Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24-72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33-1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481-1491.

Intravenous autologous bone marrow mononuclear cells for ischemic stroke.

OBJECTIVE: Cellular therapy is an investigational approach for stroke. Mononuclear cells (MNCs) from the bone marrow reduce neurological deficits in animal stroke models. We determined if autologous MNC infusion was feasible and safe in patients with ischemic stroke. METHODS: We conducted an open-label prospective study of a bone marrow harvest followed by readministration of autologous MNCs in 10 patients, 18 to 80 years old, with acute middle cerebral artery ischemic stroke. Bone marrow was aspirated from the iliac crest, and MNCs were separated at a Good Manufacturing Practices facility and administered intravenously up to a maximum of 10 million cells/kg. The harvest and infusion had to occur between 24 and 72 hours after stroke. Patients were monitored for 6 months. RESULTS: Bone marrow aspiration was successfully completed in all patients. Eight received 10 million cells/kg, and 2 received ≥7 million cells/kg. There were no significant adverse events related to harvest or infusion. Two patients had infarct expansion between enrollment and harvest and underwent hemicraniectomy after cell infusion. One patient died at 40 days due to a pulmonary embolism related to the stroke. There were no study-related severe adverse events. Median National Institutes of Health Stroke Scale score was 13 before harvest, 8 at 7 days, and 3 at 6 months. At 6 months, all surviving patients had shifted down by at least 1 point on the modified Rankin Scale compared to day 7. Seven of 10 patients achieved a Barthel Index ≥90. INTERPRETATION: This study suggests that a bone marrow harvest and reinfusion of autologous MNCs were safe and feasible in acute stroke patients.

Longitudinal neuroimaging evaluation of the corticospinal tract in patients with stroke treated with autologous bone marrow cells.

Bone marrow mononuclear cells (MNCs) attenuate secondary degeneration and enhance recovery in stroke animal models. In a nonrandomized clinical trial, we imaged 37 patients with stroke: 17 patients treated with MNCs (treated) and 20 patients who received standard of care (nontreated) at 1, 3, and 12 months onset of stroke on 3.0T MRI system. Three-dimensional anatomical and diffusion tensor images were obtained. The integrity of the corticospinal tract was assessed by measuring absolute and relative fractional anisotropy (FA) and mean diffusivity (MD) in the rostral pons (RP), posterior limb of the internal capsule, and corona radiata by drawing regions of interest. Infarct volume and stroke severity, which was assessed via the NIH Stroke Scale (NIHSS), were higher in the MNC group compared with the nontreated patients, which is a major limitation. Overall, the relative FA (rFA) of the nontreated patients exhibited continued reduction and an increase in relative MD (rMD) from 1 to 12 months, whereas despite larger infarcts and higher severity, treated patients displayed an increase in rFA from 3 to 12 months and no change in rMD. Contrary to the nontreated group, the treated patients' rFA was also significantly correlated (P < .05) with NIHSS score in the RP at all time points, whereas rMD at the last two.

Cognitive deficits in acute mild ischemic stroke and TIA and effects of rt-PA.

Introduction: It is unknown if treatment with rt-PA in mild acute ischemic stroke (MIS) is associated with improvement in long term cognition. Methods: Forty-five patients with suspected acute mild stroke or transient ischemic attacks with NIHSS ≤6 were enrolled in a prospective cohort. Cognitive testing was performed within 24 h of symptom onset. Follow-up assessment was performed at Day 90 on 25 patients. Prestroke baseline cognition was based on age, years of education (YrE), history of cognitive impairment, and the Fazekas score. Results: Eighty-five percent patients with suspected MIS or TIA showed cognitive abnormalities within 24 h of onset. There was no significant difference in age, sex, Fazekas score, or YrE between rt-PA versus No-rt-PA groups (N = 8 vs. 17).Two sample t-test for change in performance in the WMS-III sub-tests (follow-up - baseline) ± SD, indicated a difference between rt-PA 0.74 ± 0.77 and no-rt-PA groups -0.02 ± 0.83 (P = 0.044). Logistic regression for predicting normal status using the mental control subtest, at follow-up showed an OR 8.96, CI 0.98-82.12 (P = 0.05) favoring the rt-PA group. Improvement in Mental Control at 90 days occurred in patients with low white matter disease compared to high white matter disease, 0.60 ± 0.46 (P = 0.048). A statistical trend was observed and suggested an improvement on SDMT and Trail Making tests, 1.43 ± 0.8 (P = 0.077). Conclusion: Suspected MIS and TIA patients have cognitive impairment within 24 h of onset. rt-PA administration might be associated with improvement on some cognitive tests at 90 days.

Serial Cerebral Metabolic Changes in Patients With Ischemic Stroke Treated With Autologous Bone Marrow Derived Mononuclear Cells.

