{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:17:28Z","timestamp":1792084648010,"version":"4.4.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1998,3,31]]},"abstract":"<jats:p>\n            <jats:italic>Background<\/jats:italic>\n            \u2014Preclinical studies have indicated that angiogenic growth factors can stimulate the development of collateral arteries, a concept called \u201ctherapeutic angiogenesis.\u201d 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.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Methods and Results<\/jats:italic>\n            \u2014Gene 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 \u03bcg of naked plasmid DNA encoding the 165-amino-acid isoform of human vascular endothelial growth factor (phVEGF\n            <jats:sub>165<\/jats:sub>\n            ) 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\u00b10.05 to 0.48\u00b10.03,\n            <jats:italic>P<\/jats:italic>\n            =.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.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Conclusions<\/jats:italic>\n            \u2014These 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.\n          <\/jats:p>","DOI":"10.1161\/01.cir.97.12.1114","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:41:02Z","timestamp":1339461662000},"page":"1114-1123","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":838,"title":["Constitutive Expression of phVEGF\n            <sub>165<\/sub>\n            After Intramuscular Gene Transfer Promotes Collateral Vessel Development in Patients With Critical Limb Ischemia"],"prefix":"10.1161","volume":"97","author":[{"given":"Iris","family":"Baumgartner","sequence":"first","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Pieczek","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orit","family":"Manor","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Blair","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Kearney","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Walsh","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Isner","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine (Cardiology) (I.B., A.P., J.M.I.), Radiology (R.B.), and Biomedical Research (I.B., O.M., M.K., K.W., J.M.I.), St Elizabeth\u2019s Medical Center, Tufts University School of Medicine, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","unstructured":"European Working Group on Critical Leg Ischemia. 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