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 × 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, occurred 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.