A Retrospective Analysis of Safety and Efficacy of Wharton's Jelly Stem Cell Administration in Children With Spina Bifida

Major Points and Findings:

This is one of the few published studies of stem cell treatment given after birth to children with spina bifida, and with 28 patients it is the largest of them. Children and teenagers in Poland, aged 1 to 18 years, received intravenous infusions of donor mesenchymal stem cells grown from Wharton’s jelly, the soft tissue inside the umbilical cord. This is the same tissue source as the umbilical cord mesenchymal stem cells used at Beike, although the doses, routes and treatment plans differ.

The paper reports that 21 of the 26 children with follow-up data improved in some way, most often in bladder and bowel control and muscle strength, and that side effects were mild and passed on their own. However, it is a retrospective review of treatment given and paid for in routine practice, with no control group, and the outcomes were scored by one neurologist on a simple scale that recorded improvement only. The 5 children who did not improve had all stopped after a single infusion, which makes the link between dose and response hard to interpret. Both authors work for the company that produced the cells, and that company sponsored the study. The results are encouraging but cannot show that the cells caused the improvements.

Aim:

To describe the safety and outcomes of Wharton’s jelly mesenchymal stem cell (WJ-MSC) administration in children with spina bifida treated as a medical therapeutic experiment, and to look for factors that predict a response.

Methods:

A retrospective analysis of the medical records of 28 Polish patients aged 1 to 18 years (median age 4 years) treated between November 2014 and March 2018. The cells were given by a doctor as part of a commercial procedure in daily clinical practice, not in a planned trial, and there was no comparison group. The authors state that they had no influence on patient selection, dose, number of doses, route or the way outcomes were judged. Ethics approval came from the Medical University of Lublin and the Regional Chamber of Physicians and Dentists in Lublin, and parents gave written consent.

The cells were donor (allogeneic) mesenchymal stem cells from the Wharton’s jelly of umbilical cords of healthy Polish newborns, prepared and frozen under Good Manufacturing Practice in the laboratory of Polski Bank Komórek Macierzystych S.A. (PBKM, FamiCord Group). Viability after thawing was 91 to 100% (median 96%). Most cells were used at passage 4 or lower, and 7 batches after passage 5.

Each child received 1 to 5 intravenous injections in one course, about two months apart. Each injection held 10, 20, 30 or 40 million cells depending on body weight, aiming at roughly 1 million cells per kg. Over the course, the total was 0.9 to 5.0 million cells per kg (median 2.6 million per kg). One child with a very good response had a second course of 2 more injections 15 months later.

The same neurologist, who was the study investigator, examined every child on the day of each infusion. She rated quality of life and self-service (the ability to look after oneself in daily activities) on a six-point scale running from 0 (no improvement) to 5 (excellent improvement), each time compared with the previous visit. She also recorded improvement, worsening or no change in 17 areas of function. For 5 children, parents’ and therapists’ reports were collected by PBKM and compared with her ratings. Changes in the 17 areas were tested with a sign test, which the authors describe as low-powered, and possible predictors of response were tested with several correlation and chi-square tests.

Results:

Follow-up data were available for 26 of the 28 children (aged 1 to 15 years, median 4).

• Overall: 21 of 26 children (81%) showed some improvement in their health status.
• Quality of life: 21 children (81%) had a higher quality-of-life score, with a median gain of 2 points among them.
• Self-service: 10 children (38%) had a slight increase in self-service, with a median gain of 1 point. All 10 had received at least 3 infusions.
• Response groups: 10 children improved in both quality of life and self-service, 11 in quality of life only, and 5 in neither. All 5 non-responders had received only one infusion. Of the 8 children with no improvement after the first infusion, 5 did not continue treatment.
• Areas of function: Improvement was recorded in 12 of the 17 areas. Five reached significance on the sign test: control of urination and defecation (11 children, 42%), muscle strength (9, 35%), cognitive function (8, 31%), muscle tension (6, 23%) and gross motor development (6, 23%). Deep and superficial sensation improved in 4 children each and communication in 5, but these changes were not significant. No improvement was recorded in fine motor skills, the senses, circulation, emotions or engagement.
• Parents’ views: In the 5 children with parental reports, parents tended to see more improvement than the investigator.
• Predictors of response: Age, the size of a single dose and body weight were not linked to the average improvement in quality of life. The total number of cells per kg over the course was linked to it (correlation 0.54, p = 0.005, explaining about 23% of the variation). Children who received at least 2.6 million cells per kg had larger jumps in quality of life. Results on the first infusion were mixed: a good early response was linked to a better overall response, but once the first visit was left out, early non-responders did not do worse later.
• Safety: The investigator saw no reactions during or shortly after the infusions. Parents reported problems in the following days in 3 children: emotional sensitivity (3), raised temperature (2), and single reports of headache, nausea, vomiting, muscle pain, sleepiness, reduced appetite, low temperature, high blood pressure and infections. Their link to the cells was unclear. All were mild and temporary and passed without treatment, and they were not related to dose.

Conclusions:

In the abstract the authors state that WJ-MSC administration is safe and effective and improves motor function, bladder and bowel control, cognitive function and quality of life in children with spina bifida. The conclusions section is more careful, saying intravenous WJ-MSCs “seem” safe and effective “at least in some children”, that the response varies, and that large randomised trials with proper scales are needed. They suggest a minimum of 2.6 million cells per kg per course before judging the effect.

The authors list many limitations themselves: no control group, retrospective design, irregular visit schedules, other therapies given at the same time (physiotherapy, educational and animal therapies), no long-term follow-up, approximate doses and the use of a simple scale instead of standard tools such as GMFM or PedsQL. In addition, the rating scale could only record improvement, the single rater knew every child was being treated, and outside views were collected for only 5 children. The dose finding is hard to separate from the number of infusions, because each infusion added about 1 million cells per kg and families whose children did not improve early tended to stop. The authors themselves raise this as an alternative explanation. Side effects were recorded through parents for only a few children, so mild events in others may have been missed. Young children also improve with growth and ongoing care, so some change would be expected without any cell treatment.

Background Information:

The study was sponsored by Polski Bank Komórek Macierzystych S.A. (FamiCord Group), Warsaw, a private cord blood and tissue bank, and both authors are employees of its Medical Department. The cells were made in the company’s laboratory and the cord tissue was collected as part of its commercial services. The infusions were paid for by parents, a foundation or an association, and the cost rose with the dose. Patient selection, supervision during treatment and follow-up examinations were credited to a paediatric neurologist at the Medical University of Lublin.

The authors describe the treatment as a medical therapeutic experiment. Under Polish law this allows a doctor to use a new or partly tested treatment for an individual patient when standard methods have not worked well enough, outside a formal clinical trial.

A later trial from Vietnam (Nguyen and colleagues, 2023), in which 11 children received their own bone marrow mononuclear cells into the spinal fluid, cites this study as earlier evidence that cell therapy in spina bifida is safe and may help motor, bladder and bowel function. Neither study was controlled.