Constitutive expression of phVEGF(165) after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia

Article

关键词: ENDOTHELIAL GROWTH-FACTOR;    VASCULAR-PERMEABILITY FACTOR;    ARTERIAL OCCLUSIVE DISEASE;    PLASMID DNA;    THERAPEUTIC ANGIOGENESIS;    SKELETAL-MUSCLES;    RABBIT MODEL;    BLOOD-FLOW;    IN-VIVO;    MITOGEN;   

DOI  :  10.1161/01.CIR.97.12.1114

来源: SCIE

【 摘 要 】

Background - Preclinical studies have indicated that angiogenic growth factors can stimulate the development of collateral arteries, a concept called therapeutic angiogenesis. The objectives of this phase 1 clinical trial were (1) to document the safety and feasibility of intramuscular gene transfer by use of naked plasmid DNA encoding an endothelial cell mitogen and (2) to analyze potential therapeutic benefits in patients with critical limb ischemia. Methods and Results - Gene transfer was performed in 10 limbs of 9 patients with nonhealing ischemic ulcers (n = 7/10) and/or rest pain (n = 10/10) due to peripheral arterial disease. A total dose of 4000 mu g of naked plasmid DNA encoding the 165-amino-acid isoform of human vascular endothelial growth factor (phVEGF(165)) was injected directly into the muscles of the ischemic limb. Gene expression was documented by a transient increase in serum levels of VEGF monitored by ELISA. The ankle-brachial index improved significantly (0.33 +/- 0.05 to 0.48 +/- 0.03, P = .02); newly visible collateral blood vessels were directly documented by contrast angiography in 7 limbs; and magnetic resonance angiography showed qualitative evidence of improved distal flow in 8 limbs. Ischemic ulcers healed or markedly improved in 4 of 7 limbs, including successful limb salvage in 3 patients recommended for below-knee amputation. Tissue specimens obtained from an amputee 10 weeks after gene therapy showed foci of proliferating endothelial cells by immunohistochemistry. PCR and Southern blot analyses indicated persistence of small amounts of plasmid DNA, Complications were limited to transient lower-extremity edema in 6 patients, consistent with VEGF enhancement of vascular permeability. Conclusions - 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.

【 授权许可】

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