Gene Therapy for Myocardial Angiogenesis

Abstract

Background —We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. Methods and Results —VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF 165 ) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75±15/min versus post-GTx=80±16/min, P =NS), systolic BP (114±7 versus 118±7 mm Hg, P =NS), or diastolic BP (57±2 versus 59±2 mm Hg, P =NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm 3 , and total chest tube drainage was 110 to 395 cm 3 . Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8±0.4 versus postanesthesia=4.1±0.3 versus 24 hours postoperative=6.3±0.8, P =0.02). Time to extubation after closure was 18.4±1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9±10.0/wk pre-GTx versus 9.8±6.9/wk post-GTx, P <0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. Conclusions —This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.

Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle

“…The clinical utility of gene therapy using the VEGF gene has been recently reported for the treatment of critical limb ischemia and myocardial ischemia. [4][5][6][7][8][9][10][11] Instead of VEGF, other angiogenic growth factors such FGF, HGF and a transcription factor for angiogenesis, HIF (hypoxiainducible factor), have been considered candidates for therapeutic angiogenesis as gene therapy for the treatment of patients with critical limb ischemia. [12][13][14][15][16][17][18][19][20] Although the feasibility of therapeutic angiogenesis using these angiogenic growth factors has been reported in experimental models and human clinical trials, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] there are still unresolved problems such as undesirable side-effects.…”

“…Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia [4][5][6][7] and myocardial ischemia. [8][9][10][11] In addition to VEGF, the utility of gene transfer of other angiogenic growth factors such as fibroblast growth factor (FGF) or hepatocyte growth factor (HGF) has been reported to stimulate collateral formation. [12][13][14][15][16][17][18][19][20] The feasibility of gene therapy using angiogenic growth factors to treat peripheral arterial disease seems to be superior to recombinant protein therapy for the following reasons: (1) It has the potential to maintain an optimally high and local concentration over time.…”

“…Interestingly, most successful clinical trials of treating peripheral arterial disease using angiogenic growth factors have been performed by intramuscular transfection of naked plasmid DNA, [4][5][6][7][8] although in vivo gene transfer using direct injection of 'naked' DNA into cardiac and skeletal muscle is inefficient. It is apparent that a more efficient gene transfer method is required to achieve therapeutic effects.…”

Effects of intramyocardial pVEGF165 delivery on regional myocardial blood flow: evidence for a spatial ‘delivery–efficacy’ mismatch

“…2 Initial clinical studies have been reported with variable results. 3,4 A large body of evidence from preclinical studies supports the strategy of therapeutic angiogenesis by direct intramyocardial delivery of genes encoding VEGF using naked DNA (pVEGF 165 5 ) or adenoviruses (Ad-VEGF 121 6 ). In addition to the primary therapeutic goal of improving myocardial blood flow, structural changes in the vasculature of the treated myocardial segments (capillary density and collateral development) have also been demonstrated.…”

Molecular switches for regulating therapeutic genes

“…There are currently several clinical trials in progress to determine the therapeutic potential of directly injected VEGF and basic fibroblast growth factor genes and proteins to stimulate angiogenesis in ischaemic myocardium and ischaemic limbs (see Ref. 9 and references therein). Delivery of these factors by tissue-specific hypoxia-regulated vectors may be a more efficient and safer way to accomplish this goal, avoiding possible spillover of the viral transgene to other areas where increased angiogenesis is not desired.…”