Infusion of high-dose umbilical cord blood cells normalized brain connectivity and improves motor function in children with cerebral palsy

Cerebral palsy is a congenital disorder that adversely affects movement, muscle tone and posture. Because those who suffer from congenital cerebral palsy are bone with it, there is often little that can be done to predict or prevent it. Cerebral palsy or CP is usually due to abnormal brain development prior to birth, but it can also result from in utero strokes, or oxygen deprivation during development or delivery. CP causes exaggerated reflexes, floppy or rigid limbs, and involuntary motions and there is a generalized weakness of skeletal muscles. CP affects 2-3 per 1,000 live births and the investment required by schools to accommodate CP children is substantial.  Furthermore, the personal investment of the heroic parents of CP children is substantial and, at times, exhausting.

Fortunately, animal models of CP have shown that the infusion of stem cells into the brains of young AP animals improves motor (movement-based) function.  In particular, human umbilical cord blood cells seem to facilitate repair of neural networks in the brain and improve movement. One study (Pediatric Research 2006; 59(2): 244-249) by Carola Meier and others from Ruhr-University in Bochum, Germany used an oxygen-deprivation model of CP in rats to show that treatment of these animals with human Umbilical Cord Blood Cells (hUBCs) substantially alleviated spastic paresis as assessed by walking track analysis. Also, examination of brain slices established that administered hUCBs incorporated themselves around the brain lesion (a phenomenon called “homing”) in large numbers. This study showed that the administration of hUCB stem cells after perinatal brain damage to could significantly reduce potential motor deficits.  A second paper (Developmental Neuroscience 2015;37(4-5):349-62) by Drobyshevsky and others from North Shore University Health System in Evanston, IL and collaborators from Duke University used a CP rabbit model to assess the efficacy of hUBCs to treat CP. In this experiment, Drobyshevsky and others induced oxygen deprivation when the rabbits were at 70% of their in utero lives. Then a group of the newborn rabbits were treated with hUCBs while others were not. The hUBC-treated animals showed significant improvements in posture, righting reflex, locomotion, tone, and dystonia (involuntary muscle contractions that cause repetitive or twisting movements). Unfortunately, the swimming test however showed that joint function was not restored by the hUBC treatment, but these other functions were. Tracking studies of the infused hUBC cells did not indicate that the cells penetrated into the brain with any efficiency, and Drobyshevsky and others suggested that the cells exerted their beneficial effects by means of “paracrine signaling,” which is to say that the cells secreted molecules that induced healing by activating native cells rather than differentiating into new neurons that created neural networks.

 

On the strength of these animal experiments, Jessica Sun from Duke University Medical Center and her colleagues and collaborators from multiple institutions extended these studies into human CP patients.  This, I’m sure, was a very dicey experiment to run because the subjects were children.  Getting approval for clinical experiments on children is very difficult and time-consuming.  Sun and her colleagues had shown that her hUBC infusion protocol was safe in a previous publication (Transfusion 2010; 50: 1980-1987) in which Sun and others reported treating 184 children with a single infusion of their own umbilical cord blood. The paper reported that the adverse effects of this treatment were rare and minimal. Because this was a Phase I study, it was only designed to assess the safety of the hUBC infusions and not their efficacy.

 

In a second publication, Sun and others have reported the results of their Phase II study in which they treated 63 CP children with various doses of hUBCs. This was a rigorous double-blind, placebo-controlled, crossover study in which Sun and her colleagues gave 10-50 million hUBCs per kilogram body weight to CP children between the ages 1 to 6 years.  These children received either their own umbilical cord blood or a placebo at the start of the experiment, followed by an alternate infusion 1 year later. After 1 year, those children who had received their own UBCs at the beginning of the trial, received the placebo, and those who had received the placebo at the start of the trial received their own UBCs. The children were assessed by means of specific motor function tests and their brains were imaged by means of magnetic resonance imaging brain connectivity studies. These assessments were done at the start of the trial, and then 1, and 2 years after the treatment.  To assess their motor skills, children were tested with a clinical tool called the Gross Motor Function Measure-66 tool.  This clinical tool evaluates changes in motor function in CP children.  Children are asked to perform a range of everyday activities from lying and rolling to walking, running, and jumping.  The children are given a composite score for all 66 tasks they are asked to do and this score reflects the depth of their motor skill. Changes in the Gross Motor Function Measure-66 (GMFM-66) indicates an improvement or decrease in motor function.  The primary endpoint was change in motor function 1 year after baseline infusion.

Two years after the initial treatments, the children were given further evaluations. Of the 63 CP children, 32 received their own umbilical cord blood and 31 received the placebo at the start of the experiments. One year after the trial began, Sun and her team detected no average change in GMFM-66) scores between the placebo and treated groups.  However, two years after the start of the trials, those CP children who had received higher doses of their own umbilical cord blood (20 million cells or more) showed significantly greater increases in their GMFM-66 scores.  In fact, their GMFM-66 scores were above what CP children at this specific age usually score. Another test that was administered was the Peabody Developmental Motor Scales test, which consists of six subtests that measure abilities in early motor development and assesses gross and fine motor skills in children from birth through five years of age. Gross Motor Quotient scores from the Peabody Developmental Motor Scales tests also revealed that children who had received the higher dose UBC treatments showed normalized scores, which indicates that the motor development of these children had become more normal rather than delayed.

Finally, the MRIs revealed normalized brain connectivity in the CP children who had received the higher doses of their own umbilical cord blood cells.

While this study is still preliminary, it suggests that appropriately doses of a child’s own umbilical cord blood stem cells improves brain connectivity and gross motor function in young children with CP.