Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study

Article metrics

Abstract

The purpose of this phase I clinical trial was to evaluate the safety, tolerability and potential efficacy of VM202, naked DNA expressing two isoforms of hepatocyte growth factor, as an adjunct therapy to coronary artery bypass grafting (CABG) in patients with ischemic heart disease (IHD). Nine patients were assigned to receive increasing doses (0.5 to 2.0 mg) of VM202 injected into the right coronary artery (RCA) territory following completion of CABG for the left coronary artery territory. Patients were evaluated for safety and tolerability, and changes in myocardial functions were monitored via echocardiography, cardiac magnetic resonance imaging and myocardial single photon emission computed tomography throughout 6-month follow-up period. No serious complication related to VM202 was observed throughout the 6-month follow-up period. Global myocardial functions (wall motion score index, P=0.0084; stress perfusion, P=0.0002) improved during the follow-up period. In the RCA region, there was an increase in the stress perfusion (baseline vs 3-month, P=0.024; baseline vs 6-month, P=0.024) and also in the wall thickness of the diastolic and systolic phases. Intramyocardial injection of VM202 can be safely used in IHD patients with the tolerable dose of 2.0 mg. In addition, VM202 might appear to have improved regional myocardial perfusion and wall thickness in the injected region.

Introduction

Despite the importance of complete revascularization for the treatment of ischemic heart disease (IHD), about 10 to 25% of patients who undergo coronary intervention such as percutaneous coronary intervention or coronary artery bypass grafting (CABG) still remain incompletely revascularized.1, 2, 3 In these patients, adjunct therapies are necessary in addition to maximal anti-anginal medication. Although ischemia induces collateral flow, it is sometimes insufficient to satisfy coronary perfusion demands. Thus, therapeutic angiogenesis using a growth factor that leads to complete revascularization could increase the survival rate of patients who have not been completely healed by coronary grafting alone.

Hepatocyte growth factor (HGF) is one of the most promising candidates for novel biologics due to its mitogenic, motogenic, angiogenic and anti-apoptotic effects.4, 5 In addition, HGF can generate more ideal vasculature in the ischemic area by promoting migration of vascular smooth muscle cells as well as endothelial cell proliferation.6, 7, 8, 9 HGF has received great attentions for its functions of cardiac protection and angiogenesis via HGF-c-met system that exists for the heart.10, 11, 12 We have demonstrated that intramyocardial injection of naked DNA expressing two isoforms of HGF, VM202RY and pCK-HGF-X7, hereinafter VM202, induced significant angiogenesis at the infarct-border zone, and increased the left ventricular stroke volume in a porcine myocardial infarction model.13 In addition, two phase I clinical trials for critical limb ischemia patients using VM202 were previously performed in China and US, which demonstrated both the safety and therapeutic potentials (as evidenced by increase of ankle-brachial index and toe-brachial index, and decrease of pain severity) of VM202.14, 15

The aims of this study were to evaluate the safety and tolerability, as well as to investigate the potential efficacy of VM202 as an adjunct therapy to CABG in patients with reversible perfusion defect in right coronary artery (RCA) region that have not been amenable to revascularization.

Results

Patient demographics

Among sixteen patients who were pre-enrolled, nine completed the study protocol. Two third of the patients (6/9) were male, and the mean patient age was 62.6±8.8 years. All patients had histories of ischemic cardiomyopathy, and although some had taken previous anti-anginal medications, none had undergone any intervention such as percutaneous coronary intervention and CABG. The detailed subject demographics are summarized in Table 1. At baseline, six out of nine patients had histories of hypertension and diabetes mellitus. Among the six diabetes patients, two had diabetic retinopathy but there was no evidence of proliferative pattern upon fundoscopic examination. In addition, all patients were shown to have severe three vessel disease including hypoplastic RCA as per the baseline coronary angiography.

Table 1 Patient demographics and CABG distal anastomosis

Safety and tolerability

A total of nine subjects were treated with VM202 in the RCA territory. Intramyocardial injection of VM202 was well tolerated at doses as high as 2.0 mg. There were no signs of systemic and/or local inflammatory reactions directly related to VM202 or the injection procedure throughout the 6-month follow-up period. A total of 112 non-drug-related adverse events (AEs) was reported in nine patients (cohort I, 58; cohort II, 18; and cohort III, 36). They were caused mainly by the general prognosis of CABG and the deterioration resulting from the underlying disease. All AEs were resolved with or without additional treatments during the follow-up period. One patient (cohort I) experienced 41 non-drug-related AEs. This subject had previously been diagnosed as a spinal stenosis, and while being prepared for lumbar/lumbosacral spinal surgery, she was diagnosed as angina pectoris. She was treated with 0.5 mg of VM202 in the RCA territory as an additional therapy to off-pump CABG. No unexpected serious adverse events (SAEs) or deaths were observed during the follow-up period. HGF protein levels in plasma remained stable throughout the study without any noticeable change, and antibodies to human HGF proteins expressed by VM202 injection were not detected in serum during the follow-up period (Table 2).

