Autologous bone marrow mesenchymal stromal cell therapy for “no-option” critical limb ischemia is limited by karyotype abnormalities

Sara Azhari Mohamed,Linda Howard,Veronica Mcinerney,Amjad Hayat,Janusz Krawczyk,Sean Naughton,Andrew Finnerty,Miriam Holohan,Aoife Duffy,Tony Moloney,Eamon Kavanagh,Paul Burke,Aaron Liew,Muhammad Tubassam,Stewart Redmond Walsh,Timothy O'Brien

doi:10.1016/j.jcyt.2020.02.007

Abstract

BackgroundCritical limb ischemia (CLI) is the most severe manifestation of peripheral vascular disease. Revascularization is the preferred therapy, but it is not achievable in 25%–40% of patients due to diffuse anatomic distribution of the disease or medical comorbidities. No-option CLI represents an unmet medical need. Mesenchymal stromal cells (MSCs) may provide salvage therapy through their angiogenic and tissue-trophic properties. This article reports a phase 1b clinical study examining the safety and feasibility of intramuscular transplantation of autologous bone-marrow MSCs for patients with no-option CLI. MethodsTwelve patients were enrolled in the clinical trial, and nine proceeded to bone marrow aspiration and culture expansion of MSCs. ResultsA high rate of karyotype abnormality (>30%) was detected in the produced cell batches, resulting in failure of release for clinical administration. Four patients were treated with the investigational medicinal product (IMP), three with a low dose of 20 × 106 MSCs and one with a mid-dose of 40 × 106 MSCs. There were no serious adverse events related to trial interventions, including bone marrow aspiration, IMP injection or therapy. ConclusionsThe results of this trial conclude that an autologous cell therapy approach with MSCs for critical limb ischemia is limited by the high rate of karyotype abnormalities.

Highlights

Peripheral vascular disease (PVD) is a growing health problem in Western societies, affecting up to 3%À10% of the population [1]
From March 2015 to January 2019, 263 Critical limb ischemia (CLI) patients were prescreened for suitability for inclusion in the study
Nine patients proceeded to bone marrow (BM) harvest after confirmation of eligibility, with one patient undergoing a second marrow aspiration due to the failed release of the first Mesenchymal stromal cells (MSCs) cell batch

Summary

Introduction

Peripheral vascular disease (PVD) is a growing health problem in Western societies, affecting up to 3%À10% of the population [1]. Surgical or endovascular revascularization is the preferred therapy; it is unachievable in 25%À40% of patients due to medical comorbidities or anatomically diffuse disease [2]. These “no-option” patients are at high risk for amputation and death, with a 40% risk of amputation [4] and 20% risk of mortality within 6 months [1]. Conclusions: The results of this trial conclude that an autologous cell therapy approach with MSCs for critical limb ischemia is limited by the high rate of karyotype abnormalities

Methods

Results

Discussion

Conclusion