 years follow-up in patients with severe CAD. The efficacy results observed must be taken cautiously given the uncontrolled, open-label study design.
Favaloro Foundation University Hospital, Buenos Aires, Argentina.
Liliana
L
Favaloro
Mirta
M
Diez
Oscar
O
Mendiz
Gustavo Vera
GV
Janavel
León
L
Valdivieso
Roxana
R
Ratto
Guillermo
G
Garelli
Fabián
F
Salmo
Marcelo
M
Criscuolo
Andrés
A
Bercovich
Alberto
A
Crottogini
D000368:Aged; D001118:Argentina; D003097:Collateral Circulation; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D003326:Coronary Circulation; D025401:Echocardiography, Stress; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007267:Injections; D008297:Male; D008875:Middle Aged; D055414:Myocardial Perfusion Imaging / Q000379:methods; D018919:Neovascularization, Physiologic; D010957:Plasmids; D019275:Radiopharmaceuticals; D012720:Severity of Illness Index; D013318:Stroke Volume; D017256:Technetium Tc 99m Sestamibi; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017256:Technetium Tc 99m Sestamibi