Combined Intra-Arterial and Intra-Muscular Transfer of Wharton’s Jelly Mesenchymal Stem/stromal Cells in No-Option Critical Limb Ischemia – the CIRCULATE N-O CLI Pilot Study

Introduction: Despite progress in pharmacologic and revascularization therapies, no-option critical limb ischemia poses a major clinical and societal problem. Prior cell-based strategies involved mainly autologous (limited) cell sources.Aim: To evaluate the safety and feasibility of a novel ischemic tissue reparation/regeneration strategy using Wharton's jelly mesenchymal stem/stromal cells (WJMSCs) as an "unlimited" cell source in N-O CLI (first-in-man study, FIM).Material and methods: Enrollment criteria included Rutherford-4 to Rutherford-6 in absence of anatomic/technical feasibility for revascularization and adequate inflow via the common femoral artery with patency of at least one below-the-knee artery. 30 x 106 WJMSCs were administered intra-arterially and intra-muscularly (50%/50%) over 3-6-week intervals (3-6 administrations). Safety, feasibility and potential signals of efficacy were assessed at 12 and 48 months.Results: Five patients (age 61-71, 60% male, Rutherford-6 20%, Rutherford-5 60%, Rutherford-4 20%) were enrolled. WJMSCs were administered per protocol in absence of administration technique-related adverse events. Hyperemia, lasting 12-24 h, oc-curred in 4/5 subjects. Transient edema and pain (reactive to paracetamol) occurred in 3 (60%) patients. Amputation-free survival was 80% after 12 and 48 months. In those who avoided amputation, ischemic ulcerations healed and Rutherford stage improved. 4/5 patients were free of resting pain after 3-6 doses.Conclusions: This FIM study demonstrated the safety and feasibility of WJMSCs use in patients with N-O CLI and suggested treatment efficacy with >= 3 doses. Our findings provide a basis for a randomized, double-blind clinical trial to assess the efficacy of WJMSC-based therapeutic strategy in N-O CLI patients.