Table 2 Serum HGF protein and anti-human HGF antibody in plasma

Efficacy analysis

The global and regional myocardial functions were assessed at 3 and 6 months after the VM202 treatment using cardiac magnetic resonance imaging (MRI) and myocardial single photon emission computed tomography (SPECT) and trans-thoracic echocardiography (TTE).

Global myocardial function

There was no statistical change in left ventricular ejection fraction (LVEF) on TTE throughout the 6-month follow-up period (P=0.6477; Table 3). However, improvement of wall motion score index (WMSI) became more statistically significant as time elapsed (P=0.0084). Cardiac MRI showed that cardiac output remain unchanged during the follow-up period (P=0.5514). Myocardial SPECT for global myocardial function revealed a total of 84 segments of under-perfusion (rest perfusion−stress perfusion: 7%) at baseline. Stress perfusion was significantly increased 3 and 6 months after the VM202 treatment (P=0.0002). Also, there was a tendency of rest perfusion improvement during the follow-up (P=0.0801). In addition, an increase of systolic thickening was observed 6 months after the treatment (P=0.038, by Wilcoxon signed rank test).

Table 3 Changes of global myocardial function

Regional myocardial function

Using myocardial SPECT, we investigated the stress and rest perfusion of the two VM202-injected segments (apical and mid inferior walls) among the total of 20 segments(Table 4 and Figure 1). There was a statistically significant increase in stress perfusion 3 and 6 months after the VM202 injection (baseline (58.3±10.2%) vs 3-month (64.3±9.6%) vs 6-month (63.9±9.7%), P=0.0031; Figure 1a and Table 4). The magnitude of positive effects decreased with time. Similar tendency was found in the rest perfusion analysis. As shown in Figure 1b, the rest perfusion increased considerably during the first 3 months after the treatment (baseline vs 3-month, 70.2±8.6% vs 74.5±7.5%, P=0.015) and then decreased to near baseline value during the next 3 months (baseline vs 6-month, 70.2±8.6% vs 72.2±7.9%, P=0.401). Regarding systolic thickening, there was no statistically meaningful increment during the study period (P=0.7479, Figure 1c). The thickness of the mid inferior wall of the left ventricle on the short-axis view was examined using cardiac MRI. Although statistically insignificant, there was a tendency of increase in systolic (P=0.0650, Figure 1d) and diastolic wall thickness (P=0.0731, Figure 1e). However, there was no noticeable change in systolic thickening in the same territory (P=0.6544, Figure 1f). Gadolinium enhancement on the apical and mid inferior wall, the infarct area on injected site, demonstrated no significant change among the three cohorts or all time intervals (data not shown).

Table 4 Changes of regional myocardial function (VM202 injected area)
Figure 1
figure1

Effect of intramyocardial VM202 injection on regional myocardial function. Significant increase of stress and rest perfusion (a, b) in the RCA region on myocardial SPECT was observed at 3 and/or 6 months after VM202 treatment. Also, improved tendency of the systolic and diastolic wall thickness (d, e) in the RCA region on cardiac MRI was observed at 3 and 6 months after the treatment. Systolic thickenings measured by myocardial SPECT and cardiac MRI were not improved after the treatment (c, f). P=0.024 (baseline vs 3-month), P=0.018 (baseline vs 6-month) and *P=0.015 (baseline vs 3-month) by Wilcoxon signed rank test.

Discussion

This phase I clinical study evaluated the safety, tolerability and potential efficacy of VM202 injected trans-epicardially to IHD patients. There are three major findings: (1) the intramyocardial injections of VM202 were safe and well tolerated at doses as high as 2.0 mg without any significant AEs related to VM202 itself or the injection procedure during the 6-month follow-up period; (2) this study, though small in scale, demonstrated that the territory injected by VM202 showed improvement of regional myocardial perfusion, particularly in the stress phase, and the wall thickness; (3) elevation of the HGF protein level in plasma and presence of anti-HGF antibodies in serum were not detected in all patients.

