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.

Short-term safety and curative effect of recombinant adenovirus carrying hepatocyte growth factor gene on ischemic cardiac disease.

BACKGROUND: Adenovirus-mediated angiogenic growth factor gene transfer provides a new therapeutic strategy for treatment of coronary heart disease. Preclinical studies showed that direct intramyocardial injection of recombinant adenovirus with hepatocyte growth factor gene (Ad-HGF) was able to promote neovascularization, improve heart function and abate the area of ischemic myocardia in animal models. However, the safety and therapeutic effect of Ad-HGF were not evaluated in clinical trials. PATIENTS AND METHODS: A open-label, safety and tolerance trial of Ad-HGF in 18 patients suffering from coronary heart disease was performed. Three groups, each with 6 patients, received 5x10(8) (low dosage), 1.5 x 10(9) (medium dosage) and 5x10(9) (high dosage) pfu of Ad-HGF/person respectively, by direct multipoint injection into the myocardium while accepting coronary artery bypass surgery. The changes of vital symptoms, blood and urea routine analyses, as well as myocardial perfusion before and after treatment were analyzed. RESULTS: There was no evidence of systemic or cardiac-related adverse events after intramyocardial administration of the Ad-HGF. Myocardial perfusion of the Ad-HGF-injected area was improved in 3 cases of the low-dose group, 5 cases of the medium-dose group, and all of the high-dose group. CONCLUSION: These preliminary clinical data indicate that direct intramyocardial administration of Ad-HGF was well tolerated and could improve myocardial perfusion with a dose-effect relationship, encouraging larger and randomized efficacy trials.

Treatment of chronical myocardial ischemia by adenovirus-mediated hepatocyte growth factor gene transfer in minipigs.

Growth factor gene transfer-induced therapeutic angiogenesis has become a novel approach for the treatment of myocardial ischemia. In order to provide a basis for the clinical application of an adenovirus with hepatocyte growth factor gene (Ad-HGF) in the treatment of myocardial ischemia, we established a minipig model of chronically ischemic myocardium in which an Ameroid constrictor was placed around the left circumflex branch of the coronary artery (LCX). A total of 18 minipigs were randomly divided into 3 groups: a surgery control group, a model group and an Ad-HGF treatment group implanted with Ameroid constrictor. Ad-HGF or the control agent was injected directly into the ischemic myocardium, and an improvement in heart function and blood supply were evaluated. The results showed that myocardial perfusion remarkably improved in the Ad-HGF group compared with that in both the control and model groups. Four weeks after the treatment, the density of newly formed blood vessels was higher and the number of collateral blood vessels was greater in the Ad-HGF group than in the model group. The area of myocardial ischemia reduced evidently and the left ventricular ejection fraction improved significantly in the Ad-HGF group. These results suggest that HGF gene therapy may become a novel approach in the treatment of chronically ischemic myocardium.

Recruitment of stem cells by hepatocyte growth factor via intracoronary gene transfection in the postinfarction heart failure.

We aim to study the amelioration effect of adenovirus5-mediated human hepatocyte growth factor gene transfer on postinfarction heart failure in swine model. Twelve Suzhong young swine were randomly divided into 2 groups of 6 pigs each: Ad(5)-HGF group and mock-vector Ad(5) group. Four weeks after ligation of the left anterior descending coronary artery, Ad(5)-HGF was intracoronarily transferred into the myocardium. Simultaneously, gate cardiac perfusion imaging was performed to evaluate the heart function. Three weeks later, gate cardiac perfusion imaging was performed again, then the hearts were removed and sectioned for immunohistochemical examination to illustrate the effects of Ad(5)-HGF on infarcted myocardium. The expression of HGF was examined by ELISA. The results were: (1) compared with the mock-vector Ad(5) group, high expression of human HGF was observed in the myocardium of Ad(5)-HGF group; (2) in the Ad(5)-HGF group, the number of CD117(+) cells co-expressing c-Met per mm(2) was significantly larger; (3) the improvement in LVEF was greater in the Ad(5)-HGF group than in the mock-vector Ad(5) group. We concluded that: (1) high expression of human HGF was observed in the myocardium through intracoronary gene transfection; (2) HGF can improve the mobilization of CD117(+)/c-Met(+) stem cells into ischemic myocardium. The amelioration effect of HGF on postinfarction heart failure could not be limited to stimulating angiogenesis, anti-apoptosis, anti-fibrosis, but was also involved in the recruitment of stem cells into myocardium.

