Published today in Circulation: Cardiovascular Interventions, the LEGenD-1 trial represents a step toward a potential milestone in regenerative medicine and limb preservation. The study, titled “Anatomically Directed Lower Extremity Gene Therapy for Ulcer Healing: A Double-Blind, Randomized, Placebo-Controlled Study,” demonstrates that gene therapy can safely potentially accelerate wound healing in patients with chronic limb-threatening ischemia (CLTI) and neuroischemic ulcers.
The Investigators Behind the Work
This landmark study was led by a collaborative team of podiatric, vascular, and plastic surgeons, dermatologists, and clinical trial specialists from across the United States including:
- David G. Armstrong, DPM, MD, PhD — Division of Surgery, Keck School of Medicine, University of Southern California (USC)
- Michael S. Conte, MD — Division of Vascular and Endovascular Surgery, University of California, San Francisco (UCSF)
- Joseph L. Mills, MD — Division of Vascular Surgery and Endovascular Therapy, Baylor College of Medicine
- Matthew T. Menard, MD — Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, Harvard Medical School
- Dennis P. Orgill, MD, PhD — Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School
- Robert D. Galiano, MD — Division of Plastic and Reconstructive Surgery, Feinberg School of Medicine, Northwestern University
- Robert S. Kirsner, MD, PhD — Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine
- Alik Farber, MD, MBA — Division of Vascular and Endovascular Surgery, Boston Medical Center
- John C. Lantis, MD — Department of Surgery, Mount Sinai West, Icahn School of Medicine at Mount Sinai
- Charles M. Zelen, DPM — Department of Surgery, Virginia Tech Carilion School of Medicine
- Marissa J. Carter, PhD, MA — Strategic Solutions, Inc.
- Caitlin W. Hicks, MD, MS — Division of Vascular Surgery and Endovascular Therapy, Johns Hopkins University School of Medicine
- Richard J. Powell, MD — Division of Vascular Surgery, Dartmouth Geisel School of Medicine
Together, this multidisciplinary team represents the first successful anatomically directed gene therapy trial for ulcer healing in CLTI.
Together, this multidisciplinary team represents the first successful anatomically directed gene therapy trial for ulcer healing in CLTI.
Why LEGenD-1 Matters
Patients with CLTI face devastating risks—non-healing ulcers, amputation, and mortality rates that rival many cancers. Revascularization remains the gold standard, but patients with moderate ischemia and neuroischemic ulcers often fall into a therapeutic void: too ischemic to heal, yet not candidates for surgical bypass or other intervention. To date, no FDA-approved therapy exists to directly promote wound healing in this group.
LEGenD-1 investigated whether intramuscular delivery of AMG0001, a plasmid encoding hepatocyte growth factor (HGF), could promote therapeutic angiogenesis and accelerate ulcer closure by improving microvascular perfusion or possibly through anti inflammatory effects.
Study Design
Conducted across 22 U.S. clinical sites, LEGenD-1 was a phase II, double-blind, randomized, placebo-controlled trial involving 75 participants with CLTI and neuroischemic ulcers. Subjects were assigned to receive 4 mg AMG0001, 8 mg AMG0001, or placebo, administered through four intramuscular injections delivered over 84 days along a pre-mapped “target artery path.”
Key Findings
Median time to healing: AMG0001 shortened median time to healing to 84 days vs. 280 days for placebo (P = 0.007). Both 4 mg and 8 mg doses produced significant improvements (P = 0.017 and 0.022, respectively). Complete ulcer healing: By 6 months, 63.3% of AMG0001-treated patients achieved complete healing compared with 38.5% for placebo (P = 0.053). At 12 months, healing reached 77.6% vs. 46.2% (P = 0.010). Safety: Adverse events were balanced across groups. Two participants in the placebo group and five in the AMG0001 groups underwent endovascular revascularization after the 6-month primary endpoint window. None of these procedures influenced outcome assessment.
A Potential Paradigm Shift:
Unlike prior biologic trials that targeted “no-option” patients using amputation-free survival as the primary endpoint, LEGenD-1 focused on earlier-stage CLTI and ulcer healing as a measurable and meaningful clinical endpoint.
By addressing the microcirculation, HGF gene therapy could bridge the gap between revascularization and regenerative medicine, introducing a biologic complement to surgical care.
Looking Ahead
LEGenD-1 is the first randomized, anatomically directed gene therapy trial to show a significant improvement in wound healing in people with CLTI.
If data continue in this direction, this approach could mark the beginning of a new era in biologic limb preservation—one focused not only on perfusion but on tissue repair, angiogenesis, and remission.
Full Citation
Armstrong DG, Conte MS, Mills JL, Menard MT, Orgill DP, Galiano RD, Kirsner RS, Farber A, Lantis JC, Zelen CM, Carter MJ, Hicks CW, Powell RJ.
Anatomically Directed Lower Extremity Gene Therapy for Ulcer Healing: A Double-Blind, Randomized, Placebo-Controlled Study (LEGenD-1).
Circulation: Cardiovascular Interventions. 2026;19:e015648. DOI: 10.1161/CIRCINTERVENTIONS.125.015648.
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