Except for the abnormal reactions related to CABG procedure, there was no dose-limiting toxicity that met the definition of ‘severe abnormal reaction’ from Spilker’s classification or ‘over grade 3’ from WHO toxicity scale. Therefore, the dose of cohort III (2 mg per 4 ml) was determined to be the tolerated dose. A total of 112 AEs was reported in nine patients during the study period. However, none was related to VM202, and no patient was excluded from the study due to abnormal reactions. Also, there were no clinically abnormal findings from laboratory tests, physical examinations, and vital signs. One SAE found in one patient (subject no. 3 of cohort I) was the delayed discharge from the hospital due to worsening of spinal stenosis and infectious spondylitis; thus, this SAE was irrelevant to the intramyocardial injection of VM202. Although subject no. 1 and subject no. 2 of cohort I developed supraventricular tachycardia and hypertensive retinopathy, respectively, these events did not seem to be associated with the VM202 treatment because transient supraventricular tachycardia is a common post-cardiac surgery reaction, and, unlike proliferative retinopathy, hypertensive retinopathy has no known relationship with HGF. In addition, the absence of other types of SAEs was confirmed by various methods; there were no hematoma around the injected region (by TTE and cardiac MRI), no significant electrocardiography change, no continuous arrhythmia (by TTE) and no major adverse cardiac event (MACE) during the follow-up period. Recently, Henry et al.14 reported that there were no serious complications and adverse effects related to VM202 occurred in patients with critical limb ischemia in a 12-month survey. The present study provides additional safety data on VM202, which in this case was intramyocardially administered to patients with IHD.

The present study showed that global myocardial functions such as WMSI and stress perfusion significantly improved 6 months after CABG combined with VM202 injections. It appears that these global improvements were a direct result of CABG itself, because all grafts were widely patent on left coronary artery system. However, it is noteworthy that there were increases in stress perfusion and wall thickness of diastolic and systolic phases in the RCA territory injected with VM202. Even though the effects of collateral perfusion caused by left-sided CABG were taken into account, the VM202 injection appears to be another plausible cause of the improvement in the un-revascularized territory. Because this study population (n=9) was too small to be concluded as a clinical meaning, the efficacy of VM202 injection will be evaluated more precisely in the next stage of the clinical study by comparing the VM202-treated group with the control group receiving only CABG on the left anterior descending artery and left circumflex artery territory leaving RCA territory untreated.

There are many reports about the efficacy of HGF in ischemic conditions.7, 8, 9, 10, 11, 12, 13, 16, 17 One proposed mechanism of HGF in ischemia would be that HGF exerts cardio-protective effects by inducing proliferation and migration of endothelial cells, migration of vascular smooth muscle cells, and reduction in apoptotic cell death at the infarct border zone. In our previous animal studies, it was shown that VM202 would be more effective than vascular endothelial growth factor in aspects of angiogenesis and myocardial perfusion.13 It has also been reported that VM202 could lead to nearly complete recovery of LVEF and improve the radial and circumferential strain of remote, peri-infarcted, and infarcted regions in swine models.18, 19, 20 HGF plasmid DNA has been also used for peripheral vascular diseases. Morishita et al., Gu et al. and Henry et al. reported the safety and therapeutic potential of naked DNAs expressing single isoform or dual-isoforms of HGF in patients with critical limb ischemia.14, 15, 16, 17

Generation of the anti-HGF antibody is one of the often raised concerns toward the HGF gene therapy because it may result in SAEs by inhibiting natural functions of HGF.21, 22, 23 Gu et al.15 and Henry et al.14 reported that no cohort showed generation of antibodies to the two isoforms of HGF protein in critical limb ischemia patients. Powell et al.17 also showed that no patient developed antibodies to the single isoform of HGF protein during their study. Consistent with the findings from the previous studies, intramyocardially injected VM202 did not lead to the generation of anti-HGF antibodies. One possible explanation for these phenomena would be that VM202 produces the HGF protein identical to the endogenous HGF protein. One other possible reason would be that the plasma level of HGF in patients with acute coronary syndrome might be high enough to mask the effects of the HGF protein produced by VM202.23 In addition, intramyocardial injection of VM202 did not increase the HGF concentration in plasma, and this observation is consistent with the results shown in previous preclinical studies.24, 25 Taken together, it could be concluded that direct local injection of VM202 could produce therapeutic effects without off-target effects such as aggravation of diabetic proliferative retinopathy or malignancies.