[Effect of intracoronary adenovirus vector encoding hepatocyte growth factor gene on hematopoietic stem cells mobilization in patients with extensive coronary heart disease].

OBJECTIVE: To investigate the effect of intracoronary adenovirus vector encoding hepatocyte growth factor gene (Ad(5)-HGF) on hematopoietic stem cells mobilization in patients with extensive coronary heart disease. METHODS: Patients with extensive coronary heart disease were treated with intracoronary infusion of adenovirus vector encoding hepatocyte growth factor (Ad(5)-HGF 5 x 10(9) pfu) gene plus stent implantation (n = 9) or equal physiological saline plus stent implantation (n = 9). Angioplasty and stent implantation was performed according to standard clinical practice by the femoral approach and blood samples were drawn from each patient at baseline before PCI, 6 to 24 hours and 6 days post procedure. The number of CD34(+), CD38(+) and CD117(+) cells in peripheral blood was analyzed by flow cytometer. RESULTS: The number of circulating CD34(+) cells in Ad(5)-HGF gene treatment group 6 hours after procedure and the number of circulating CD117(+) cells 6 days post procedure were significantly higher in Ad(5)-HGF gene treatment group than those in the control group (0.104 +/- 0.082 vs. 0.022 +/- 0.012, P = 0.021) and (0.058 +/- 0.058 vs. 0.012 +/- 0.009, P = 0.034), respectively. CONCLUSION: Intracoronary administration of Ad(5)-HGF could mobilize hematopoietic stem cells into peripheral blood and the consequent role of this observation on myocardial regeneration warrants further detailed studies.

Induction of collateral artery growth and improvement of post-infarct heart function by hepatocyte growth factor gene transfer.

AIM: To study the effect of adenovirus5-mediated human hepatocyte growth factor (Ad(5)-HGF) transfer on post-infarct heart failure in a swine model. METHODS: Twelve young Suzhong swine were randomly divided into 2 groups: the Ad(5)-HGF group (n=6) and the null-Ad(5) group (n=6). Four weeks after left anterior descending coronary artery (LAD) ligation, Ad5-HGF was transferred into the myocardium via the right coronary artery. Coronary angiography and gated cardiac perfusion imaging were performed at the end of 4 and 7 weeks after LAD ligation, respectively, to evaluate collateral artery growth and cardiac perfusion. Then all animals were killed, the expression of HGF and alpha-smooth muscle actin (alpha-SMA) were evaluated by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Compared with the null-Ad(5) group, higher expression of human HGF was observed in the myocardium in the Ad(5)-HGF group (109.3+/-7.8 vs 6.2+/-2.6, t=30.685, P<0.01). The left ventricular ejection fraction was higher in the Ad(5)-HGF group than in the null-Ad(5) group (43.9+/-4.3 vs 30.4+/-2.8, t=6.514, P<0.01). From the 4th week to the 7th week after operation, left ventricular end systolic volume (42.1+/-3.0 vs 31.0+/-4.9, t=12.800, P<0.01) and left ventricular end diastolic volume (62.2+/-4.2 vs 55.0+/-4.8 t=13.207, P<0.01) were improved in the Ad(5)-HGF group. Cardiac perfusion was significantly improved in the Ad(5)-HGF group. In the Ad(5)-HGF group, growth of collateral arteries was obviously greater (average rank sum 9.17 vs 3.83, n=6, u=-2.687, P<0.01), and the number of alpha-SMA(+) vessels/mm(2) was significantly greater (56.1+/-4.2 vs 16.4+/-3.5, t=17.731, P<0.01) than in the null-Ad(5) group. CONCLUSION: High expression levels of human HGF were observed in the myocardium because of non-infarct-related vessel transfer. HGF can increase the number of functional arterioles and improve collateral artery growth. HGF can improve cardiac perfusion and heart function.