Translational potential of bone marrow mononuclear cells for treatment of ischemic stroke
Abstract
Ischemic stroke imposes tremendous public health burden in terms of morbidity and mortality. With limited treatment options, cellular therapy offers hope and promise for enhancing post stroke recovery. However, a careful evaluation of safety and efficacy of various cell types is necessary. This project undertook evaluation of the potential of bone marrow derived mononuclear cells (BM MNCs) for clinical application in ischemic stroke patients. A systematic review of pre-clinical literature was carried out followed by meta-analyses of histological and behavioral outcomes in rodents. The evidence suggests beneficial effects of BM MNCs for reduction in stroke lesion volume. Standardized mean difference (SMD), 95% confidence interval (CI) for absolute reduction was (-3.3, -4.33, -2.27) and for relative reduction was (-1.6, -2.47, -0.73). Animals treated with BM MNCs were also found to have favorable behavioral outcomes, SMD and 95% CI estimated by random effects analyses for cylinder test (-2.42, -3.17, -1.66), for adhesive removal test (1.18, 0.51, 1.84), and for neurological deficit score (-1.04, -1.8, -0.28) were all statistically significant. We further analyzed data from a phase I clinical trial whereby 25 ischemic stroke patients underwent bone marrow aspiration and intravenous re-infusion of autologous BM MNCs within 24 - 72 hours after stroke. These patients were monitored closely during hospitalization and were later followed up. All study procedures were completed under protocol stipulated timelines, mean (SD) time to cell infusion from symptom onset was 54.5 (13.0) hours. Maximal targeted dose of 10 million cells / kg was administered to most patients, mean (SD) dose infused was 9.1 (1.6) million cells / kg. Cytological analysis of infused cells demonstrated > 96% cell viability. During 1 year follow up, 10.6% of all reported adverse events were classified as serious adverse events. None of these were adjudicated to be study related by an independent data safety monitoring board. With a view to provide an estimate of a possible treatment effect of BM MNC therapy we compared 90 day functional outcomes of BM MNC treated patients with a historical cohort identified from University of Texas Houston Stroke Registry. We use propensity score (PS) based control and matching to provide these estimates. A proportional odds model with control for PS showed that BM MNC treated patients were more likely to have lower modified rankin scores (mRS) at day 90 as compared to historical controls (OR: 2.4, 95% CI: 1.07, 5.4). Matching on PS resulted in 86.6% bias reduction and showed that BM MNC treated patients had 1 point lower median mRS at day 90 as compared to controls. This project uses a systematic approach for evaluation of scientific evidence as development of new therapy gets translated from bench to the bed side. With initial evidence of safety and some signal of treatment effect, further clinical trials in the filed may be conducted for continued evaluation of safety and determining efficacy.
Subject Area
Medicine|Epidemiology
Recommended Citation
Vahidy, Farhaan, "Translational potential of bone marrow mononuclear cells for treatment of ischemic stroke" (2014). Texas Medical Center Dissertations (via ProQuest). AAI3689793.
https://digitalcommons.library.tmc.edu/dissertations/AAI3689793