Additionally, taking into account numerous experimental and clinical data demonstrating rather insufficient therapeutic potential of VEGF, we called into question the role of this protein in limb ischemia and vessel regeneration.
In case of vascular endothelial growth factor (VEGF), a cytokine secreted from intact cells, bioavailability and meaningful angiogenic bioactivity was shown to be achievable by intramuscular gene transfer in patients with chronic critical limb ischemia.
As part of a phase I clinical trial to document the safety and efficacy of intramuscular gene transfer of naked plasmid DNA-encoding vascular endothelial growth factor (phVEGF165) in the treatment of critical limb ischemia, we treated TAO in 6 patients.
These findings may be cautiously interpreted to indicate that intramuscular injection of naked plasmid DNA achieves constitutive overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with critical limb ischemia.
Effective sEVs (e-sEVs) also improved vascular remodeling and prevented muscle damage in a mouse model of acute hind limb ischemia. e-sEV angiogenic proteomic and transcriptomic analyses show a positive correlation with matrix-metalloproteinase activation and extracellular matrix organization, cytokine and chemokine signaling pathways, Insulin-like Growth Factor and platelet pathways, and Vascular Endothelial Growth Factor signaling.
Pre-clinical studies and Phase I clinical trials using VEGF and fibroblast growth factor (FGF) demonstrated promising results; however, more rigorous Phase II and III clinical trials failed to demonstrate benefits for CLI patients.
Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.
HIF1α protein levels in the muscles after hind limb ischemia surgery were also significantly lower in BubR1<sup>L/-</sup> mice compared with WT mice (P < .05).
Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF-1alpha subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age-dependent critical limb ischemia.
Our results indicate that NOS1177D gene delivery to the ischemic skeletal muscle can be efficient to reverse critical limb ischemia in pathological settings, which are refractory to treatments with a single growth factor, such as vascular endothelial growth factor.
This study investigated the efficacy and safety of intramuscular injection of naked plasmid DNA encoding the human hepatocyte growth factor gene in Japanese patients with Buerger's disease and critical limb ischemia.
In the present study, we evaluated the therapeutic potential of gene-modified adipose-derived stromal cells (ADSC) that overexpress hepatocyte growth factor (HGF) in a mice hind limb ischemia model.
The current advances of clinical trials of plasmid and adenovirus HGF in the treatment of critical limb ischemia and coronary heart disease in China are introduced.