Background: Cerebral palsy (CP) results from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult, or hemorrhage. Current treatments are supportive, focusing on managing sequelae with physical therapies, medications, and surgery. However, there are no therapies to address the underlying brain injury. Umbilical cord blood (CB) has been shown to prevent neurologic damage in children with leukodystrophiesand to improve motor function in animal models of brain injury and CP. Previously, we demonstrated safety of intravenous autologous CB infusion in young children with brain injuries. The Cerebral Palsy-Autologous Cord Blood (CP-AC) study was designed to assess the efficacy of a single intravenous infusion of autologous CB in young children with spastic CP.
Methods: The CP-AC study is a prospective, randomized, double blind, placebo controlled crossover study of a single intravenous infusion of autologous CB in children ages 1-6 years with spastic CP. The Gross Motor Classification System (GMFCS) was utilized to classify the level of motor function at study entry and follow-up. Children were eligible if they were (1) GMFCS level 2-4 or (2) GMFCS level 1 with hemiplegia if they used their affected hand as an assist only. Children with known genetic conditions, intractable seizures, or severe microcephaly were ineligible. Autologous CB units had to have a documented pre-cyropreservation total cell dose of ≥1x107/kg, negative sterility culture, negative maternal infectious disease screening, and confirmed identity through HLA typing of the subject and a segment attached to the CB unit. Subjects were evaluated at baseline, one year, and two years with functional evaluations (Gross Motor Function Measure-66 (GMGM-66), Peabody Developmental Motor Scales-2, Assisting Hand Assessment, Bayley Scales of Infant Development) and brain MRI. They were randomized to the order in which they received CB and placebo infusions (given one year apart). The primary endpoint was change in GMFM-66 score at one year after the initial infusion (CB or placebo). Cryopreserved CB units were shipped to and stored at Duke until the day of treatment when they were thawed and washed in dextran 40 +5% human serum albumin (DA). Infusions, dosed at 1-5x107/kg based on the pre-cryopreservation total nucleated cell count (TNCC) and diluted in 1.25mL/kg of DA, were administered intravenously over 5-10 minutes in the outpatient setting after premedication with oral acetaminophen, IV Benadryl, and IV Solumedrol. Subjects received IV fluids and were monitored for 2-4 hours post-infusion.
Results: Sixty-three children were enrolled with a median age of 2 years (range 1- 6) at baseline. Median TNCC of CB infusion was 2x107/kg (range 0.4-5) with a median CD34 dose of 0.5x105/kg (range 0.05-4). Despite negative pre-cryopreservation cultures, one CB unit grew β-hemolytic strepfrom a sample of the thawed CB unit. There were no clinical infections in this or any other study patient. One subject had transient infusion reactions consisting of hives +/- low-grade fever after each infusion; an additional dose of Benadryl was administered after the first reaction. Preliminary analysis of the 63 patients at one year showed no statistically significant overall difference in GMFM-66 change scores between placebo and treated groups (6.9 vs. 7.5, p =0.72). However, treated subjects who received pre-cryopreservation cell doses of >2.5x107/kg demonstrated statistically significant improvement in GMFM-66 change scores compared to subjects who received lower cell doses (p <0.01). A similar result was observed comparing subjects who received above (or below) the median infused cell dose of 1.98x107/kg (p =0.05) (Figure 1). The infused cell dose was not related to type of CP (p =0.32) or severity (p=0.46).
Conclusions: When adequately dosed, cord blood may improve motor function in young children with spastic CP. We observed improvement at pre-cryopreservation cell doses (>2.5x107/kg) that correspond with the minimum cell dose used for hematopoietic reconstitution in patients undergoing allogeneic CB transplantation. In order to extend this therapy to children who do not have adequate autologous CB units available, safety and efficacy of allogeneic CB products should be investigated.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.