Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease.
OBJECTIVE
Therapeutic angiogenesis is a new strategy for treatment of vascular insufficiency. Hepatocyte growth factor (HGF)-induced angiogenesis has been applied to induce the neovascularization of ischemic adult tissues in preclinical studies. This report summarizes a phase I clinical trial on the safety of adenovirus-mediated human HGF (Ad-HGF) gene transfer to treat clinically significant coronary artery disease.


METHODS
The 18 patients with severe and diffused triple vessel disease determined by coronary angiography, 1-3 of the main coronary arteries not amenable to bypassing grafting and to catheter-based revascularization were assigned to 3 study groups according to the dose of Ad-HGF (from low to high), and the total dose as follows: 5 x 10(9) pfu (group A, n = 6); 1 x 10(10) pfu (group B, n = 6); 2 x 10(10) pfu (group C, n = 6). Arterial gene transfer was performed by over-the wire balloon to the distal of the accessible artery or otherwise the ostium of the target vessels by diagnostic coronary catheter. General safety parameters and cardiac-specific parameters were measured through the preoperative period and on day 7, 21, and 35 postoperatively. The safety and tolerance of Ad-HGF for patients were evaluated according to functional and cytological assessments.


RESULTS
During the acute phase up to day 35 and at 11-14 months of follow-up there were no serious adverse events. A mild fever during the first 3 days was not present at day 4, and no long term or paroxysmal fever was found. There were no acute alterations in hemodynamic parameters and the electrocardiogram remained normal. No serious pericardial effusion was reported and there were no arrhythmia on Holter registrations. Moreover, the serum levels of HGF were not changed and the serum anti-adenovirus in the patients was not detected up to day 35.


CONCLUSIONS
The present study demonstrates that it is feasible to safely use an adenovirus gene-transfer vector to deliver the human hepatocyte growth factor gene to individuals with clinically significant coronary artery disease by direct intracoronary injection. However, a great deal of additional work must be done before administration of Ad-HGF can be recommended for clinical practice.
Yang
Zhi-Jian
ZJ
Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300, Nanjing, 210029, Jiangsu Province, People's Republic of China. enzhijia@yahoo.com.cn
Zhang
You-Rong
YR
Chen
Bo
B
Zhang
Shu-Lan
SL
Jia
En-Zhi
EZ
Wang
Lian-Sheng
LS
Zhu
Tie-Bing
TB
Li
Chun-Jian
CJ
Wang
Hui
H
Huang
Jun
J
Cao
Ke-Jiang
KJ
Ma
Wen-Zhu
WZ
Wu
Bin
B
Wang
Li-Sheng
LS
Wu
Chu-Tse
CT
D000256:Adenoviridae; D000368:Aged; D000369:Aged, 80 and over; D002404:Catheterization; D003327:Coronary Disease / Q000150:complications / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012449:Safety; D016896:Treatment Outcome
D017228:Hepatocyte Growth Factor