Can we give people more time in ischemic remission?
That is the question I keep coming back to after reading the new editorial from our longtime friends Marco Meloni, Luigi Uccioli, and colleagues in Italy. Their paper, “Is ‘No-Option Critical Limb Threatening Ischaemia’ a Right Definition?”, published October 9 in The International Journal of Lower Extremity Wounds, asks us to reconsider what “no option” means as autologous cell therapy develops.
I share their enthusiasm. The possibility of treatments beyond endovascular and open reconstruction deserves serious attention. My hope is that carefully selected biological therapies may eventually help us extend the interval between limb-threatening episodes, complement revascularization, and intervene earlier in selected patients with CLTI.
That is a hypothesis worth testing. The evidence already gives us reasons to pursue it, along with important boundaries.
A conversation that goes back years
In our 2018 post on the Tor Vergata team’s work, we wrote: “Our patients are in vascular remission just as they are in diabetic foot remission.”
The underlying study followed 304 people with ischemic diabetic foot ulcers after angioplasty; 74, or 24.3%, required repeat angioplasty during a mean follow-up of 12.5 months. Successful treatment had opened a valuable period of relative stability. Continued surveillance and protection still mattered.
We returned to Marco and Luigi’s work in 2023, discussing peripheral blood mononuclear cells. The new editorial continues that conversation. It proposes a change in how we think about patients after conventional revascularization has failed. It is an editorial, rather than a new randomized trial.
What the cell-therapy evidence adds
One particularly relevant prospective study, published online in 2024, enrolled 52 patients whose wounds remained ischemic after indirect revascularization. All received three cycles of peripheral blood mononuclear cells. At one year, 44 had healed and survived; another two had healed before dying. No major amputations were recorded.
That is an encouraging adjunctive-treatment signal. Because there was no control group, we cannot separate the contribution of the cells from revascularization, wound care, patient selection, or other factors.
The team’s 2026 two-year observational study adds longer follow-up, but compares 48 treated patients with 30 historical controls from an earlier era. Its three recurrent-CLTI readmissions requiring revascularization were recorded only in the treated group. It therefore cannot show that cell therapy lengthened the interval between procedures.
The PB-MNC approach discussed here uses cells derived from the patient’s own blood. Randomized results across cell products have not been uniformly positive: the 213-patient PACE trial of placental-derived PLX-PAD did not significantly improve major-amputation-free survival versus placebo. It is a different product, underscoring the need for product-specific evidence.
LEGenD-1 opens another window
Gene therapy is a distinct approach. LEGenD-1, which we covered when it appeared online in November 2025, studied intramuscular delivery of AMG0001, a plasmid encoding hepatocyte growth factor. I was an investigator and coauthor; my disclosure appears below.
This phase II, double-blind, placebo-controlled trial randomized 75 participants across 22 U.S. sites with neuroischemic ulcers and CLTI with relatively moderate ischemia. Eligibility included toe pressure or transcutaneous oxygen pressure of 30–59 mmHg; gangrene and more severe ischemia were excluded.
The combined treatment groups had a median healing time of 84 days versus 280 days with placebo (P=.007). The other coprimary endpoint, complete healing at six months, was 63.3% versus 38.5% (P=.053), which did not meet the conventional .05 threshold. At 12 months, a secondary endpoint, healing was 77.6% versus 46.2% (P=.010).
Adverse events were similar between groups, but 75 participants cannot establish broad or long-term safety. The trial supports further investigation of ulcer healing in this selected population. It does not establish prevention of amputation, fewer repeat procedures, or longer ischemic remission.
The earlier treatment window is particularly interesting: patients can have limb-threatening wounds without the most severe measured ischemia. That is a population we should study carefully.
A treatment axis with overlapping possibilities
The conceptual figure below imagines a broader set of options across the PAD and CLTI spectrum. Its most important feature is the overlap.
Best medical therapy remains the foundation: lipid lowering, appropriate antithrombotic treatment, blood-pressure and diabetes management, smoking cessation, and preventive foot care. GLP-1 receptor agonists and other cardiometabolic therapies belong where clinically indicated. Offloading, infection management, and wound care remain essential when an ulcer is present. The 2024 multisociety PAD guideline anchors that approach.
Endovascular and open reconstruction remain central when revascularization is indicated. The choice depends on anatomy, limb threat, patient risk, available conduit, and the person’s goals. Severity alone does not dictate a sequence from one procedure to another.
I would place cell and gene therapies in a clearly marked investigational band. The research question is where they might add benefit: after an inadequate revascularization result, in selected earlier CLTI, or eventually during the interval following successful treatment. Those are different clinical questions and require different trials. The Global Vascular Guidelines place therapeutic angiogenesis within registered clinical trials. Experimental therapy should never delay indicated vascular assessment or revascularization.
Let’s measure the time we give back
For me, ischemic remission (like diabetic foot ulcer remission) is a useful way to frame the next question: how long can we help a person remain stable, mobile, and free of another limb-threatening episode? This does not imply cure of PAD or normal perfusion. Remission needs a prospectively defined, reproducible trial endpoint before we can claim to have extended it.
Future studies should measure recurrent ischemia, repeat revascularization, durable wound closure, ulcer recurrence, major amputation, and survival. Analyses must account for death and amputation as competing events. Studies should also ask about pain, walking, treatment burden, hospital-free days, and quality of life. An artery, a wound, and a person can tell us different things about the same treatment.
For patients today, the practical message is to stay connected with a multidisciplinary limb-preservation team, keep up vascular and foot surveillance, and seek prompt assessment for new wounds, rest pain, or worsening symptoms. Trial participation may be worth discussing when eligibility and local availability fit.
Marco, Luigi, and colleagues have helped move this conversation forward for years. Bravo to our Italian friends for continuing to challenge us. The next chapter should aim to give people more ulcer-free, hospital-free, activity-rich days, with the evidence to show how we got there.
Disclosure: I served as a co-principal investigator of LEGenD-1 and on its Scientific Advisory Board, receiving research funds for meeting attendance and travel expenses. The study was supported by AnGes USA Inc. Published disclosure.
#ActAgainstAmputation #LimbPreservation #CLTI #DiabeticFoot
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