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. 2015 Aug 3;108(1):4–20. doi: 10.1093/cvr/cvv205

Table 4.

Gene therapy clinical trials for therapeutic angiogenesis

Trial Gene Country Vector Delivery method Dose Clinical condition (no. of patients) Findings
FIRST
(FGF Initiating RevaScularization Trial) 2002		 FGF2 USA Plasmid DNA Intracoronary infusion (single dose) Dose escalation (0.3, 3, and 30 µg/kg) Coronary artery disease (337)

  • – No improvement in exercise tolerance

  • – No improvement in myocardial perfusion

  • – Trend towards symptomatic improvements
AGENT-I
Angiogenic GENe Therapy (2002)		 FGF4 USA Adeno-virus Intracoronary infusion (single dose) Five doses: (3.3 × 108, 1.0 × 109, 3.3 × 109, 1.0 × 1010, 3.3 × 1010 viral particles) Chronic stable angina (79)

  • – No major adverse events

  • – Favourable anti-ischaemic effects
AGENT-Ii
Angiogenic GENe Therapy (2003)		 FGF4 USA Adeno-virus Intracoronary infusion (single dose) 1010 adenoviral particles Chronic stable angina (52)

  • – Trend for improved myocardial perfusion without statistical difference with placebo
KAT
Kuopio Angiogenesis Trial (2003)		 VEGF-A165 Finland Adeno-virus/plasmid liposome Intracoronary infusion (single dose) Two groups: VEGF-Adv, 2 × 1010pfu
VEGF-P/L; 2000 µg of DNA with 2000 µL of DOTMA:DOPE		 Coronary artery disease (103)

  • – No major adverse events

  • – No differences in clinical restenosis rate or minimal lumen diameter
VIVA
(Vascular endothelial growth factor in Ischaemia for Vascular Angiogenesis) (2003)		 VEGF-A165 USA Plasmid DNA Intracoronary infusion (day 0) plus intravenous infusions (Days 3, 6, and 9) Low dose: 17 ng kg−1 min−1
High dose: 50 ng kg−1 min−1 		Stable exertional angina (178)

  • – No safety concerns

  • – No evidence of myocardial perfusion improvement

  • – Trend towards improvements in angina class and frequency
EUROINJECT—One (2005) VEGF-A165 Denmark, Poland, Sweden, and Austria Plasmid DNA Direct intramyocardial injection via NOGA-Myostar© 0.5 mg of phVEGF-A165 Severe stable ischaemic heart disease (80)

  • – No difference with placebo in clinical, perfusion, and wall motion characteristics

  • – Improved regional wall motion
REVASC-II (2006) VEGF-A121 Canada Adeno-virus Direct intramyocardial injections 4 × 1010 viral particles AdVEGF121 Severe coronary artery disease (67)

  • – No improvement in myocardial perfusion by SPECT nuclear imaging
AGENT-III/IV
Angiogenic GENe Therapy (2008)		 FGF4 USA, Europe Adeno-virus Intracoronary infusion (single dose) Low dose of 4, 1 × 109 viral particles (vp), and a high dose of 1 × 1010 vp Recurrent stable angina (AGENT-III: 416; AGENT-IV: 116)

  • – No differences between placebo and treatment for any primary or secondary endpoints

  • – No significant safety concerns

  • – Difference in placebo response between men and women
Phase I intracoronary administration of Ad-Hhgf (2009) hHGF China Adeno-virus Intracoronary infusion (single dose) Three doses: 5.0 × 109, 1.0 × 1010, 2.0 × 1010 pfu Severe and diffuse triple vessel coronary disease (18)

  • – No adverse events related to the vector

  • – Improved activity tolerance
NORTHERN
(NOGA angiogenesis Revascularization THErapy: assessment by RadioNuclide imaging) (2009)		 VEGF-A165 Canada Plasmid DNA Endocardial route using an electro-anatomical NOGA guidance catheter Total dose, 2 mg Refractory Canadian Cardiovascular Society (CCS) Class 3 or 4 angina symptoms (93)

  • – No evidence of improved myocardial perfusion assessed by single-photon emission tomography (SPECT)
Multicentre Phase I and Safety Study (2010) HIF1α Germany, UK Adeno-virus Intramyocardial injections during CABG Three doses: 1.0 × 1010, 3.0 × 1010, and 1.0 × 1011 viral particles Hypo-perfused area of viable ventricular muscle (13)

  • – No safety concerns related to vector administration
VIF-CAD (2011) Bicistronic [VEGF/FGF] plasmid Poland Plasmid DNA Percutaneous intramyocardial injection using NOGA guidance catheter Total dose, 0.5 mg Refractory coronary artery disease (52)

  • – No demonstrated improvement in cardiac perfusion assessed by SPECT

  • – Functional class improved

  • – Improved exercise tolerance
GENESIS I (2012) VEGF-A165 Argentina Plasmid DNA Intramyocardial injections Total dose, 3.8 mg Severe CAD not amenable for revascularization (10)

  • – Safe at 2 years follow-up

  • – Trend towards improved myocardial perfusion assessed by SPECT
ASPIRE (2013) FGF4 Russia Adeno-virus intracoronary infusion during induced transient ischaemia 6 × 109 viral particles Ad5FGF4 Stable angina pectoris (100)

  • – In recruitment phase

  • – Assessments for safety and efficacy after 1 year of follow-up
KAT301 (2013) VEGF-D Finland Adeno-virus Endocardial injection system (NOGATM) Escalating dose of 1 × 109, 1 × 1010, and 1 × 1011 vpu injected into 10 sites of the myocardium Severe coronary artery disease (30)

  • – In recruitment phase

  • – Assessments for safety and efficacy after 1 year of follow-up