Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke

Abstract

BackgroundStroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW).Methods/designRAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001–01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6–10 patients suffering from moderate to 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. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001–01 is 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, 18F–fuorodeoxyglucose positron emission tomography, and 123I–Iomazenil single­photon emission computed tomography will be performed for 1 year after the administration.DiscussionThis is a first-in-human trial for HUNS001–01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms.Trial registrationThe trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease

“…Pittsburgh cell implantation cannula and stylet (SB2023, Synergetics, O'Fallon, USA), Mizuho Biopsy/Injection needle (MES-CG07-200-01, Mizuho, Tokyo, Japan), and our newly designed cannula, MK01, were examined in this experiment. The Pittsburg and Mizuho cannulas have been used in clinical trials for injecting stem cells into the brain [6,10,13]. The basic parameters of the cannulas are listed in Table 1.…”

“…Cell Culture. Human bone marrow stem cell (BMSC) and platelet lysate (PL) were harvested from three healthy donors, as previously reported [10]. Briefly, bone marrow mononuclear cells were isolated via density-gradient centrifugation in Ficoll-Hypaque® (Pharmacia, Uppsala, Sweden), and cells were seeded in a 175 cm 2 uncoated flask (EasYFlask 159910; Nunc) at a density of approximately 20 × 10 5 cells/cm 2 in 25 mL α-minimum essential medium containing 10% PL derived from healthy volunteers and 40 μg/mL of gentamicin sulfate.…”

“…Although, an ideal transplantation route has not been determined yet, intraparenchymal transplantation remains an option for cell delivery, since it enables delivery of a sufficient amount of cells into the damaged brain compared to that achieved with intravascular transplantation [6,8,9]. To date, no cannula has been approved for cell transplantation by regulatory agencies, including the FDA, and different types of cannulas specially designed or adopted from other uses are being used for clinical trials [6,10]. How-ever, one main concern of direct transplantation is the potential risk of brain injury by the transplantation cannula.…”

Cell therapy for central nervous system disorders: Current obstacles to progress

“…In Japan, several clinical studies are ongoing. Shichinohe and teammates reported their protocol of intracerebral administration of autologous MSCs in the subacute phase of stroke . They proposed to use cells labeled with superparamagnetic iron oxide for cell tracking, which may reveal the distribution of the transplanted cells over time.…”

Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders

“…However, recent studies suggest that the main driving force behind the therapeutic efficacy of MSCs is the paracrine factors secreted by these cells and propose the administration of MSC-conditioned media for regenerative medicine applications [89]. In particular, MSCs have been demonstrated to provide beneficial effects in the treatment of neurological diseases, such as Parkinson [90], ischemic stroke [91], and multiple sclerosis [92]. Also, MSCs have been tested to promote-myocardium and liver regeneration.…”