Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study.

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3-10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36-2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Intramyocardial adenoviral vascular endothelial growth factor-D∆N∆C gene therapy does not induce ventricular arrhythmias.

BACKGROUND: The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-DΔNΔC (AdVEGF-D) gene therapy (GT) to alleviate symptoms in refractory angina (RA) patients. In KAT301, 30 patients with RA were randomized to AdVEGF-D or the control group in 4:1 ratio. The treatment was found to be feasible, increasing myocardial perfusion and reducing angina symptoms at 1-year follow-up. However, there is some evidence suggesting that the intramyocardial delivery route and overexpression of (vascular endothelial growth) VEGFs might induce ventricular arrhythmias. Thus, we investigated whether intramyocardial AdVEGF-D GT increases the risk of ventricular arrhythmias in patients treated for RA. METHODS: We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up. RESULTS: We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. CONCLUSIONS: In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.

Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

AIMS: We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DΔNΔC gene therapy in patients with refractory angina. METHODS AND RESULTS: Thirty patients were randomized to AdVEGF-DΔNΔC (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00 ± 0.36) at 3 months (1.31 ± 0.46, P = 0.045) and 12 months (1.44 ± 0.48, P = 0.009) whereas MPR in the reference area tended to decrease (2.05 ± 0.69, 1.76 ± 0.62, and 1.87 ± 0.69; baseline, 3 and 12 months, respectively, P = 0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months (1.26 ± 0.37, 1.57 ± 0.55, and 1.48 ± 0.48; respectively, P = 0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94 ± 0.32 and 1.76 ± 0.41 baseline and 12 months, respectively, P = 0.023). CONCLUSION: AdVEGF-DΔNΔC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.

Intramyocardial Gene Therapy Directed to Hibernating Heart Muscle Using a Combination of Electromechanical Mapping and Positron Emission Tomography.

Cardiac gene transfer for the treatment of ischemic diseases has suffered from low gene transfer efficiency and inability to target treatment genes to the ischemic myocardium. A combined method has been developed based on electromechanical mapping and radiowater PET imaging to target gene therapy to viable but ischemic and hibernating areas of the myocardium. Electromechanical NOGA mapping produces three-dimensional images of myocardium with both an electric activity map and a myocardial contractility map. These have been converted to 17-segment 2D bull's-eye maps, which were superimposed onto PET radiowater perfusion imaging maps of the myocardium. This technique was applied in a Phase I/IIa clinical trial to target gene therapy for refractory angina patients. It was found that by combining electromechanical map with PET imaging, targeting of gene therapy to hibernating ischemic myocardium can be significantly improved. Here, the methods for the identification of viable, ischemic, and hibernating myocardium for gene transfer are described, and examples of treated refractory angina patients who have benefited from the improved gene transfer method to the ischemic myocardium are presented.