The present study shows that intramyocardial administration of naked DNA expressing two isoforms of HGF is safe at doses as high as 2 mg and also has encouraging therapeutic potential in patients with IHD. These data support the performance of a next-stage clinical trial with VM202 as an adjunct therapy to CABG or minimal invasive surgical injection of VM202 alone without CABG.

Materials and methods

Study design

This phase I clinical trial was an open label, non-placebo controlled, dose-escalation, single center study (http://www.clinicaltrials.gov; registration number: NCT01422772). This study was approved by the institutional review board of Seoul National University Hospital (no. H-0604-028-172). From January 2007 to February 2010, consent from a total sixteen patients was obtained; among them, six patients whose RCA branches (PDA (posterior descending artery) or PLbr (posterolateral branch)) showed an enough size for anstomosis were excluded intraoperatively and one patient failed to pass the screening procedure preoperatively. As a result, a total of nine patients (three per dose cohort) were enrolled to receive 0.5 mg (cohort I: four injections, 0.125 mg per 0.25 ml per injection), 1.0 mg (cohort II: eight injections, 0.125 mg per 0.25 ml per injection) or 2.0 mg (cohort III: eight injections, 0.25 mg per 0.5 ml per injection) of VM202 via single trans-epicardial injections into the RCA region after CABG (Figure 2). Following the intramyocardial injection of VM202, changes in myocardial functions, as well as the safety and tolerability of the study drug, were evaluated at baseline (injection date) and throughout the subsequent 6-month follow-up period.

Figure 2
figure2

Injection. (a) Left-sided coronary arteries were anastomosed by CABG procedure (composite Y graft). The right coronary artery was salvaged by intramyocardial VM202 injection around PDA course. (b) A total of nine patients (three per cohort) were enrolled to receive 0.5 (cohort I), 1.0 (cohort II) or 2.0 mg (cohort II) of VM202 as single intramyocardial injection. Open circle: injection sites of VM202 around PDA course, Red line: composite Y graft, Black line: coronary arteries.

Patient eligibility

Inclusion criteria included the followings: among all the patients who were selected as candidates for CABG, patients who had been experiencing reduction of perfusion in the inferior wall (rest perfusion−stress perfusion:7% on myocardial SPECT) but were not eligible for anastomosis of PDA and/or PLbr) due to narrowness of the vessel diameters were selected as the initial candidates. The age limitation for enrollment was from 19- to 75-years old. Patients who had small-sized PDAs and/or PLbrs (diameters:<1 mm) or hypoplastic RCA without a left dominant pattern on their pre-operative coronary angiography were enrolled. However, patients who had graftable right coronary artery systems according to intra-operative findings were excluded.

Exclusion criteria included the followings: on-going heart failure symptoms over Killip classification II, severe low LVEF (<25%), history of ventricular arrhythmia or uncontrolled arrhythmia, history of cerebrovascular accident, proliferative retinopathy, hepatic failure (SGOT (serum glutamic oxaloacetic transaminase)/SGPT (serum glutamic pyruvic transaminase):>2 × upper normal limit), and renal failure (serum creatinine:>2 mg dL−1, anuria, acute renal failure, on hemodyalysis dependent person). Patients scheduled to have combined cardiac operation or redo-sternotomy were also excluded from the study.

Study material

VM202 (pCK-HGF-X7) is a plasmid DNA that is designed to produce two isoforms of HGF protein consisting of 723 and 728 amino acids.13, 14, 15, 18, 19, 20, 24, 25, 26 Detailed information about VM202 is described by Pyun et al.24 Bulk drug substance and lyophilized drug product of VM202 used in the present study were manufactured by Strathmann Biotec (Hannover, Germany) and Pegasus Pharma (Hannover, Germany). VM202 was supplied in a sterile glass vial containing 2 mg of lyophilized study product and stored at 2 to 8 °C. Two milligram of lyophilized VM202 was diluted with 4 ml of water for injection and melted for 5 min at room temperature of the operating field. Then, a 1-ml syringe was used for injection (0.5 mg per 1 ml per syringe).

Operative procedures and injection

All procedures for CABG were performed by off-pump technique because any effect of cardiopulmonary bypass had to be excluded. The procedures of off-pump CABG have been clearly described in our previous paper.27 After revascularization of the left coronary artery system, VM202 was injected into 4 or 8 sites around the PDA course as shown in Figure 2 following protamine half reversal. A 27-gauze syringe was used for each epicardial injection. After the injection, any occurrences of hematoma or bleeding in the injected area were closely observed until pericardial closure.