Purpose: Cell-based therapy offers new opportunities for the development of novel treatments to promote tissue repair, functional restoration, and cerebral metabolic balance. N-acetylasperate (NAA), Choline (Cho), and Creatine (Cr) are three major metabolites seen on proton magnetic resonance spectroscopy (MRS) that play a vital role in balancing the biochemical processes and are suggested as markers of recovery. In this preliminary study, we serially monitored changes in these metabolites in ischemic stroke patients who were treated with autologous bone marrow-derived mononuclear cells (MNCs) using non-invasive MRS. Materials and Methods: A sub-group of nine patients (3 male, 6 female) participated in a serial MRS study, as part of a clinical trial on autologous bone marrow cell therapy in acute ischemic stroke. Seven to ten million mononuclear cells were isolated from the patient's bone marrow and administered intravenously within 72 h of onset of injury. MRS data were obtained at 1, 3, and 6 months using a whole-body 3.0T MRI. Single voxel point-resolved spectroscopy (PRESS) was obtained within the lesion and contralesional gray matter. Spectral analysis was done using TARQUIN software and absolute concentration of NAA, Cho, and Cr was determined. National Institute of Health Stroke Scale (NIHSS) was serially recoreded. Two-way analysis of variance was performed and p < 0.05 considered statistically significant. Results: All metabolites showed statistically significant or clear trends toward lower ipsilesional concentrations compared to the contralesional side at all time points. Statistically significant reductions were found in ipsilesional NAA at 1M and 3M, Cho at 6M, and Cr at 1M and 6M (p < 0.03), compared to the contralesional side. Temporally, ipsilesional NAA increased between 3M and 6M (p < 0.01). On the other hand, ipsilesional Cho showed continued decline till 6M (p < 0.01). Ipsilesional Cr was stable over time. Contralesional metabolites were relatively stable over time, with only Cr showing a reduction 3M (p < 0.02). There was a significant (p < 0.03) correlation between ipsilesional NAA and NIHSS at 3M follow-up. Conclusion: Serial changes in metabolites suggest that MRS can be applied to monitor therapeutic changes. Post-treatment increasing trends of NAA concentration and significant correlation with NIHSS support a potential therapeutic effect.

Ongoing Secondary Degeneration of the Limbic System in Patients With Ischemic Stroke: A Longitudinal MRI Study.

Purpose: Ongoing post-stroke structural degeneration and neuronal loss preceding neuropsychological symptoms such as cognitive decline and depression are poorly understood. Various substructures of the limbic system have been linked to cognitive impairment. In this longitudinal study, we investigated the post-stroke macro- and micro-structural integrity of the limbic system using structural and diffusion tensor magnetic resonance imaging. Materials and Methods: Nineteen ischemic stroke patients (11 men, 8 women, average age 53.4 ± 12.3, range 18-75 years), with lesions remote from the limbic system, were serially imaged three times over 1 year. Structural and diffusion-tensor images (DTI) were obtained on a 3.0 T MRI system. The cortical thickness, subcortical volume, mean diffusivity (MD), and fractional anisotropy (FA) were measured in eight different regions of the limbic system. The National Institutes of Health Stroke Scale (NIHSS) was used for clinical assessment. A mixed model for multiple factors was used for statistical analysis, and p-values <0.05 was considered significant. Results: All patients demonstrated improved NIHSS values over time. The ipsilesional subcortical volumes of the thalamus, hippocampus, and amygdala significantly decreased (p < 0.05) and MD significantly increased (p < 0.05). The ipsilesional cortical thickness of the entorhinal and perirhinal cortices was significantly smaller than the contralesional hemisphere at 12 months (p < 0.05). The cortical thickness of the cingulate gyrus at 12 months was significantly decreased at the caudal and isthmus regions as compared to the 1 month assessment (p < 0.05). The cingulum fibers had elevated MD at the ipsilesional caudal-anterior and posterior regions compared to the corresponding contralesional regions. Conclusion: Despite the decreasing NIHSS scores, we found ongoing unilateral neuronal loss/secondary degeneration in the limbic system, irrespective of the lesion location. These results suggest a possible anatomical basis for post stroke psychiatric complications.

Recruiting Patients With Stroke Into Cell Therapy Trials: A Review.

IMPORTANCE: Clinical trials are under way to test the safety and efficacy of different types of cell therapies in patients with ischemic stroke. The informed consent process for recruitment of patients with stroke in cell therapy trials is complex and requires extensive discussions on multiple aspects. OBSERVATIONS: Various issues in approaching patients with stroke and their families and discussing participation in cell therapy studies are described, including participation in clinical trials, clarifying the perception of stem cell therapy and the risks of bone marrow harvest, and discussing risks vs benefits, cell-based therapies for chronic stroke, and consent for minority and immigrant populations. CONCLUSIONS AND RELEVANCE: Informed consent for cell therapy studies in patients with stroke requires lengthy discussions about several issues unique to clinical trials in stroke patients. Careful thought is needed to create an informative consent process.

Challenges enrolling patients with acute ischemic stroke into cell therapy trials.

Infusion of autologous bone marrow-derived mononuclear cells (MNCs) is a promising investigational therapeutic approach for patients with acute ischemic stroke. Preclinical models indicate that MNCs can reduce neurological deficits and enhance recovery. We recently concluded a phase I clinical trial to determine the safety and feasibility of these cells in patients with acute ischemic stroke. In this article, we discuss practical barriers and challenges encountered during the trial and provide lessons learned for the design and planning of future clinical trials testing novel cell therapies for acute ischemic stroke.