Efficacy of Phase 1 Clinical trial of Autologous Quality and Quantity Cultured vascular and tissue regenerative cell therapy for Diabetic Patients with Chronic Non Healing Ulcer
Rica Tanaka, MD PhD, Makiko Kado, MD, Satoshi Fujimura, PhD, Kayo Arita, PhD, Rie Hirano, BS, Hiroshi Mizuno, MD PhD.
Juntendo University School of Medicine, Tokyo, Japan.
Background and Objective: Non-healing wounds are a major cause of morbidity and mortality in diabetic patients. Recently, we have reported the novelty of endothelial progenitor cell (EPC) therapy with serum free ex vivo expansion system called Quantity and Quality Culture System (QQc) using peripheral blood mononuclear cells (PbMNC) as non-invasive and effective new generation cell therapy. After demonstrating high vasculogenic and wound healing potential of this technology with murine and porcine animals, thus obtaining permission under the law of regenerative therapy in Japan, we have begun enrolling diabetic patients with chronic wounds in a prospective phase I/II clinical trial. The objective of this study is to investigate the safety and efficacy of QQ cultured PbMNC on diabetic non-healing wounds.
Material and Methods: 200ml of peripheral blood was drawn from Type 2 diabetic patients with chronic (>3 months) ischemic foot ulcers in an outpatient basis. Mononuclear cells were isolated and cultured in QQc for one week without passaging or media changes. Under local anesthesia, 2x107 cells were injected within 20 cm2 of the chronic wound and wound healing was monitored by photometrically. The adverse effects were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Wound closure, VAS scale, skin perfusion pressure (SPP), TcPo2, laser doppler, thermography and angiography were performed to evaluate efficacy post 2,4,8 and 12 weeks therapy.
Results: A total of seven patients, eight limbs were enrolled. The age ranged from 64 to 74 years old. Six males and one female. Six patients had diabetes with renal failure and one with collagen disease as past medical history. Blood sugar levels were controlled for all patients, and hbA1C was below 8.0%. All of the wounds extended into bone or tendon and were located in the digits of the foot. Case one with adverse effect underwent infection from injection site with alternative ulcer which had later healed. All patients were ambulant but wounds of two patients, three limbs did not heal. There was no death, other serious adverse events, or major amputation seen 12 weeks following transplantation. Increased vascular perfusion with decrease in VAS scale were seen in all patients. Interestingly, SPP significantly increase post therapy. (27.1±11.7mmHg pre-therapy vs 55.5±9.5 at 2 weeks, 54.3±12.1 mmHg at 4 weeks, 65.4±20.8mmHg at 12 weeks)
Conclusion: The outcomes of this prospective clinical study indicate the safety and feasibility of MNC-QQc cell therapy in patients with diabetic ischemic nonhealing wounds. This methodology will allow us to transplant highly vasculogenic EPCs from small amount of blood draw. This will be the world`s first non-invasive and effective peripheral blood vascular stem cell therapy for diabetic limb salvage.
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