Yasuyuki Fujita

Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34 positive cells in patients with critical limb ischemia

BACKGROUND Our phase I/IIa clinical trial revealed that intramuscular transplantation of autologous, GCSF-mobilized CD34+ cells was safe, feasible and potentially effective at week 4 and 12 post cellular therapy in 17 patients with chronic critical limb ischemia (CLI) (5 patients with atherosclerotic peripheral arterial disease (PAD) and 12 with Buergers disease). However, long-term outcome of the cell therapy has yet to be reported. METHODS AND RESULTS Incidence of major clinical events and physiological parameters of limb ischemia were evaluated at week 52, 104, 156 and 208 post CD34+ cell therapy. No patients died by week 104, whereas 3 patients with PAD died by week 156 and 1 patient with Buergers disease died by week 208 due to cardiac complications. No patients underwent major amputation, whereas 1 patient with Buergers disease underwent unplanned minor amputation by week 104. CLI-free ratio was 88.2% at week 52 and 104, 92.3% at week 156 and 84.6% at week 208 in all patients. Significant improvement of toe brachial pressure index versus baseline was sustained up to week 208 and that of transcutaneous partial oxygen pressure was kept up to week 156. The Wong-Baker FACES pain rating scale, ulcer size and exercise tolerance significantly improved at week 52, the final evaluation time point, compared with baseline. Subgroup analysis revealed the similar outcome in patients with Buergers disease. CONCLUSIONS Favorable clinical outcomes as well as physiological evidences strongly indicate the long-term benefit of GCSF-mobilized CD34+ cell transplantation for retrieval from CLI, especially in patients with Buergers disease.

Regenerative medicine legislation in Japan for fast provision of cell therapy products

A new legal framework consisting of three laws for cell‐based and tissue‐based therapies went into effect in November 2014 in Japan. Among the provisions of the laws, the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act) allows conditional and time‐limited approval for regenerative medical products based on the ensured safety and estimated efficacy in small‐scale clinical trials. The new legislation is expected to accelerate safe and fast provision of the innovative products to patients with intractable diseases.

Cell-Based Therapies for Peripheral Arterial Disease

Chronic critical limb ischemia (CLI) is defined as the end-stage of lower limb ischemia due to atherosclerotic peripheral arterial disease (PAD) or vasculitis including thromboangitis obliterance (Buerger’s disease). CLI patients are at very high risk of amputation and experience poor physical function, leading to severe morbidity and mortality despite the development of surgical bypass technique or endovascular approach. Therefore, exploring novel strategies for blood flow recovery of ischemic limbs is urgently needed for patients with CLI. Although researchers initially focused on gene therapy using proangiogenic growth factors, recent discovery of somatic stem/progenitor cells including bone marrow (BM)-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) has drastically developed the field of therapeutic angiogenesis for CLI. In 2002, the first clinical trial of intramuscular injection of BM-derived mononuclear cells (BM-MNCs) demonstrated safety, feasibility and efficacy for CLI patients. Since then, at least 50 clinical trials of BM- and peripheral blood (PB)-derived MNC therapy, 4 trials of CD34+ cell (an EPC-enriched fraction) therapy and 8 trials of MSC therapy have been performed for CLI. Overall, the results of these early phase clinical trials regarding stem/progenitor cell therapies may be safe, feasible and effective. However, only few late-phase clinical trials have been conducted. Currently, at least 3 phase III trials including 2 trials using BMMNCs and 1 trial using granulocyte-colony stimulating factor (G-CSF)-mobilized PB-MNCs are ongoing. This review provides an overview of the preclinical and clinical reports to demonstrate the usefulness and the current limitations of the cell-based therapies.

Angiogenesis in Myocardial Ischemia

Progress in cardiovascular biology including the identification of various angiogenic growth factors and the discovery of somatic stem/progenitor cells including bone marrow-derived endothelial progenitor cells, mesenchymal stem cells, skeletal myoblasts, adipose tissue-derived regenerative cells, and resident cardiac stem/progenitor cells has drastically developed the field of therapeutic angiogenesis for refractory ischemic heart disease. Accumulating evidences in both animal studies and human clinical trials support the notion that protein or gene therapy of various angiogenic growth factors and transplantation of the somatic stem/progenitor cells may have significant potency of enhancing new blood vessel formation in ischemic myocardium. This chapter provides an overview of the preclinical and clinical reports to demonstrate the usefulness and the current limitations of the therapeutic strategy.

Ninjurin1 – A Novel Regulator of Angiogenesis Mediated by Pericytes –

which encodes a predicted 16-kDa polypeptide. Ninj1 has 2 hydrophobic transmembrane domains (72–100 aa, and 118– 139 aa) and a putative N-glycosylation site.7 In addition, the 12-residues on the N-terminal ectodomain of Ninj1 are crucial for its hemophilic binding activity (Figure).8 In mammals, there are 2 types of Ninjurin, Ninj1 and Ninj2, which share conserved hydrophobic regions for their transmembrane domains but differ in adhesion motifs and they do not interact with each other.8 Furthermore, the tissue distribution of Ninjurins ngiogenesis, the growth of new capillary from existing blood vessels, is an important natural process that is central to various pathophysiological processes in the body, not only during fetal development but also in postnatal tissue repair and disease development. Angiogenesis is a hallmark of wound healing, cancer development, ischemic and inflammatory diseases.1,2