Primary end points

Dose-limiting toxicity and tolerated dose were observed for 4 weeks after the VM202 treatment. Safety evaluations including AEs, vital sign, physical examination and laboratory findings were performed throughout the 6-month follow-up period. All events including cardiac death, myocardial infarction and ventricular arrhythmia related to VM202 injection and readmission for revascularization were defined as ‘MACE’ in this study. The occurrence of complications that might be related to VM202 injection (for example, proliferative retinopathy, hematoma formation on injection region and arrhythmia) were closely monitored during the 6-month follow-up period. Baseline changes in plasma HGF protein level were observed at week 1, 2, 4, 8, 12 and 24 using human HGF enzyme-linked immunosorbent assay (ELISA, R&D systems, Minneapolis, MN, USA), and generation of anti-human HGF antibody in serum was analyzed at week 2, 4 and 24 using competitive ELISA developed by ViroMed Co., Ltd. (Seoul, Korea).

Secondary end points

The changes in global and regional myocardial functions were investigated using cardiac MRI, myocardial SPECT and TTE at baseline, 3 and 6 months after the VM202 treatment.

TTE: left ventricular diameters, WMSI and LVEF were obtained and compared between each period for global myocardial function. WMSI was expressed by the regional 16 segment model.

Myocardial SPECT: The perfusion images from the rest and stress tests were evaluated using dipyridamole. The changes in regional myocardial perfusion and systolic wall thickening shown in the traditional 20 segment model were analyzed. Among the 20 segments, the segments that were under the normal value of stress perfusion were analyzed for global myocardial function. Two (apical inferior and mid inferior) of the 20 segments were analyzed for the evaluation of VM202 injected area.

Cardiac MRI: The left ventricular volume, wall motion index, wall thickness, LVEF and cardiac output were checked during the study period. In addition, the extent of late enhancement of gadolinium and systolic thickening on the injected area were evaluated, with a particular focus on the inferior wall to assess the injection region.

Statistical methods

SAS version 9.1 (SAS Institute Inc., Cary, NC, USA) was adopted for statistical analysis. All continuous values were expressed as mean±s.d. or median value with range, and a P<0.05 was considered to be statistically significant. Safety parameters were analyzed by Fisher’s exact test among dose-cohorts. To compare continuous variables between time frames, both non-parametric repeated measures analysis of variance (RMANOVA) test (with post hoc analysis) and Wilcoxon’s signed rank test were performed. Kruskal–Wallis test was used for non-parametric comparison among the cohorts.

References

  1. 1

    Mukherjee D, Bhatt DL, Roe MT, Patel V, Ellis SG . Direct myocardial revascularization and angiogenesis—how many patients might be eligible? Am J Cardiol 1999; 84: 598–600; A8.

  2. 2

    Scott R, Blackstone EH, McCarthy PM, Lytle BW, Loop FD, White JA et al. Isolated bypass grafting of the left internal thoracic artery to the left anterior descending coronary artery: late consequences of incomplete revascularization. J Thorac Cardiovasc Surg 2000; 120: 173–184.

  3. 3

    Caputo M, Reeves BC, Rajkaruna C, Awair H, Angelini GD . Incomplete revascularization during OPCAB surgery is associated with reduced mid-term event-free survival. Ann Thorac Surg 2005; 80: 2141–2147.

  4. 4

    Naldini L, Vigna E, Narsimhan RP, Gaudino G, Zarnegar R, Michalopoulos GK et al. Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. Oncogene 1991; 6: 501–504.

  5. 5

    Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991; 251: 802–804.

  6. 6

    Morishita R, Aoki M, Hashiya N, Yamasaki K, Kurinami H, Shimizu S et al. Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther 2004; 4: 199–206.

  7. 7

    Jayasankar V, Woo YJ, Bish LT, Pirolli TJ, Chatterjee S, Berry MF et al. Gene transfer of hepatocyte growth factor attenuates postinfarction heart failure. Circulation 2003; 108 (Suppl 1): II230–II236.

  8. 8

    Funatsu T, Sawa Y, Ohtake S, Takahashi T, Matsumiya G, Matsuura N et al. Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor. J Thorac Cardiovasc Surg 2002; 124: 1099–1105.

