Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial

Abstract

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 10⁷ total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 10⁷ /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071-2078.

Keywords: Autologous stem cell transplantation; Cellular therapy; Clinical Trials; Cord blood; Human cord blood; Nervous system; Umbilical cord blood.

Figure 1

Study schema and distribution of subjects in analysis cohorts. (A): Gross motor evaluations (GMFM‐66, Peabody Developmental Motor Scales‐2 [PDMS‐2]) and brain MRI were performed at each visit. (B): Diagram of subjects evaluable via change in observed‐expected GMFM‐66 score (pink), PDMS‐2 score (green), and MRI (yellow) from baseline to 1 year. (C): Diagram of subjects evaluable via change in observed‐expected GMFM‐66 score, PDMS‐2 gross motor quotient score, and MRI 1 year after cord blood treatment (given at either baseline or 1 year). Abbreviations: GMFM‐66, Gross Motor Function Measure‐66; MRI, magnetic resonance imaging.

Figure 2

GMFM‐66 scores from baseline to year 1 by randomized treatment assignment and cell dose. (A): Distribution of GMFM‐66 score at baseline and 1 year in patients randomized to placebo and autologous cord blood. Lines connect the group means (circles) over time. (B): GMFM‐66 change scores based on median cell doses (Precryopreservation doses: Low, <3 × 10⁷/kg, N = 16 vs. High, ≥3 × 10⁷/kg, N = 16; Infused doses: Low, <1.98 × 10⁷/kg, N = 16 vs. High: ≥1.98 × 10⁷/kg, N = 16). (C): One year Observed‐Expected GMFM‐66 scores in patients ≥2 years of age at baseline based on infused cell dose (Low, N = 10; High, N = 9; Placebo, N = 19). (D): PDMS‐2 gross motor quotient change scores based on infused cell dose (Low, N = 13; High, N = 11; Placebo, N = 25). Abbreviation: GMFM‐66, Gross Motor Function Measure‐66.

Figure 3

Gross motor function and brain connectivity 1 year after autologous cord blood treatment by cell dose. High dose ≥2 × 10⁷/kg, low dose <2 × 10⁷/kg. (A): Observed‐Expected GMFM‐66 scores 1 year after treatment in patients ≥2 years of age at the time of ACB infusion. (B): Peabody Developmental Motor Scales‐2 gross motor change scores 1 year after treatment. (C): Change in normalized whole brain connectivity 1 year after treatment. (D): Connectome representation. The nodes and edges included are those that demonstrated significantly increased improvement in children receiving high doses compared with those receiving low doses, as indicated by the color chart, with insignificant nodes shown in gray. Representative nodes in the sensorimotor network with significant changes correlated with improvement in GMFM‐66 scores include the pre‐ and post‐central gyri, basal ganglia, and brain stem. Abbreviation: GMFM‐66, Gross Motor Function Measure‐66.