Abstract 23: Intracerebral Transplantation of Autologous Bone Marrow Stem Cell (BMSC) for Subacute Ischemic Stroke, Phase 1 Clinical Trial (RAINBOW Trial)

Background: Recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. We investigated the safety and feasibility of intracerebral transplantation of autologous BMSC in the subacute phase of stroke (RAINBOW trial). Several new aspects including cell labeling and tracking, socioecomonic analysis using QALY, and the use of human platelet lysate instead of fetal bovine serum were adopted. (UNIN ID: UMIN000026130) Methods/Design: This is a phase 1, open-label, uncontrolled, dose-response study enrolling adults with severe motor deficits (mRS>3) 14 days after stroke. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset, and BMSCs are cultured with allogeneic human platelet lysate (PL) and are labeled with superparamagnetic iron oxide for cell tracking using MRI. BMSCs are stereotactically administered around the area of infarction approximately 2 months from the ischemic stroke. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18 F-fuorodeoxyglucose positron emission tomography, and 123 I-Iomazenil single photon emission computed tomography will be performed throughout 1 year after the administration. Results: All 7 patients have been successfully finished transplantation, and there was no severe adverse event in any of the patient regarding the surgical procedure nor cell quality. Favorable motor recoveries (change in mRS > 1) are seen in 5 of 7 patients, and cell engraftment and migration to ischemic site was also observed. Discussion: This is a first-in-human trial to use labelled BMSC to the patients with subacute ischemic stroke. Intracerebral transplantation of autologous BMSC is safe and well tolerated. Cell migration to the ischemic boundary can clarify the therapeutic mechanisms.

Multimodal Therapeutic Effects of Neural Precursor Cells Derived from Human-Induced Pluripotent Stem Cells through Episomal Plasmid-Based Reprogramming in a Rodent Model of Ischemic Stroke

Stem cell therapy is a promising option for treating functional deficits in the stroke-damaged brain. Induced pluripotent stem cells (iPSCs) are attractive sources for cell therapy as they can be efficiently differentiated into neural lineages. Episomal plasmids (EPs) containing reprogramming factors can induce nonviral, integration-free iPSCs. Thus, iPSCs generated by an EP-based reprogramming technique (ep-iPSCs) have an advantage over gene-integrating iPSCs for clinical applications. However, there are few studies regarding the in vivo efficacy of ep-iPSCs. In this study, we investigated the therapeutic potential of intracerebral transplantation of neural precursor cells differentiated from ep-iPSCs (ep-iPSC-NPCs) in a rodent stroke model. The ep-iPSC-NPCs were transplanted intracerebrally in a peri-infarct area in a rodent stroke model. Rats transplanted with fibroblasts and vehicle were used as controls. The ep-iPSC-NPC-transplanted animals exhibited functional improvements in behavioral and electrophysiological tests. A small proportion of ep-iPSC-NPCs were detected up to 12 weeks after transplantation and were differentiated into both neuronal and glial lineages. In addition, transplanted cells promoted endogenous brain repair, presumably via increased subventricular zone neurogenesis, and reduced poststroke inflammation and glial scar formation. Taken together, these results strongly suggest that intracerebral transplantation of ep-iPSC-NPCs is a useful therapeutic option to treat clinical stroke through multimodal therapeutic mechanisms.

Abstract 45: Intracerebral Transplantation of Autologous Bone Marrow Stem Cell (BMSC) Against Acute Ischemic Stroke, Preliminary Data of Phase 1 Clinical Trial (RAINBOW Project)

Background: Recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Prior studies have demonstrated that bone marrow stromal cells (BMSC) have therapeutic potential against stroke. In this study, we investigated the use of autologous BMSC transplantation for acute ischemic stroke through direct transplantation route with several new aspects including cell labeling and tracking, socioecomonic analysis using QALY, and the use of human platelet lysate (PL) instead of fetal bovine serum. This study is called the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW, UNIN ID: UMIN000026130). Methods/Design: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC administered to the patients with acute ischemic stroke. Estimated enrollment is 7 patients suffering severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset, and BMSCs are cultured with allogeneic PL and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). BMSCs are stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18 F-fuorodeoxyglucose positron emission tomography, and 123 I-Iomazenil single photon emission computed tomography will be performed throughout 1 year after the administration. Results: 6 patients have successfully finished cell transplantation, and there was no severe adverse event in any of the patient during surgical and follow-up period. Favorable motor recoveries are seen in 5 of 6 patients, and cell engraftment and migration to ischemic site was also observed by magnetic resonance imaging. Discussion: This is a first-in-human trial to use labelled BMSC to the patients with acute ischemic stroke. Intracerebral transplantation of autologous BMSC is safe and well tolerated. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms.