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. Author manuscript; available in PMC: 2016 May 17.
Published in final edited form as: Circ Res. 2015 Apr 24;116(9):1561–1578. doi: 10.1161/CIRCRESAHA.115.303565

Table 1.

Selected Clinical Trials of Gene Therapy Products for Critical Limb Ischemia

Reference (Trial) Product Dosage Delivery Method n Rutherford Class Follow-Up Duration Outcomes: Bioactivity Parameters Improved
Fibroblast growth factor
 Belch et al55 (TAMARIS) FGF-1; plasmid 8×0.5 mg injections for 4 sessions IM 525 Class 5–6 12 mo No changes in major amputation or death rates
 Comerota et al152 FGF-1; plasmid Dose escalation; 1×500, 1×1000, 1×2000, 1×4000, 1×8000, 1×16 000 mcg; or 2×500, 2×1000, 2×4000, 2×8000 mcg IM 51 Class 4–6 6 mo Decrease in pain, aggregate ulcer size; Increased TcPO2, ABI
 Nikol et al153 (TALISMAN-201) FGF-1; plasmid 8×0.5 mg injections for 4 sessions IM 125 No option CLI 12 mo Decreased amputation rate; no changes in ulcer healing
 Lederman et al56 (TRAFFIC) FGF-2; recombinant 30 mcg/kg single dose or 30 mcg/kg double dose (day 1+day 30) IA 190 Class 2–3 3 mo Increase peak walking time at 90 days; no change in quality of life or ABI
Vascular endothelial growth factor
 Rajagopalan et al58 (RAVE) VEG121; adenovirus Low dose 4×109 pu; high dose 4×1010 pu; 20 injections IM 105 Class 1–3 6 mo No changes in peak walking time or ABI; increased peripheral edema
 Baumgartner et al154 VEGF165; plasmid 4000 mcg IM 9 Class 4–6 10 wk Increased vascularity on digital subtraction angiography (DSA); healing of ischemic ulcers; proliferation of endothelial cells on pathology
 Makinen et al155 VEG165; plasmid and adenovirus 2×1010 pfu VEGF-Ad; or 2 mg/2mL VEGF plasmid IA 56 Class 1–6 3 mo Increased vascularity on DSA
 Kusumanto et al156 VEGF165; plasmid 2 mg each for 2 session IM 54 Class 4–6 100 days No changes in amputation rates or rest pain; improvements in skin ulceration, ABIs, TBIs
Hypoxia-inducible factor 1-alpha
 Rajagopalan et al60 HIF-1alpha; adenovirus Dose escalation; 1×108 to 2×1011 viral particles IM 34 No option CLI 12 mo No serious adverse events attributable to study treatment; no amputations in 2 highest dose groups; complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients
 Creager et al59 HIF-1alpha; adenovirus 2×109; 2×1010; 2×1011 viral particles; or placebo IM 289 Class 1–3 12 mo No significant differences in peak walking time, claudication onset time, ABI, or quality of life
Developmental endothelial locus-1
 Grossman et al157 Del-1; plasmid 42 mg plasmid or placebo over 21 injections in each leg (84 mg per subject) IM 105 PAD and stable exercise-limiting IC 12 mo Improvement in peak walking time, ABI, claudication onset time, and quality of life but no difference between control group
Hepatocyte growth factor
 Morishita et al63 HGF; plasmid Either 2 or 4 mg (4 or 8 injections) IM 22 Fontaine IIb, III, or IV, 2 yr ABI, pain relief, and ulcer healing were improved in the majority of patients
 Powell et al158 (HGF-STAT) HGF; plasmid 0.4 mg×8 for 3 sessions (low); 4 mg×8 for 2 sessions (mid); 4 mg×8 for 3 sessions (high) IM 104 Class 4–6 12 mo Increased TcPO2 at 6 mo in high-dose group; no changes in amputation, death, ulcer size, wound healing, ABI, TBI
 Powell et al159 (HGF-0205) HGF; plasmid 0.5 mg×8 for 3 sessions IM 27 Class 5–6 6 mo No change in wound healing or amputation; increase in TBI at 6 mo; increase rest pain improvement
 Shigematsu et al160 HGF; plasmid 0.5 mg×8 for 2 sessions IM 40 Class 4–5 3 mo Increased reduction in ulcer size; increased quality of life; no change in rest pain or ABI
 Henry et al161 HGF (VM202); plasmid Dose escalation 2–16 mg IM 12 No option CLI 12 mo Increase in median ABI/TBI; decrease in pain (visual analog scale)
 Gu et al162 HGF (VM202); plasmid 4 mg; 8 mg; 12 mg; 16 mg IM 21 Class 4–6 3 mo Increase in mean ABI and TcPO2; decrease in pain; improved wound healing

ABI indicates ankle brachial index; Del-1, developmental endothelial locus-1; CLI, critical limb ischemia; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; HIF-1α, hypoxia-inducible factor-1 alpha; IA, intra-arterial; IC, intermittent claudication; IM, intramuscular; PAD, peripheral artery disease; TBI, toe brachial index; TcPO2, transcutaneous oxygen pressure; and VEGF, vascular endothelial growth factor.