{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:48:26Z","timestamp":1788234506074,"version":"build-2803163510"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Cardiovascular Interventions"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>People with chronic limb-threatening ischemia lack Food and Drug Administration-approved therapies for wound healing, creating an unmet need for novel approaches. Prior studies of biologics in chronic limb-threatening ischemia have largely targeted end-stage patients with amputation-free survival as the primary outcome. This trial evaluated the efficacy of intramuscular administration of AMG0001, a plasmid encoding human HGF (hepatocyte growth factor), to promote ulcer healing in patients with chronic limb-threatening ischemia and neuroischemic ulcers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>LEGenD-1 was a double-blind, randomized, placebo-controlled phase II trial conducted at 22 US sites. Seventy-five participants with neuroischemic ulcers and toe pressure or transcutaneous oxygen pressure between 30 and 59 mm\u2009Hg were randomized to receive AMG0001 at 4 mg, 8 mg, or placebo. Injections were administered intramuscularly along an angiographically guided target artery path on days 0, 28, 56, and 84. The 2 coprimary end points were time to complete healing and the proportion of subjects with ulcers healed by 6 months in a pooled AMG0001 analysis. Secondary end points included healing by 12 months, ulcer recurrence, and hemodynamic changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Baseline characteristics were comparable across groups (mean age 62.6 years; 80.0% male; 70.7% with diabetes). Mean toe pressure was 46.1 mm\u2009Hg, and transcutaneous oxygen pressure was 49.8 mm\u2009Hg. Median time to healing was significantly shorter with AMG0001 versus placebo (84 versus 280 days;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.007); 4 mg: 98 days (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.017); 8 mg: 84 days (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.022). By 6 months, 63.3% of AMG0001-treated participants healed versus 38.5% of placebo (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.053). By 12 months, healing rates were 77.6% versus 46.2% (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.010). Adverse events were similar across groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Anatomically targeted intramuscular delivery of AMG0001 significantly accelerated healing in patients with moderate chronic limb-threatening ischemia and neuroischemic ulcers and may represent a promising nonsurgical therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT04267640.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circinterventions.125.015648","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:00:13Z","timestamp":1762250413000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Anatomically Directed Lower Extremity Gene Therapy for Ulcer Healing: A Double-Blind, Randomized, Placebo-Controlled Study (LEGenD-1)"],"prefix":"10.1161","volume":"19","clinical-trial-number":[{"clinical-trial-number":"nct04267640","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1887-9175","authenticated-orcid":true,"given":"David G.","family":"Armstrong","sequence":"first","affiliation":[{"name":"Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles (D.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9119-192X","authenticated-orcid":true,"given":"Michael S.","family":"Conte","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, University of California, San Francisco School of Medicine (M.S.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4955-4384","authenticated-orcid":true,"given":"Joseph L.","family":"Mills","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery &amp; Endovascular Therapy, Baylor College of Medicine, Houston, TX (J.L.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-7978","authenticated-orcid":true,"given":"Matthew T.","family":"Menard","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery (M.T.M.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8279-7310","authenticated-orcid":true,"given":"Dennis P.","family":"Orgill","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery (D.P.O.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Galiano","sequence":"additional","affiliation":[{"name":"Division of Plastic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL (R.D.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6824-9844","authenticated-orcid":true,"given":"Robert S.","family":"Kirsner","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, FL (R.S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7231-4189","authenticated-orcid":true,"given":"Alik","family":"Farber","sequence":"additional","affiliation":[{"name":"Division of Vascular and Endovascular Surgery, Department of Surgery, Boston University Chobanian &amp; Avedisian School of Medicine, Boston Medical Center, MA (A.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3615-6512","authenticated-orcid":true,"given":"John C.","family":"Lantis","sequence":"additional","affiliation":[{"name":"Department of Surgery, Icahn School of Medicine at Mount Sinai, NY (J.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5682-7056","authenticated-orcid":true,"given":"Charles M.","family":"Zelen","sequence":"additional","affiliation":[{"name":"Professional Education and Research Institute, Roanoke, VA 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