  9. 9

    Ahmet I, Sawa Y, Yamaguchi T, Matsuda H . Gene transfer of hepatocyte growth factor improves angiogenesis and function of chronic ischemic myocardium in canine heart. Ann Thorac Surg 2003; 75: 1283–1287.

  10. 10

    Yasuda S, Goto Y, Baba T, Satoh T, Sumida H, Miyazaki S et al. Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function. J Am Coll Cardiol 2000; 36: 115–121.

  11. 11

    Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S . Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation 1997; 95: 2552–2558.

  12. 12

    Jin H, Yang R, Li W, Ogasawara AK, Schwall R, Eberhard DA et al. Early treatment with hepatocyte growth factor improves cardiac function in experimental heart failure induced by myocardial infarction. J Pharmacol Exp Ther 2003; 304: 654–660.

  13. 13

    Cho KR, Choi JS, Hahn W, Kim DS, Park JS, Lee DS et al. Therapeutic angiogenesis using naked DNA expressing two isoforms of the hepatocyte growth factor in a porcine acute myocardial infarction model. Eur J Cardiothorac Surg 2008; 34: 857–863.

  14. 14

    Henry TD, Hirsch AT, Goldman J, Wang YL, Lips DL, McMillan WD et al. Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study. Gene Therapy 2011; 18: 788–794.

  15. 15

    Gu Y, Zhang J, Guo L, Cui S, Li X, Ding D et al. A phase I clinical study of naked DNA expressing two isoforms of hepatocyte growth factor to treat patients with critical limb ischemia. J Gene Med 2011; 13: 602–610.

  16. 16

    Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension 2004; 44: 203–209.

  17. 17

    Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 2008; 118: 58–65.

  18. 18

    Carlsson M, Osman NF, Ursell PC, Martin AJ, Saeed M . Quantitative MR measurements of regional and global left ventricular function and strain after intramyocardial transfer of VM202 into infarcted swine myocardium. American journal of physiology. Heart Circ Physiol 2008; 295: H522–H532.

  19. 19

    Saeed M, Saloner D, Do L, Wilson M, Martin A . Cardiovascular magnetic resonance imaging in delivering and evaluating the efficacy of hepatocyte growth factor gene in chronic infarct scar. Cardiovasc Revasc Med 2011; 12: 111–122.

  20. 20

    Perin EC, Silva GV, Vela DC, Zheng Y, Baimbridge F, Gahremanpour A et al. Human hepatocyte growth factor (VM202) gene therapy via transendocardial injection in a pig model of chronic myocardial ischemia. J Card Fail 2011; 17: 601–611.

  21. 21

    Nakamura T, Mizuno S . The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. ProcJapan Acad 2010; 86 (6): 588–610.

  22. 22

    Burr AW, Toole K, Chapman C, Hines JE, Burt AD . Anti-hepatocyte growth factor antibody inhibits hepatocyte proliferation during liver regeneration. J Pathol 1998; 185: 298–302.

  23. 23

    Heeschen C, Dimmeler S, Hamm CW, Boersma E, Zeiher AM . Simoons ML. Prognostic significance of angiogenic growth factor serum levels in patients with acute coronary syndromes. Circulation 2003; 107: 524–530.

  24. 24

    Pyun WB, Hahn W, Kim DS, Yoo WS, Lee SD, Won JH et al. Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia. Gene Therapy 2010; 17: 1442–1452.

  25. 25

    Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH et al. Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model. J Gene Med 2011; 13: 549–555.

  26. 26

    Lee Y, Park EJ, Yu SS, Kim DK, Kim S . Improved expression of vascular endothelial growth factor by naked DNA in mouse skeletal muscles: implication for gene therapy of ischemic diseases. Biochem Biophys Res Commun 2000; 272: 230–235.

  27. 27

    Kim KB, Cho KR, Chang WI, Lim C, Ham BM, Kim YL . Bilateral skeletonized internal thoracic artery graftings in off-pump coronary artery bypass: early result of Y versus in situ grafts. Ann Thorac Surg 2002; 74: S1371–S1376.

Download references

Acknowledgements

This study was supported by grants from ViroMed Co., Ltd (06-2006-273-0) and Reyon Pharmaceuticals Co., Ltd, Seoul, Korea.

Author information

Correspondence to K-B Kim.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, J., Hwang, H., Cho, K. et al. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study. Gene Ther 20, 717–722 (2013) doi:10.1038/gt.2012.87

Download citation

Keywords

  • gene transfer
  • hepatocyte growth factor
  • angiogenesis
  • naked DNA
  • incomplete revascularization

Further reading